CN101420923A - Intravascular devices and fibrosis-inducing agents - Google Patents

Abstract

Implant and fibrosis-inducing agent are combined to induce the fibrosis which can not occur in the opposite condition while the implant is placed in an animal body or can increase the fibrosis between the implant and the host.

Description

Medical implant and induce fibrotic reagent

Background of invention

Invention field

The present invention relates generally to pharmaceutical composition, method and apparatus, and more specifically, relate to compositions and the method for preparing medical implant, so that they adhere to more or more easily are combined in the living tissue.Described medicament and compositions are used for being created in implant and the medical apparatus that surrounding tissue is induced the new pharmaceutical pack quilt of fibre modification reaction, thereby make the original position grappling and improve its performance effectively of described device.

Association area is described

Thereby the clinical performance of many medical apparatus depends on the device that effectively is anchored to surrounding tissue structural support is provided or promotes cicatrization and healing.But it is not successful easily that described device effectively is attached to surrounding tissue always.Adhering to an invalid reason is that implantable medical apparatus is made up of such material usually, thereby described material is high degree of biocompatibility and is designed to reduce host tissue and replys.These materials (rustless steel for example, based on the alloy of titanium, fluoropolymer and pottery) typically do not provide good substrates and the ingrowth that adheres at host tissue in the cicatrization process.As the relatively poor internuncial result between described device and host tissue, device can have the tendency of migration in conduit of being implanted by them or tissue.The degree that the medical apparatus of particular type can move or move after implantation depends on many factors, comprise the type and the design of described device, form the material of described device, engineering properties (for example ability of elasticity and the geometry around implantation site adapts to), the porosity of surface nature and described device or apparatus surface.The tendency that device unclamps after implantation also depends on the type of tissue and at the geometry for the treatment of the site, the ability around the described device of wherein said pseudometaplasia can help to protect described device at implantation site usually.Device migration can cause plant failure, and depends on the type of described device and the location of described device, can cause seepage, angiemphraxis and/or to the damage of surrounding tissue.

Having proposed many method and apparatus improves with protection in vivo at the implantable medical apparatus of settling the site.In a method, described medical apparatus mechanically is anchored to biological tissue.For example, can artificial implantation be anchored to surrounding tissue by physics and mechanical system (for example, screw, cement (cement) and porosity surface) or by friction.For example, by using fastener, device for mechanical can be connected in described site such as suture or nail.In another method, in its design, described device comprises the mechanical system that is fixed in surrounding tissue.For example, described device can comprise that metal furcella, anchor, hook, agnail, pin, clip or flange or lip (see that for example U.S. Patent number 4,523,592 described device is invested suitable position; 6,309,416; 6,302,905; With 6,152,937).Yet when using institute's device, the unfavorable of metal fastener is that they can damaged tissue or blood vessel wall.

Other method of holdout device migration has concentrated on the surface nature that mechanicalness changes described device.Such method comprises scratch or the surface of the described implant of wearing and tearing.Coarse surface promotes cell, thereby bone or tissue adhesion make described implant adhere in the body (seeing, for example WO96/29030A1) better.Can be with binding agent, the bone cement that makes such as polymethyl methacrylate (PMMA) bone cement or by calcium phosphate and calcium aluminate (for example is fixed in host tissue with medical apparatus such as transplantable orthopedic device, bone) (sees, for example U.S. Patent number 6,723, and 334).Yet the defective of bone cement is to pass in time, can be degenerated by the bone of cementation-prosthese interface, and/or cement meeting weakening itself and inefficacy, cause unclamping of implant.

Chemistry or biological improvement the with described apparatus surface is used to increase transplantable medical apparatus and the adhesion between the host tissue on every side.For example, thus gone apparatus for coating to improve cure method and/or increased adhesion between described device and the host tissue with material.In a method, developed transplantable medical apparatus, it is allowed by the desirable histiocytic infiltration of specificity.The infiltration of one type tissue comprises and is called " internalization " process, and promptly endotheliocyte moves on on the described apparatus surface or the described apparatus surface from contiguous tissue.Promote the method for internalization to comprise porous coatings applications in described device, it allows that tissue growth (sees, for example WO96/37165A1) in the space of implant surface.Charging in improving the tissue contacting surface that other trial that adheres between the ingrown ability of host tissue and implant and the host tissue is included in described device or ionic species (for example, fluoropolymer) (see, for example WO95/19796A1; J.E.Davies, in SurfaceCharacterization of Biomaterials, B.D.Ratner, ed., pp.219-234 (1988); With U.S. Patent number 5,876,743), promote osteogenetic biocompatibility organic polymer (for example, using carbon, the polymer that sulfur or phosphorous hydroxy acid group replace) (see, for example, U.S. Patent number 4,795,475) at host-implant interface; With the coating (for example, U.S. Patent number 5,002,583) that increases tissue repairing, growth and adaptation in implant-organizational interface by biomaterial (for example collagen protein) making.

Yet said method all can not provide gratifying long-term solution for the device migration problem.Therefore, still exist for transplantable medical apparatus is anchored in the biological tissue or in the biological tissue effectively, the needs of long-lasting and biocompatibility method.

The invention summary

In brief, the invention provides by medical implant or transplantable medical apparatus and send selected treatment combination of agents thing, and the method for preparing and use these implants and device.In one aspect of the invention, the implant and the medical apparatus of pharmaceutical pack quilt or medicine infiltration is provided, it induces adhesion or fibre modification in organizing around, or promotes the original position " grappling " of described device/implant therefore to have increased effectiveness.In various embodiments, part by the specificity medicament or whole body discharge induces fibre modification, and described medicament is positioned contiguous tissue.

After mechanicalness or surgical operation interference, the repairing of tissue comprises two independently processes: (damaged cells is replaced and (2) fibre modification (damaged cells is replaced by connective tissue) by the cell of same type in (1) regeneration.There are four general ingredients for the process of fibre modification (or cicatrization), comprise: form neovascularity (blood vessel generations), fibroblasts proliferation and migration, the deposition of extracellular matrix (ECM) and reinvent (the ripe and formation of fibrous tissue).In the time of as used herein, should be appreciated that " inducing (promotion) fibre modification " refers to reagent or compositions, the formation of its increase or accelerating fibers sex organization is (that is, by inducing or promoting that blood vessel takes place, fibroblast moves or propagation, ECM produces, and/or remodeling process is one or more).In addition, many treatment reagent of the present invention's description can have the other benefit that also promotes tissue regeneration.

In one embodiment of the invention, implant or device are adapted to comprise or release reagent, and described reagent is induced fibre modification or regeneration by one or more above-mentioned mechanism.Therefore, the invention provides device, it comprises that medical apparatus and at least a following substances (i) fibre modification derivant (ii) comprise the compositions of fibre modification derivant.When implant is put into animal, induce under reverse situation the fibrotic formation that (may otherwise not occur) do not take place thereby described reagent presents, or increase fibre modification in significant mode on the statistics.In yet another aspect, the present invention relates to method, wherein the compositions that implant and at least a following substances (i) fibre modification derivant is (ii) comprised the fibre modification derivant is put into animal, and described reagent causes the fibrotic formation that do not take place under reverse situation, or increases fibre modification in significant mode on the statistics.Summarized below in these and other aspect of the present invention.

Therefore, each independently aspect, the invention provides as follows: a kind of device, the compositions that it comprises rectificating surgery implant and fibre modification derivant or comprises the fibre modification derivant, wherein said reagent is induced fibre modification; A kind of device, the compositions that it comprises sterile implant of sex and fibre modification derivant or comprises the fibre modification derivant, wherein said reagent is induced fibre modification; A kind of device, the compositions that it comprises the implant and the fibre modification derivant of treatment or prevention urinary incontinence device or comprises the fibre modification derivant, wherein said reagent is induced fibre modification; A kind of device, comprise treatment or prevention stomach esophagus adverse current disease (gastroesophageal reflux disease) (GERD) implant and fibre modification derivant or comprise the compositions of fibre modification derivant, wherein said reagent is induced fibre modification; A kind of device, the compositions that it comprises the implant and the fibre modification derivant of treatment or prevent obesity or comprises the fibre modification derivant, wherein said reagent is induced fibre modification; A kind of device, the compositions that it comprises the implant and the fibre modification derivant of treatment or prevention feces incontinence device or comprises the fibre modification derivant, wherein said reagent is induced fibre modification; A kind of device, the compositions that it comprises thromboembolism implant and fibre modification derivant or comprises the fibre modification derivant, wherein said reagent is induced fibre modification; A kind of device, the compositions that it comprises soft palate implant and fibre modification derivant or comprises the fibre modification derivant, wherein said reagent is induced fibre modification; A kind of device, it comprises the compositions that hernia is repaired mesh implant and fibre modification derivant or comprised the fibre modification derivant, wherein said reagent is induced fibre modification; With a kind of device, the compositions that it comprises stent (stent) graft and fibre modification derivant or comprises the fibre modification derivant, wherein said reagent is induced fibre modification.These and other device is described in detail at this paper.

In each aforementioned means, aspect independent, the invention provides described reagent and be: ductus arteriosus wall stimulant (irritan); Be selected from by Pulvis Talci, metallic beryllium and oxide thereof, copper, silk, Silicon stone, crystalline silicate, Talcum is in the group that quartz dust and ethanol are formed; Be selected from fibronectin, collagen protein, fibrin, or the component of the extracellular matrix of factor I; Be selected from by polylysine poly-(ethylene-common vinyl acetate), chitosan, the proteinic polymer of N-carboxybutyl chitosan and RGD; Vinyl chloride or vinyl chloride-base polymer; Be selected from by the binding agent in cyanoacrylate and the crosslinked poly-group that (ethylene glycol)-methylated collagenic protein is formed; Inflammatory cytokine (for example TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone); Connective Tissue Growth Factor (CTGF); Bone morphogenetic protein (BMP) (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7); Leptin and bleomycin or its analog or derivant.Randomly, described device can comprise the multiplication agent that stimulates cellular proliferation in addition.The example of multiplication agent comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA), and analog and derivant.

Aspect other, for each each aforementioned means in conjunction with aforementioned agents, for each combination, disclosing described reagent independently can appear in the compositions with polymer.In an embodiment aspect this, described polymer is biodegradable.In other embodiment aspect this, described polymer is not biodegradable.Other characteristics and the feature of described polymer that can describe each combination of device of the present invention and described reagent is described in more detail at this paper.

In yet another aspect, the invention provides compositions, it comprises fibre modification derivant and filler, and wherein said fibre modification derivant is induced fibre modification.In yet another aspect, the invention provides compositions, it comprises fibre modification derivant and sealant, and wherein said reagent is induced fibre modification.Exemplary fibers degeneration derivant includes, but are not limited to: be selected from by Pulvis Talci metallic beryllium and oxide thereof, copper, silk, Silicon stone, crystalline silicate, Pulvis Talci, the ductus arteriosus wall stimulant (irritan) in the group that quartz dust and ethanol are formed; Be selected from fibronectin, collagen protein, fibrin, or the component of the extracellular matrix of factor I; Be selected from by polylysine poly-(ethylene-common vinyl acetate), chitosan, the proteinic polymer of N-carboxybutyl chitosan and RGD; Vinyl chloride or vinyl chloride-base polymer; Be selected from by the binding agent in cyanoacrylate and the crosslinked poly-group that (ethylene glycol)-methylated collagenic protein is formed; Inflammatory cytokine (for example TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-8, IL-6, and growth hormone); CTGF; BMP (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7); With bleomycin or its analog or derivant.Randomly, described device can comprise the medicament that stimulates cellular proliferation in addition.The example of multiplication agent comprises: dexamethasone, and isotretinoin, 17-, estradiol, diethylstibesterol, Ciclosporin A, complete-trans retinoic acid (ATRA), and analog and derivant.Filler and sealant are described at this paper.

Outside the removal apparatus, the present invention also provides method.For example, of the present invention other aspect, for each aforementioned means, with each aforementioned combination for device and fibrotic derivant, the method that the invention provides will specifically be installed thus and be implanted in the animal, and the concrete reagent related with described device is induced in the fibre modification that does not take place under the reverse situation or on statistics significantly mode increase fibre modification.Each device that this paper identifies can be " a concrete device ", and each fibre modification derivant of this paper can be " fibre modification derivant ", in embodiment independently, the invention provides each possible combination of described device and described reagent.

Before described device was placed in the animal, described reagent can be connected with described device.For example, described reagent (or comprising described combination of agents thing) can be coated on the implant, and the device that then will obtain places animal.In addition, perhaps alternatively, described reagent can be placed animal independently, its position described device will or be placed in site in the animal near.For example, described reagent can be sprayed or be placed in addition described tissue, described tissue can contact described medical implant or can be experienced cicatrization in addition.For this purpose, aspect independently, the invention provides: treatment or prevention Aranea vein (spider veins) or cirsoid method, it comprises injects the compositions that comprises the fibre modification derivant in vein; Make the method for female patient sterillization, it comprises injects the compositions that comprises the fibre modification derivant in fallopian tube; The method of treatment or prevention urinary incontinence, it comprises injects the compositions that comprises the fibre modification derivant in urethra; The method of treatment or prevention GERD, it comprises the compositions that comprises the fibre modification derivant to the lower esophageal sphincter injection; The method of treatment or prevention fecal incontinence, it comprises the compositions that comprises the fibre modification derivant to the anal sphincter injection; The method of treatment or prevention snoring or sleep apnea, it comprises the compositions that comprises the fibre modification derivant to soft palate injectable; The method of sealing tremulous pulse, it comprises the compositions that comprises the fibre modification derivant to intra-arterial injection; The method of air leaks comprises the compositions that comprises the fibre modification derivant is sprayed on the surface of lung in the sealing lung; The method of treatment or prevention diverticulosis, it comprises to diverticulum sends the compositions that comprises the fibre modification derivant; The treatment or prevent arthritic method, it comprises the compositions that comprises the fibre modification derivant to impaired joint injection; Repair the method for impaired shoulder tunicle (capsule), it comprises and will comprise the composition spray of fibre modification derivant in the tunicle of front; Repair the impaired tendon or the method for ligament, it comprises and will comprise the composition spray of fibre modification derivant on tendon or ligament; Treat the method for impaired spinal disc (spinal disc), it comprises the compositions that comprises the fibre modification derivant to the intervertebral disc space injection.

Aspect other, for each each preceding method that is used in combination of aforementioned agents, for every kind of combination, disclosing described reagent independently can exist with compositions.In an embodiment aspect this, described polymer is biodegradable.In another embodiment aspect this, described polymer is not biodegradable.Other characteristics and the feature of described polymer that can describe each combination of above-mentioned device of the present invention and reagent proposes in more detail at this paper.In addition, or in the situation of polymer, described compositions can comprise collagen protein.

These and other fermentation of the present invention can become apparent with reference to after the detailed description subsequently.In addition, the various lists of references of some method of more detailed description and/or compositions (for example, polymer) are illustrated at this paper, and therefore they are incorporated herein by reference in full.

The accompanying drawing summary

Fig. 1 shows the chart of Ciclosporin A to the influence of human smooth muscular cells propagation.

Fig. 2 shows the chart of dexamethasone to the propagation influence of human fibroblasts.

Fig. 3 shows the chart of all-trans retinoic acid (ATRA) to the influence of human smooth muscular cells propagation.

Fig. 4 shows the chart of isotretinoin to the influence of human smooth muscular cells propagation.

Fig. 5 shows the chart of 17-to the influence of human fibroblasts propagation.

Fig. 6 shows 1 α-25-dihydroxy-vitamin D ₃Chart to the influence of human smooth muscular cells propagation.

Fig. 7 shows the chart of PDGF-BB to the influence of smooth muscle cell proliferation.

Fig. 8 is a bar chart, and it shows with respect to being exposed to the tremulous pulse that does not wrap by the PU film, the area of the granulation tissue in the carotid artery of the blood vessel week of contact silk bag quilt polyurethane (PU) film.

Fig. 9 is a bar chart, and it shows with respect to being exposed to the tremulous pulse that does not wrap by the PU film, the area of the granulation tissue in the carotid artery of the blood vessel week of contact silk suture bag quilt PU film.

Figure 10 is a bar chart, and it shows with respect to matched group, and at the silk powder that is exposed to natural and purification and wrapped up the area of the granulation tissue in the carotid artery of blood vessel week PU film, in described matched group, tremulous pulse has only wrapped up blood vessel week PU film.

Figure 11 is a bar chart, and it shows with respect to matched group, is spraying Pulvis Talci and is wrapping up the area of the granulation tissue (at 1 month and 3 months) in the carotid artery of blood vessel week PU film, and in described matched group, tremulous pulse has only wrapped up all PU films of blood vessel.

Figure 12 is explicit declaration area by granulation tissue of quantized blood vessel week of area of computer aided MORPHOMETRIC ANALYSIS OF EXFOLIATED in rat carotid artery, and described carotid artery is not handled with wrapping by the contrast of PU film with in order to the PU film that comes unstuck and unworn silk chain is handled.As shown in FIG., two types silk significantly is increased in the growth of circumvascular granulation tissue with identical degree.

Figure 13 is presented at the representative Histological section in the rat carotid artery, described carotid artery with bag by to come unstuck and the PU film of unworn silk chain is handled.As shown in FIG., two types silk is induced processed circumvascular significant tissue reaction.Movat dyeing, 100X.

Figure 14 is presented at the representative Histological section in the rat carotid artery, and described carotid artery by to come unstuck and the PU film of unworn silk chain is handled, shows the granulation tissue of growth around processed blood vessel with bag.Described silk chain be broken down into by giant cell and macrophage around granule.Described granulation tissue is by the height vascularization and comprise many inflammatory cells and fibroblast.Extrtacellular matrix deposition also is a large amount of.H ﹠amp; E dyeing, 200X.

The release profiles that Figure 15 shows as analyzes by HPLC from the Ciclosporin A of polyurethane film.

Detailed Description Of The Invention

The open medicament of the present invention, it promotes the generation of fibroid (scar) tissue or one or more aspects of regeneration. In addition, composition and method are described, with the medicine delivering compositions, to be coated with medical device and implant, thereby for fibre modification occurs, with curing in the sufficient cycle, with treatment level, are sending described medicament. The present invention also describes various compositions, and has described and increase contiguous or in the method for the generation of implant lip-deep cicatricial tissue. Described many concrete implants and device, as the result that is coated with by medicament, they can produce more excellent clinical effectiveness, and other relevant advantage, and described medicament promotes cicatrization and healing.

Definition

Before illustrating the present invention, the definition of at first illustrating some some term that hereinafter will use may help to understand the present invention.

" medical device " (or " implant ", or " medical implant " or transplantable medical device) point out in recovering physiological function, reduce/relax with the symptom of disease association and/or repairing/substitute impaired or purpose ill organ and tissue is placed in any object in body. Although usually by the biocompatibility synthetic material (for example, other stainless steel of medical grade, titanium and other metal, polymer is such as polyurethane, silicon, PLA (PLA), polyglycolic acid (PLGA) and other material), other exogenous material forms, and some medical devices and implant comprise material from animal (for example, " xenograft " is such as whole animal organ; Animal tissue is such as cardiac valves; Naturally exist or the chemical modification molecule such as collagen, hyaluronic acid, protein, carbohydrate and other), (for example, " alloplast " is such as complete organ for people's donor; Tissue is such as bone graft, skin graft and other), or from patient itself (for example, " autograft " such as saphenous vein graft, skin graft, tendon/ligament/muscle graft). Concrete application medical device in the present invention includes, but not limited to rectificating surgery implant (artificial joint, ligament and tendon, screw, plate and other implantable hardware), tooth implant, blood vessel are implanted into thing (locking device of artery and vein and implant particularly; The angiolysis implant), masculinity and femininity contraception or sterilization device and implant, for the transplantable filler of organizing of incontinence (esophagus, urethra, anus), the soft palate implant, embolism reagent, lung's sealant, the operation mesh is (for example, hernia mesh, organize support), fistula is processed, and spinal implant is (for example, artificial interverbebral disc, spinal fusion device etc.).

the formation of fibr tissue when " fibre modification ", " cicatrization " or " fibre modification reaction " refer to respond damage or medical treatment intervention. promote (also to refer to " inducing " at this paper with exchanging, " stimulation ", " causing " etc.) fibre modification or synulotic treatment reagent refers to " fibre modification derivant " interchangeably at this paper, " cicatrization agent ", " fibr tissue forming agent ", " induce the reagent of adhesion ", Deng, wherein these reagent work by the one or more following mechanism that comprises: induce or promote blood vessel to occur, stimulate phoirocyte (such as fibroblast, smooth muscle cell, VSMC) migration or propagation, induce ECM to produce, and/or promotion tissue remodeling. in addition, many treatment reagent of describing in the present invention can have the additional benefit (with the cell of same type, replacing impaired cell) that also promotes regeneration.

" sclerosis " refers to a kind of tissue reaction, wherein stimulant is applied topically to tissue, causes inflammatory reaction and stimulating the site scar tissue to form subsequently. To induce or promote the medicament of sclerosis to be called " curing agent " or " sclerosis reagent ". The representative reagent of curing agent comprises ethanol, dimethyl sulfoxide (DMSO), surfactant (for example, Triton X, sorbitan monolaurate, sorbitan sesquioleate, glyceryl monostearate and polyoxyethylene, PCE etc.), sucrose, sodium chloride, dextrose, glycerine, minocycline, tetracycline, Doxycycline, Lauromacrogol 400, Sodium Tetradecyl Sulfate, sodium morrhuate, monoethanolamine, phenol, sarapin and Sotradecol.

" release of reagent " refers to that the described reagent or any of its subfraction that from implant/device, have disintegrated down statistically exist significantly.

It being understood that unless otherwise noted, any concentration range of this paper statement, percentage range, or ratio ranges is included in the concentration of any integer in this scope and mark thereof, percentage or ratio, such as one of 1/10th and one percentage of integer. In addition, it being understood that unless otherwise noted, this paper statement relate to any physics characteristics, such as the polymer subunit, any quantitative range of size or thickness is included in any integer in the statement scope. Should be appreciated that the term ＂ a ＂ of top and other place's use of this paper and " one or more " that ＂ an ＂ refers to be enumerated component. While being used for this paper, term " approximately " refers to ± 15%.

As above discuss, the invention provides the composition that relates to medical implant, method and apparatus, it has increased their cicatrization and be attached to ability in surrounding tissue in place greatly. Below discussed in detail be the method that builds medical implant, composition and produce the method that promotes fibrotic medical implantation plant, and use the method for these medical implants.

A. Medical implant

Medical implant of the present invention comprises and/or is adapted to discharge reagent, and described reagent is induced or promoted adhesion or fibre modification between implant and tissue to react. In certain embodiments, in the time of in being placed in tissue, described medical implant discharges reagent, and described reagent is induced or promoted adhesion or fibre modification between implant and tissue to react. In other embodiments, described medical implant comprises or the fibr tissue forming agent, consists of, but does not discharge the fibr tissue forming agent. In these embodiments, the fibr tissue forming agent that is included in medical implant contacts to induce or promote fibre modification by the tissue that described reagent and implant are placed in wherein.

The representative example of medical implant comprises: rectificating surgery implant (artificial joint, ligament and tendon, screw, plate and other implantable hardware), dental implants, blood vessel implant (tremulous pulse and venous locking device and implant particularly; The angiolysis implant), masculinity and femininity contraception or sterillization device and implant are at the transplantable tissue filling agent of incontinence (esophagus, urethra, anus), the soft palate implant, thromboembolism reagent, pulmonary's sealant, the surgical operation mesh is (for example, hernia mesh, organization bracket), fistula is handled, and spinal implant (for example, artificial intervertebral disc, spinal fusion device etc.).

B. Treatment reagent

In brief, many therapeutic agents (being also referred to as " therapeutic agent " or " medicine " at this paper) that can utilize in the context of the invention have been identified.Described reagent can with one or more other materials, for example polymer support is prepared together, wherein preparation is discussed below.Specifically identified many suitable therapeutic agents at this paper, and based on (animal) model in the external and body such as at embodiment 13-20; 33-34; With 40 in provide those take easily to determine other therapeutic agent.Can identify by body inner model such as rat carotid artery model and promote fibrotic therapeutic agent (embodiment 17-20).

On the one hand, fibre modification or adhesion derivant are silks.Silk refers to a kind of fibrin, can obtain from multiple source, typically obtains from Aranea and silkworm.Fibroin typically comprises about 75% the true fiber that is called fibroin, and about 35% sericin, and described sericin is the viscous protein matter that filament is kept together.The general very thin of filament and reach 300-900 rice.Have several different family's sericulture species to be used for commercial silk and produce, still, silkworm (Bombyx mori) is the most frequently used, and most of silks are all from this source.Other suitable silkworm comprises Semen Ricini silkworm (Philosamiacynthia ricini), giant silkworm (Antheraea yamamai), Antherea pernyi Guerin-Meneville (Antheraea pernyi) and Antheraea mylitta.Spider silk is difficult to obtain relatively more, but, recombinant technique promise to be a kind of means that obtain the spider silk of economically valuable (see, for example, U.S. Patent number 6,268,169; 5,994,099; 5,989,894; With 5,728,810, it is exemplary).Other source that biotechnology allows the software engineering researchers invent silk to produce comprises animal (for example, goat) and plant (for example, Rhizoma Solani tuber osi).Silk from any of these source may be used to the present invention.

A kind of commercially available fibroin can be from Croda, Inc., of Parsippany, N.J. obtain, with trade name CROSILK LIQUID (Silk Amino Acids), CROSILK 10,000 (silk of hydrolysis), CROSILK POWDER (pulverous silk) and CROSILKQUAT (cocodiammoniumhydroxypropyl Silk Amino Acids) sell.Another example of commercially available fibroin is SERICIN, can be from Pentapharm, and LTD, a division of Kordia, BV, of theNetherlands obtains.The further details of this fibroin admixture can be at U.S. Patent number 4,906, finds that described patent authorizing Kim etc. transfer Sorenco in 460.Be used for comprising natural (former) silk at silk of the present invention, hydrolyzed-silk and modify after silk, promptly carried out chemistry, machinery or steam treated, for example acid treatment or acetylizad (see, for example, U.S. Patent number 5,747,015).

Raw silk typically is wound in a sufficiently solid chain and is used for braiding or knitting.Can produce four kinds of dissimilar silk threads by this method: organizine, crape, weft yarn and twisting monofilament.Organizine is to give raw silk the preliminary silk thread that twines and in opposite direction two these silk threads are intertwined and make subsequently by a direction.Crape is similar to organizine, but the winding degree is bigger.Only twining two or more raw silks in a direction makes weft yarn.The twisting monofilament is the single raw silk silk thread that only twines in one direction.The silk thread of any of these type may be used to the present invention.

Being used for silk of the present invention can exist with the appropriate format that medical implant connects with the described silk of any permission, and for example, described silk can be to exist based on silk thread or form of powder.Described silk can be prepared with powder type by some diverse ways.For example, described silk can be ground (for example, cryomil) powdered form.Perhaps, described silk can be dissolved in the suitable solvent (for example, HFIP or 9M LiBr) then its spraying (electron spray, spray drying) or add in the non-solvent to produce powder.And described silk can have any molecular weight, and wherein various molecular weight typically obtain by the hydrolysis of natural silk, wherein the molecular weight of the degree of hydrolysising condition and intensity decision product.For example, described silk can have average (number average or weight average) molecular weight of about 200 to 5,000.See that for example, introduction can be used for the JP-B-59-29199 (the Japan Patent publication of examining) of the condition of hydrolyzed-silk.

Discussion about silk can see in the following document, and it only is exemplary:

Hinman, M.B., et al. " Synthetic spider silk:a modular fibre " Trends inBiotechnology, 2000,18 (9) 374-379; Vollrath, F. and Knight, D.P " Liquidcrystalline spinning of spider silk ＂ Nature, 2001,410 (6828) 541-548; And Hayashi, C.Y., et al. " Hypotheses that correlate the sequence; structure, andmechanical properties of spider silk proteins " Int.J.Biol.Macromolecules, 1999,24 (2-3), 265-270; With U.S. Patent number 6,427,933.

Other representative example of fibre modification and adhesion derivant comprises that stimulant (for example, Talcum, Pulvis Talci, copper, metallicity beryllium (or its oxide), fine hair (wool) are (for example, animal down, wood shavings, with synthetic property fine hair), quartzy micronic dust, Silicon stone, crystalline silicate), polymer (for example, polylysine, polyurethane, polyethylene terephthalate, polytetrafluoroethylene (PTFE), poly-(alkyl cyanoacrylate) and poly-(ethylene-co-vinyl acetate); The polymer of vinyl chloride and vinyl chloride; Peptide with high-lysine content; The somatomedin and the inflammatory cytokine that relate to the synthetic and tissue remodeling of blood vessel generation, fibroblast migration, fibroblast proliferation, ECM are such as epidermal growth factor (EGF) family, transforminggrowthfactor-(TGF-α), transforming growth factor (TGF-9-1, TGF-9-2, TGF-9-3, platelet-derived somatomedin (PDGF), fibroblast growth factor (acidity-aFGF; And alkalescence-bFGF), fibroblast stimulating factor-1, activin, VEGF (comprises VEGF-2, VEGF-3, VEGF-A, VEGF-B, VEGF-C, placental growth factor-PIGF), angiogenin, insulin like growth factor (IGF), hepatocyte growth factor (HGF), Connective Tissue Growth Factor (CTGF), bone marrow colony stimulating factor (CSFs), monocyte chemoattractant protein, granulocyte-macrophage colony stimutaing factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), M-CSF (M-CSF), erythropoietin, interleukin (IL-1 particularly, IL-8, and IL-6), tumor necrosis factor-alpha (TNF9), nerve growth factor (NGF), interferon-' alpha ', interferon-beta, histamine, endothelin-1, Angiotensin II, growth hormone (GH), with synthetic peptide, the analog of these factors or derivant also are suitable for discharging in described from behind concrete implant and the device.Other example comprises CTGF (Connective Tissue Growth Factor); Inflammatory microcrystal (for example, the crystal mineral is such as crystalline silicate); Bromocriptine, methylsergide, methotrexate, chitosan, N-carboxylic butyl chitosan, carbon tetrachloride, thioacetamide, fibrosin, ethanol, bleomycin, generally natural existence or the synthetic peptide that comprises Arg-Gly-Asp (RGD) sequence at one or two end (sees that for example U.S. Patent number 5,997,895), with organize adhesive agent, such as cyanoacrylate and crosslinked poly-(ethylene glycol)-methylated collagen composition, such as what describe below.The example of other fibre modification derivant comprises bone morphogenetic protein (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15 and BMP-16).In these BMP, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7 are particularly useful.Bone morphogenetic protein exists, for example, and U.S. Patent number 4,877,864; 5,013,649; 5,661,007; 5,688,678; 6,177,406; 6,432,919; With 6,534,268 and Wozney, J.M. etc., (1988) Science:242 (4885); Be described among the 1528-1534.

Other representative example of fibre modification derivant comprises the cross-linked composition that comprises amido functional group.For example, under the alkaline buffer condition, the amino-functional Polyethylene Glycol (for example, 4-arm four-amino PEG[10k]) can react with the functionalized PEG of 4-arm NHS (for example, poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane).In another example, the PEG of 4-arm thiol-functional (for example, tetramethylolmethane poly-(ethylene glycol) ether four-mercaptan) thus can be replaced by the PEG of 4-arm amino-functional the quantity of the amido functional group in final composition can be changed.Thereby these reagent can mix the cross-linked hydrogel that original position provides formation when applying.Thereby these reagent can carry out premix produces crosslinked material.Described material can be with various forms such as bar, pipe, and film, sheet or spheroid are made.Produce microparticle material thereby can also grind to crosslinked material.Can carry out drying (for example, air, vacuum, lyophilization) and used as exsiccant dusty material to these materials.Perhaps, described material can just carry out hydration before using.These materials can also comprise one of fibre modification derivant described herein.

The component that other representative example of fibre modification derivant comprises extracellular matrix (for example, fibronectin, fibrin, fibrinogen, collagen protein (for example, bovine collagen albumen), fibril and non-protofibre collagen protein, the adhesiveness glycoprotein, proteoglycan (for example, heparin sulfate, chondroitin sulfate, dermatan sulfate), hyaluronan, be rich in the acidic secretion protein (SPARC) of cysteine, thrombospondin, tenacin and cell adhesion molecule (comprise and integrate element, vitronectin, fibronectin, laminin, hyaluronic acid, elastin laminin, bitronectin), with the protein of in basement membrane, finding, and fibrosin) and the inhibitor of matrix metalloproteinase, such as TIMPs (tissue depressant of matrix metalloproteinase) and synthetic property TIMPs, for example, marimistat, batimistat, doxycycline, tetracycline, minocycline, TROCADE, Ro-1130830, CGS27023A, and BMS-275291.

In each embodiment of the present invention, with first compositions that promotes fibre modification (and/or restenosis) with play a role and be suppressed in the treatment site or second compositions or the chemical compound of pathological process on every side come apparatus for coating.The representative example that can be suppressed at the reagent of the pathological process for the treatment of the site includes, but not limited to the chemical compound of following classification: antiinflammatory (for example, dexamethasone, cortisone, hydrogen fluorine cortisone, prednisone, prednisolone, 6 alpha-methylprednisolones, triamcinolone and betamethasone); Matrix metalloproteinase (MMP) inhibitor (for example, marimistat, batimistat, the representative example of TIMP is included in U.S. Patent number 5,665,777; 5,985,911; 6,288,261; 5,952,320; 6,441,189; 6,235,786; 6,294,573; 6,294,539; 6,563,002; 6,071,903; 6,358,980; 5,852,213; 6,124,502; 6,160,132; 6,197,791; 6,172,057; 6,288,086; 6,342,508; 6,228,869; 5,977,408; 5,929,097; 6,498,167; 6,534,491; 6,548,524; 5,962,481; 6,197,795; 6,162,814; 6,441,023; 6,444,704; 6,462,073; 6,162,821; 6,444,639; 6,262,080; 6,486,193; 6,329,550; 6,544,980; 6,352,976; 5,968,795; 5,789,434; 5,932,763; 6,500,847; 5,925,637; 6,225,314; 5,804,581; 5,863,915; 5,859,047; 5,861,428; 5,886,043; 6,288,063; 5,939,583; 6,166,082; 5,874,473; 5,886,022; 5,932,577; 5,854,277; 5,886,024; 6,495,565; 6,642,255; 6,495,548; 6,479,502; 5,696,082; 5,700,838; 6,444,639; 6,262,080; 6,486,193; 6,329,550; 6,544,980; 6,352,976; 5,968,795; 5,789,434; 5,932,763; 6,500,847; 5,925,637; 6,225,314; 5,804,581; 5,863,915; 5,859,047; 5,861,428; 5,886,043; 6,288,063; 5,939,583; 6,166,082; 5,874,473; 5,886,022; 5,932,577; 5,854,277; 5,886,024; 6,495,565; 6,642,255; 6,495,548; 6,479,502; 5,696,082; 5,700,838; 5,861,436; 5,691,382; 5,763,621; 5,866,717; 5,902,791; 5,962,529; 6,017,889; 6,022,873; 6,022,898; 6,103,739; 6,127,427; 6,258,851; 6,310,084; 6,358,987; 5,872,152; 5,917,090; 6,124,329; 6,329,373; 6,344,457; 5,698,706; 5,872,146; 5,853,623; 6,624,144; 6,462,042; 5,981,491; 5,955,435; 6,090,840; 6,114,372; 6,566,384; 5,994,293; 6,063,786; 6,469,020; 6,118,001; 6,187,924; 6,310,088; 5,994,312; 6,180,611; 6,110,896; 6,380,253; 5,455,262; 5,470,834; 6,147,114; 6,333,324; 6,489,324; 6,362,183; 6,372,758; 6,448,250; 6,492,367; 6,380,258; 6,583,299; 5,239,078; 5,892,112; 5,773,438; 5,696,147; 6,066,662; 6,600,057; 5,990,158; 5,731,293; 6,277,876; 6,521,606; 6,168,807; 6,506,414; 6,620,813; 5,684,152; 6,451,791; 6,476,027; 6,013,649; 6,503,892; 6,420,427; 6,300,514; 6,403,644; 6,177,466; 6,569,899; 5,594,006; 6,417,229; 5,861,510; 6,156,798; 6,387,931; 6,350,907; 6,090,852; 6,458,822; 6,509,337; 6,147,061; 6,114,568; 6,118,016; 5,804,593; 5,847,153; 5,859,061; 6,194,451; 6,482,827; 6,638,952; 5,677,282; 6,365,630; 6,130,254; 6,455,569; 6,057,369; 6,576,628; 6,110,924; 6,472,396; 6,548,667; 5,618,844; 6,495,578; 6,627,411; 5,514,716; 5,256,657; 5,773,428; 6,037,472; 6,579,890; 5,932,595; 6,013,792; 6,420,415; 5,532,265; 5,639,746; 5,672,598; 5,830,915; 6,630,516; 5,324,634; 6,277,061; 6,140,099; 6,455,570; 5,595,885; 6,093,398; 6,379,667; 5,641,636; 5,698,404; 6,448,058; 6,008,220; 6,265,432; 6,169,103; 6,133,304; 6,541,521; 6,624,196; 6,307,089; 6,239,288; 5,756,545; 6,020,366; 6,117,869; 6,294,674; 6,037,361; 6,399,612; 6,495,568; 6,624,177; 5,948,780; 6,620,835; 6,284,513; 5,977,141; 6,153,612; 6,297,247; 6,559,142; 6,555,535; 6,350,885; 5,627,206; 5,665,764; 5,958,972; 6,420,408; 6,492,422; 6,340,709; 6,022,948; 6,274,703; 6,294,694; 6,531,499; 6,465,508; 6,437,177; 6,376,665; 5,268,384; 5,183,900; 5,189,178; 6,511,993; 6,617,354; 6,331,563; 5,962,466; 5,861,427; 5,830,869; With 6,087, the representative example of the TIMP in 359), cytokine inhibitor (chlorpromazine, Mycophenolic Acid, rapamycin, 1 alpha-hydroxy vitamin D ₃), IMPDH (inosine monophosphate dehydrogenase) inhibitor (Mycophenolic Acid for example, ribavirin, aminothiadiazole, thiophenfurin, thiazole is held up woods, and viramidine) (representative example is included in U.S. Patent number 5,536,747; 5,807,876; 5,932,600; 6,054,472; 6,128,582; 6,344,465; 6,395,763; 6,399,773; 6,420,403; 6,479,628; 6,498,178; 6,514,979; 6,518,291; 6,541,496; 6,596,747; 6,617,323; With 6,624,184, Application No. 2002/0040022A1,2002/0052513A1,2002/0055483A1,2002/0068346A1,2002/0111378A1,2002/0111495A1,2002/0123520A1,2002/0143176A1,2002/0147160A1,2002/0161038A1,2002/0173491A1,2002/0183315A1,2002/0193612A1,2003/0027845A1,2003/0068302A1,2003/0105073A1,2003/0130254A1,2003/0143197A1,2003/0144300A1,2003/0166201A1,2003/0181497A1,2003/0186974A1,2003/0186989A1, and 2003/0195202A1, with PCT publication number WO 00/24725A1, WO 00/25780A1, WO 00/26197A1, WO00/51615A1, WO 00/56331A1, WO 00/73288A1, WO 01/00622A1, WO01/66706A1, WO 01/79246A2, WO 01/81340A2, WO 01/85952A2, WO02/16382A1, WO 02/18369A2, WO 02/051814A1, WO 02/057287A2, WO 02/057425A2, WO 02/060875A1, WO 02/060896A1, WO 02/060898A1, WO 02/068058A2, WO 03/020298A1, WO 03/037349A1, WO 03/039548A1, WO 03/045901A2, WO 03/047512A2, WO 03/053958A1, WO 03/055447A2, WO 03/059269A2, WO 03/063573A2, WO 03/087071A1, WO99/001545A1, WO 97/40028A1, WO 97/41211A1, WO 98/40381A1 and WO 99/55663A1), p38 map kinase inhibitor (MAPK) is (for example, GW-2286, CGP-52411, BIRB-798, SB220025, RO-320-1195, RWJ-67657, RWJ-68354, SCIO-469) (representative example is included in U.S. Patent number 6,300,347; 6,316,464; 6,316,466; 6,376,527; 6,444,696; 6,479,507; 6,509,361; 6,579,874; With 6,630,485, with U.S. Patent Application Publication No. 2001/0044538A1,2002/0013354A1,2002/0049220A1,2002/0103245A1,2002/0151491A1,2002/0156114A1,2003/0018051A1,2003/0073832A1,2003/0130257A1,2003/0130273A1,2003/0130319A1,2003/0139388A1,2003/0139462A1,2003/0149031A1,2003/0166647A1, and 2003/0181411A1, with PCT publication number WO 00/63204A2, WO 01/21591A1, WO 01/35959A1, WO 01/74811A2, WO 02/18379A2, WO02/064594A2, WO 02/083622A2, WO 02/094842A2, WO 02/096426A1, WO02/101015A2, WO 02/103000A2, WO 03/008413A1, WO 03/016248A2, WO03/020715A1, WO 03/024899A2, WO 03/031431A1, WO 03/040103A1, WO03/053940A1, WO 03/053941A2, WO 03/063799A2, WO 03/079986A2, WO03/080024A2, WO 03/082287A1, WO 97/44467A1, WO 99/01449A1, and immunomodulator (rapamycin, everolimus and WO99/58523A1),, ABT-578, the azathioprine azithromycin, the analog of rapamycin, tacrolimus and derivant thereof are (for example, EP 0184162B1 and be described in U.S. Patent number 6, in 258,823 those) and everolimus and derivant thereof (for example, U.S. Patent number 5,665,772).Other representative example of sirolimus analog and derivant comprises ABT-578 and see PCT publication number WO 97/10502, and WO 96/41807, and WO 96/35423, WO 96/03430, and WO 96/00282, and WO 95/16691, WO 95/15328, and WO 95/07468, and WO 95/04738, WO 95/04060, and WO 94/25022, and WO 94/21644, WO 94/18207, and WO 94/10843, and WO 94/09010, WO 94/04540, WO 94/02485, and WO 94/02137, and WO 94/02136, W0 93/25533, WO 93/18043, and WO 93/13663, and WO 93/11130, WO 93/10122, WO 93/04680, WO 92/14737 and WO 92/05179 and at U.S. Patent number 6,342,507; 5,985,890; 5,604,234; 5,597,715; 5,583,139; 5,563,172; 5,561,228; 5,561,137; 5,541,193; 5,541,189; 5,534,632; 5,527,907; 5,484,799; 5,457,194; 5,457,182; 5,362,735; 5,324,644; 5,318,895; 5,310,903; 5,310,901; 5,258,389; 5,252,732; 5,247,076; 5,225,403; 5,221,625; 5,210,030; 5,208,241; 5,200,411; 5,198,421; 5,147,877; 5,140,018; 5,116,756; 5,109,112; 5,093,338; With 5,091, those in 389.

Other example that can be included in the medicine in compositions of the present invention and the device comprises tyrosine kinase inhibitor, such as imatinib, and ZK-222584, CGP-52411, CGP-53716, NVP-AAK980-NX, CP-127374, CP-564959, PD-171026, PD-173956, PD-180970, SU-0879, and SKI-606.Other example that can be included in the medicine in compositions of the present invention and the device comprises that the MMP inhibitor is such as nimesulide, PKF-241-466, PKF-242-484, CGS-27023A, SAR-943, primomastat, SC-77964, PNU-171829, AG-3433, PNU-142769, SU-5402, and dexlipotam.Other example that can be included in the medicine in compositions of the present invention and the device comprises p38 map kinase inhibitor such as CGH-2466 and PD-98-59.Other example that can be included in the medicine in compositions of the present invention and the device comprises immunosuppressant such as argyrin B, macrolide, ADZ-62-826, CCI-779, tilomisole, amcinonide, FK-778, AVE-1726, and MDL-28842.Other example of cytokine inhibitor comprises TNF-484A, PD-172084, CP-293121, CP-353164, and PD-168787.Other example that can be included in the medicine in compositions of the present invention and the device comprises the NFKB inhibitor, such as, AVE-0547, AVE-0545, and IPL-576092.Other example that can be included in the medicine in compositions of the present invention and the device comprises the HMGCoA reductase inhibitor, such as, pravestatin, atorvastatin, fluvastatin, dalvastatin, glenvastatin, Pitavastatin, CP-83101, U-20685, natural death of cerebral cells antagonist (for example, troloxamine, TCH-346 (N-methyl-N-propargyl-10-amino methyl-dibenzo (b, f) oxepin), Caspase (caspase) inhibitor (for example, PF-5901 (benzyl alcohol, α-amyl group-3-(2-quinolyl methoxyl group)-), and jnk inhibitor (for example, AS-602801).

In each embodiment of the present invention, device in conjunction with or with the compositions of promotion fibre modification (and/or restenosis), and compositions or the chemical compound that stimulates cellular proliferation that play a role is coated with.The representative example of the medicament that stimulates cellular proliferation comprises, acetone acid, naltrexone, leptin, D-glucose, insulin, amlodipine, alginate oligosaccharide, minoxidil, dexamethasone, isotretinoin, (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME (L-NG-nitroarginine methyl ester (hydrochlorate)), all-trans retinoic acid (ATRA), and analog and derivant.Other example of the medicament that stimulates cellular proliferation comprises: sphingosine 1-phosphate acceptor agonist (for example, and FTY-720 (1, ammediol, 2-amino-2-(2-(4-octyl phenyl) ethyl)-, hydrochlorate; Immunostimulant such as Imupedone (methanone, [5-amino-2-(4-methyl isophthalic acid-piperidyl) phenyl] (4-chlorphenyl)-, DIAPEP227 synthesizes peptide (Peptor Ltd., Israel)); With the nerve growth factor agonist, for example, NG-012 (5H, 9H, 13H, 21H, 25H ,-dibenzo [k, u] [1,5,9,15,19] pentaoxacyclotetracosin-5,9,13,21,25-pentone, 7,8,11,12,15,16,23,24,27,28-decahydro-2,4,18,20-tetrahydroxy-11-(methylol)-7,15,23, the 27-tetramethyl-, NG-121, SS-701 (2,2 ': 6 ', 2 ＂-terpyridine, 4 '-(4-aminomethyl phenyl)-trihydrochloride, AMPAlex (piperidines), 1-(6-quinoxalinyl carbonyl)-, RGH-2716 (8-[4,4-two (4-fluorophenyl) butyl]-3-(1, the 1-dimethyl ethyl)-4-methylene-1-oxa--3, and TDN-345 (1-oxa--3,8-diaza spiro [4.5] decane-2-ketone 8-diaza-spiro [4.5] decane-2-ketone),, 8-[4,4-two (4-fluorophenyl) butyl]-3-(1, the 1-dimethyl ethyl)-4-methylene-).

In various embodiments of the present invention, device in conjunction with or on one side, promoted the compositions coating of fibre modification (and/or restenosis) and the compositions or the chemical compound coating that on the another side of described device, are prevented from restenosis.The representative example that suppresses the reagent of restenosis comprises paclitaxel, sirolimus, everolimus, vincristine, biolimus, Mycophenolic Acid, ABT-578, cervistatin, simvastatin, methylprednisolone, dexamethasone, actinomycin D, angiopeptin, L-arginine, estradiol, 17-, tranilast, methotrexate, batimastat, halofuginone, BCP-671, QP-2, lantrunculin D, cytochalasin A, nitrogen oxide, and analog and derivant.

Described medical implant can comprise that fibrous tissue forms agent and antithrombotic reagent and/or antiplatelet reagent, and it reduces the probability of the thrombosis incident after medical implant is implanted.In various embodiments of the present invention, device is coated with the compositions that promotes fibre modification (and/or restenosis) on one side, and is coated with thrombotic compositions of prevention or chemical compound on another side.The representative example of antithrombotic and/or antiplatelet reagent comprises heparin, heparin fragment, the organic salt of heparin, heparin complex (for example, benzalkonium heparinate, tridodecylammonium heparinate), glucosan, sulfonation carbohydrate be such as dextran sulfate, Coumadin, coumarin, heparinoid, danaparoid, the argatroban sulfated chitosan, chondroitin sulfate, danaparoid, lepirudin, hirudin, AMP, adenosine, 2-chlorine adenosine, aspirin, Phenylbutazone, indomethacin, that acid of first chlorophenol, hydrochloroquine, dipyridamole, iloprost, streptokinase, with the Xa factor inhibitor, such as DX9065a, magnesium, and tissue plasminogen activator.On the one hand, described antithrombotic reagent is the heparin compound of modifying, such as the hirudin chemical compound of hydrophobically modified heparin or modification (for example, the stearylkonium heparin, the benzalkonium heparin, cetylkonium heparin, or dotriacontyl first ammonium heparin).Other example of antithrombotic reagent comprises plasminogen, and lys-plasminogen, α-2-antifibrinolysin, urokinase, ticlopidine, clopidogrel, glycoprotein iib/iiia inhibitor be such as abciximab, eptifibatide and tirogiban.Other reagent that can influence rate of set comprises glycosaminoglycans, danaparoid, 4-hydroxycourmarin, warfarin sodium, dicoumarol, phenprocoumon, indane-1, the 3-diketone, acenocoumarol, anisindione, comprise Bromadiolone with raticide, Talon, diphenadione, chlorophacinone and pidnone.The blood coagulation of medical implant (thrombogenicity) can be reduced by being coated with implant with polymer formulations, and described polymer formulations has the antithrombotic characteristic.For example, can be coated with described medical apparatus with the hydrophilic polymer gel.Thereby described polymer gel can comprise hydrophilic, biodegradable polymer and reduce the adhesion between platelet and the apparatus surface that described biodegradable polymer is passed in time and physically removed from described apparatus surface.Described gel combination can comprise the admixture of polymer or polymer.Representative example comprises alginate, chitosan and sulphuric acid chitosan, hyaluronic acid, dextran sulfate, PLURONIC polymer ((BASF Corporation, Mt.Olive that PLURONIC polymer (for example, F-127 or F87) and chain are extended, NJ), various polyester-polyether block copolymers (for example, AB of various configurations, ABA, or BAB, wherein A is that polyester is such as PLA, PGA, PLGA, PCL or its analog), the example comprises MePEG-PLA, PLA-PEG-PLA, etc.In one embodiment, antithrombotic forms compositions and can comprise formation (for example, the crosslinked gel of combination PEG), described molecule have two or more terminal electrophilic groups and two or more nucleophilic groups from molecule.

On the one hand, the present invention also provides the combination (and method of compositions and making medical implant) of medical implant, and the combination of described medical implant comprises that fibrous tissue forms agent and infection reagent, and it reduces possibility of infection in medical implant.Infection is the common complication that foreign body such as medical apparatus is implanted.The desirable site that allogenic material provides microorganic adhesion and settles down.Also there is the infringement of host defense system in supposition, and described system of defense is at the infection of the microenvironment around allogenic material.These factors make medical implant for infect responsive especially and, if possible, in most of situations, be difficult to eradicate these infection.

The invention provides reagent (for example, chemotherapeutics), described reagent is attached on the transplantable device or wherein, or discharges from transplantable device, and it has effective antimicrobial activity at extremely low dosage.Can be used in combination with the infection reagent of broad variety and according to fibrous tissue formation agent of the present invention.What go through below is the representative example of more operable chemotherapy/infection reagent: (A) anthracyclines (for example doxorubicin and mitoxantrone), (B) fluorine pyrimidine (for example 5-FU), (C) antifol (for example methotrexate), (D) podophyllotoxin (for example etoposide), (E) camptothecine, (F) hydroxyurea and (G) platinum complexes (for example cisplatin).

A. Anthracyclines

Anthracyclines has following general structure, and wherein the R group can be different organic groups:

According to U.S. Pat 5,594,158, the suitable R group is as follows: R ₁Be CH ₃Or CH ₂OH; R ₂Be daunosamine or H; R ₃And R ₄Be OH, NO independently ₂, NH ₂, F, Cl, Br, I, CN, H or derive from their group a kind of; R ₅Be hydrogen, hydroxyl or methoxyl group; And R _6-8Be hydrogen.Perhaps, R ₅And R ₆Be hydrogen and R ₇And R ₈For alkyl or halogen or vice versa.

According to United States Patent (USP) 5,843,903, R ₁Can be the peptide of puting together.According to United States Patent (USP) 4,296,105, R ₅Can be the alkyl group of ether connection.According to United States Patent (USP) 4,215,062, R ₅Can be the alkyl of OH or ether connection.R ₁Can also be connected with the ring of anthracycline by the group by non-C (O), the group of described non-C (O) is such as being alkyl or the branched alkyl that contains C (O) coupling part endways, such as-CH ₂CH (CH ₂-X) C (O)-R ₁, wherein X is H or alkyl group (see, for example, United States Patent (USP) 4,215,062).R ₂Can alternatively be the group by functional group=N-NHC (O)-Y connection, wherein Y is this ground class group of phenyl ring such as phenyl or replacement.Alternatively, R ₃Can have following array structure:

R wherein ₉For in the plane of a loop or outer OH or be second sugar moieties, such as R ₃R ₁₀Can for H or with form secondary amine (referring to United States Patent (USP) 5,843,903) such as aromatic group, this class group of 5 or 6 yuan of heterocycles of containing the saturated or fractional saturation of at least one ring nitrogen.Alternatively, R ₁₀Can derive from and contain-C (O) CH (NHR ₁₁) (R ₁₂) aminoacid of structure, wherein R ₁₁Be H; Or R ₁₀Can with R ₁₂Form C _3-4Unit's alkylidene.R ₁₂Can be H, alkyl, aminoalkyl, amino, hydroxyl, sulfydryl, phenyl, benzyl or methyl mercapto (referring to United States Patent (USP) 4,296,105).

The example of anthracycline is doxorubicin, daunorubicin, idarubicin, epirubicin, pirarubicin, zorubicin and carubicin.Suitable compound has following structure:

Other suitable anthracycline is antramycin, mitoxantrone, menogaril, nogalamycin, Aclacnomycin A, Olivomycin A, the chromomycin A with following structure ₃And plicamycin:

Other representational anthracycline comprises FCE 23762, doxorubicin derivant (J.Liq.Chromatogr.17 (18): 3911-3923 such as Quaglia, 1994), annamycin (Zou etc., J.Pharm.Sci.82 (11): 1151-1154,1993), ruboxyl (Rapoport etc., J.Controlled Release 58 (2): 153-162,1999), anthracycline disaccharide doxorubicin analog (Pratesi etc., Clin.CancerRes.4 (11): 2833-2839,1998), N-(trifluoroacetyl group) doxorubicin and 4 '-O-acetyl group-N-(trifluoroacetyl group) doxorubicin (Berube ﹠amp; Lepage, Synth.Commun.28 (6): 1109-1116,1998), 2-pyrrolin and doxorubicin (Proc.Nat ' l Acad.Sci.U.S.A.95 (4): 1794-1799 such as Nagy, 1998), disaccharide doxorubicin analog (Arcamone etc., J.Nat ' l CancerInst.89 (16): 1217-1223,1997), 4-demethoxylation-7-O-[2, two deoxidation-the 4-O-(2 of 6-, 3,6-three deoxidations-3-amino-α-L-lysol-hexose pyrans glycosyl)-and α-L-lysol-hexose pyrans glycosyl] adriamicinone doxorubicin disaccharide analog (Monteagudo etc., Carbohydr.Res.300 (1): 11-16,1997), 2-pyrrolin and doxorubicin (Proc.Nat ' l Acad.Sci.U.S.A.94 (2): 652-656 such as Nagy, 1997), morpholinyl doxorubicin analog (Duran etc., Cancer Chemother.Pharmacol.38 (3): 210-216,1996), enamino malonyl-Beta-alanine doxorubicin derivant (Seitz etc., Tetrahedron Lett.36 (9): 1413-16,1995), cephalosporin doxorubicin derivant (Vrudhula etc., J.Med.Chem.38 (8): 1380-5,1995), hydroxyrubicin (Solary etc., Int.J.Cancer 58 (1): 85-94,1994), methoxyl group morpholinyl doxorubicin derivant (Kuhl etc., CancerChemother.Pharmacol.33 (1): 10-16,1993), (6-maleoyl-imino group caproyl) hydrazone doxorubicin derivant (Bioconjugate Chem.4 (6): 521-7 such as Willner, 1993), N-(5,5-diacetoxy penta-1-yl) doxorubicin (Cherif ﹠amp; Farquhar, J.Med.Chem.35 (17): 3208-14,1992), FCE23762 methoxyl group morpholinyl doxorubicin derivant (Ripamonti etc., Br.J.Cancer 65 (5): 703-7,1992), N-hydroxy-succinamide ester doxorubicin derivant (Demant etc., Biochim.Biophys.Acta 1118 (1): 83-90,1991), poly deoxynucleosides doxorubicin derivant (Ruggiero etc., " biochemistry and biophysics's journal " (Biochim.Biophys.Acta) 1129 (3): 294-302,1991), morpholinyl doxorubicin derivant (EPA434960), mitoxantrone doxorubicin analog (Krapcho etc., " pharmaceutical chemistry magazine " (J.Med.Chem.) 34 (8): 2373-80.1991), AD198 doxorubicin analog (Traganos etc., " cancer research " (Cancer Res.) 51 (14): 3682-9,1991), 4-demethoxylation-3 '-N-TFA base doxorubicin (Drug Des.Delivery 6 (2): 123-9 such as Horton, 1990), 4 '-epidoxorubicin (Drzewoski etc., " Polish pharmacology and materia medica magazine " (Pol.J.Pharmacol.Pharm.) 40 (2): 159-65,1988; Weenen etc., " European cancer Journal of Clinical Oncology " (Eur.J.Cancer Clin.Oncol.) 20 (7): 919-26,1984), alkylation cyano group morpholinyl doxorubicin derivant (Scudder etc., " National Cancer Institute's magazine " (J.Nat ' lCancer Inst.) 80 (16): 1294-8,1988), deoxidation dihydro iodooxorubicin (EPA275966), amycin (Kalishevskaya etc., Vestn.Mosk.Univ., 16 (Biol.1): 21-7,1988), 4 '-(Schoelzel etc. " leukocyte research " (Leuk.Res.) 10 (12): 1455-9 for the deoxidation doxorubicin, 1986), 4-demethoxylation-4 '-o-methyl doxorubicin (Giuliani etc., Proc.Int.Congr.Chemother.16:285-70-285-77,1983), 3 '-deaminizating-3 '-(Horton etc. " antibiotic magazine " (J.Antibiot.) 37 (8): 853-8 for the hydroxyl doxorubicin, 1984), 4-demethoxylation doxorubicin analog (Barbieri etc., " clinical drug experimentation " (Drugs Exp.Clin.Res.) 10 (2): 85-90,1984), N-L-leucyl doxorubicin derivant (Trouet etc., anthracyclines (Anthracyclines)-Proc.Int.Symp.Tumor Pharmacother., 179-81,1983), 3 '-deaminizating-3 '-(4-methoxyl group-piperidino) doxorubicin derivant (U.S.4,314,054), 3 '-deaminizating-3 '-(4-morpholinyl) doxorubicin derivant (U.S.4,301,277), 4 '-deoxidation doxorubicin and 4 '-o-methyl doxorubicin (Giuliani etc., " international journal of cancer " (Int.J.Cancer) 27 (1): 5-13,1981), aglycone doxorubicin derivant (Chan ﹠amp; Watson, " pharmaceutical science magazine " (J.Pharm.Sci.) 67 (12): 1748-52,1978), SM 5887 (" Japanese pharmacy " (Pharma Japan) 1468:20,1995), MX-2 (" Japanese pharmacy " (Pharma Japan) 1420:19,1994), 4 '-deoxidation-13 (S)-dihydro-4 '-iodine doxorubicin (EP 275966), morpholinyl doxorubicin derivant (EPA 434960), 3 '-deaminizating-3 '-(4-methoxyl group-piperidino) doxorubicin derivant (U.S.4,314,054), doxorubicin-14-valerate, morpholinyl doxorubicin (U.S.5,004,606), 3 '-deaminizating-3 '-(3 ＂-cyano group-4 ＂-morpholinyl doxorubicin, 3 '-deaminizating-3 '-(3 ＂-cyano group-4 ＂-morpholinyl)-13-dihydro doxorubicin, (3 '-deaminizating-3 '-(3 ＂-cyano group-4 ＂-morpholinyl) daunorubicin, 3 '-deaminizating-3 '-(3 ＂-cyano group-4 ＂-morpholinyl)-3-dihydrodaunomycin and 3 '-deaminizating-3 '-(4 ＂-morpholinyl-5-imino group doxorubicin and derivant (U.S.4,585,859), 3 '-deaminizating-3 '-(4-methoxyl group-piperidino) doxorubicin derivant (U.S.4,314,054) and 3-deaminizating-3-(4-morpholinyl) doxorubicin derivant (U.S.4,301,277).

B. Fluoropyrimidine analogue

In one aspect of the method, described therapeutic agent is a fluoropyrimidine analogue, such as 5-fluorouracil or its analog or derivant, comprises carmofur, doxifluridine, emitefur, florafur and floxuridine.Exemplary compounds has following structure:

Other suitable fluoropyrimidine analogue comprises 5-FudR (5-fluoro-BrdU) or its analog or derivant, comprises idoxuridine (5-IudR), 5-bromouracil deoxyribose (5-BudR), fluorouridine triphosphate (5-FUTP) and fluorodeoxyuridine one phosphoric acid (5-dFUMP).Exemplary compounds has following structure:

5-fluoro-2 '-BrdU: R=F

5-bromo-2 '-BrdU: R=Br

5-iodo-2 '-BrdU: R=I

Other representative example of fluoropyrimidine analogue comprises the N3-alkylation analog (Kozai etc. of 5-fluorouracil, J.Chem.Soc., Perkin Trans.1 (19): 3145-3146,1998), contain 1, (Gomez etc. " tetrahedron " (Tetrahedron) 54 (43): 13295-13312 for the 5-fluorouracil derivant of 4-oxa-loop section in heptan, 1998), 5-fluorouracil and nucleoside analog (Li, " anticancer research " (Anticancer Res.) 17 (1A): 21-27,1997), cis-and trans-5-fluoro-5,6-dihydro-6-alkoxyl uracil (Van der Wilt etc., " Britain's cancer magazine " (Br.J.Cancer) 68 (4): 702-7,1993), Pentamethylene. 5-fluorouracil analog (Hronowski ﹠amp; Szarek, " Canadian Journal of Chemistry " (Can.J.Chem.) 70 (4): 1162-9,1992), A-OT-fluorouracil (Zhang etc., " Chinese Journal of Pharmaceuticals " (Zongguo Yiyao Gongye Zazhi) 20 (11): 513-15,1989), N4-trimethoxy benzoyl-5 '-deoxidation-5-fluorine cytidine and 5 '-(Miwa etc. " chemicals bulletin " (Chem.Pharm.Bull.) 38 (4): 998-1003 for '-Deoxy-5-fluorouridine, 1990), 1-hexyl carbamoyl-5-fluorouracil (Hoshi etc., J.Pharmacobio-Dun.3 (9): 478-81,1980; Maehara etc., " chemotherapy " be (Basel) 34 (6) (Chemotherapy): 484-9,1988), B-3839 (Prajda etc., " in the body " (In Vivo) 2 (2): 151-4,1988), (Anai etc. " oncology " (Oncology) 45 (3): 144-7 for uracil-1-(2-tetrahydrofuran base)-5-fluorouracil, 1988), 1-(2 '-deoxidation-2 '-fluoro-beta-D-arabinofuranosyl adenin base)-5-fluorouracil (Suzuko etc., " molecular pharmacology " (Mol.Pharmacol.) 31 (3): 301-6,1987), doxifluridine (Matuura etc., Oyo Yakuri 29 (5): 803-31,1985), 5 '-'-Deoxy-5-fluorouridine (Bollag ﹠amp; Hartmann; " European cancer magazine " (Eur.J.Cancer) 16 (4): 427-32; 1980), 1-acetyl group-3-O-toluyl groups-5-fluorouracil (Okada; Hiroshima J.Med.Sci.28 (1): 49-66,1979), 5-fluorouracil-m-formoxyl benzene sulfonate (JP55059173), N '-(2-furan alkyls)-5-fluorouracil (JP 53149985) and 1-(2-tetrahydrofuran base)-5-fluorouracil (JP 52089680).

Think that these chemical compounds play therapeutic agent by the antimetabolite as pyrimidine.

C. Antifol

In one aspect of the method, therapeutic agent is an antifol, such as methotrexate or derivatives thereof or analog, comprises edatrexate, trimetrexate, Raltitrexed, piritrexim, 9,10-dimethylpteroylglutamic acid, Tomudex and Pteropterin.The methotrexate analog has following general structure:

Symbol R group can be selected from organic group, and particularly United States Patent (USP) 5,166, and 149 and 5,382, those groups described in 582.For example, R ₁Can be N, R ₂Can be N or C (CH ₃), R ₃And R ₃' can be H or alkyl, for example CH ₃, R ₄Can be singly-bound or NR, wherein R is H or alkyl.R ₅, R ₆, and/or R ₈Can be H, OCH ₃Or they are chosen as halogen or hydrogen group.R ₇Side chain for following general structure:

Wherein with regard to methotrexate, n=1, with regard to Pteropterin, n=3.Carboxyl on the side chain can esterified or salify, such as Zn ²⁺Salt.R ₉And R ₁₀Can be NH ₂Maybe can replace for alkyl.

Typical folic acid antagonist immunomodulator compounds has following structure:

	R 0	R 1	R 2	R 3	R 4	R 5	R 6	R 7	R 8
										Methotrexate	NH 2	N	N	H	N(CH 3)	H	H	A(n＝1)	H
Edatrexate	NH 2	N	N	H	CH(CH 2CH 3)	H	H	A(n＝1)	H
										Trimetrexate	NH 2	CH	C(CH 3)	H	NH	H	OCH 3	OCH 3	OCH 3
Pteropterin	OH	N	N	H	NH	H	H	A(n＝	H

								3)
										9,10-dimethylpteroylglutamic acid	OH	N	N	CH 3	N(CH 3)	H	H	A(n＝1)	H
Peritrexim	NH 2	N	C(CH 3)	H	Singly-bound	OCH 3	H	H	OCH 3

Other representative examples include 6-S-amino-mercaptopurine acyloxymethyl derivative (Harada Et al, "chemicals Briefing" (Chem.Pharm.Bull.) 43 (10) :793-6, 1995), 6 - mercapto purine Purine (6-MP) (Kashida et al, "Presentation biopharmaceuticals" (Biol.Pharm.Bull.) 18 (11) :1492-7, 1995), 7,8 - polymethylene-imidazo 3,2 - diaza-phospha-nonyl Rings (Diazaphosphorines) (Nilov, etc., Mendeleev Commun.2: 67,1995), azathioprine (Chifotides other "Journal of Inorganic Biochemistry" (J.Inorg.Biochem.) 56 (4) :249-64, 1994), methyl-D-glucopyranoside mercaptopurine derivatives (Da Silva et al, "European Pharmaceutical Chemistry Journal "(Eur.J.Med.Chem.) 29 (2) :149-52, 1994) and s-alkynyl derivatives mercaptopurine (Ratsino other, Khim.-Farm.Zh.15 (8) :65-7, 1981), containing the indoline ring and a modified Ornithine or glutamic acid methotrexate derivatives (Matsuoka and other "chemical drugs Briefing" (Chem. Pharm.Bull.) 45 (7) :1146-1150, 1997), containing an alkyl-substituted benzene ring C Methotrexate Derivatives (Matsuoka and other "chemical drugs Briefing" (Chem.Pharm.Bull.) 44 (12): 2287-2293,1996) containing benzoxazine or benzothiazine derivatives portion Methotrexate (Matsuoka other "Journal of Medicinal Chemistry" (J.Med.Chem.) 40 (1) :105-111, 1997), 10 - Deaza aminopterin analogues (DeGraw other "Journal of Medicinal Chemistry" (J.Med.Chem.) 40 (3): 370-376,1997), 5 - deaza aminopterin and 5,10 - bis deaza analogs of aminopterin methotrexate (Piper and other "Journal of Medicinal Chemistry" (J.Med.Chem.) 40 (3) :377-384, 1997), containing diethylene Indoline part methotrexate derivatives (Matsuoka et al, "chemical drugs Briefing" (Chem. Pharm.Bull.) 44 (7) :1332-1337, 1996), lipophilic methotrexate derivatives amide (Pignatello and other "drugs and biopharmaceuticals Technology World Conference" (World Meet.Pharm., Biopharm.Pharm.Technol.) 563-4,1995), containing L-threo - (2S, 4S) -4 - fluoro-acid And DL-3, 3 - difluoro-glutamic acid methotrexate analogues (Hart other "Journal of Medicinal Chemistry" (J.Med. Chem.) 39 (1) :56-65, 1996), methotrexate tetrahydroquinazoline base analogs (Gangjee, et al, "miscellaneous Chem ring "(J.Heterocycl.Chem.) 32 (1) :243-8, 1995), N-(α-amino acid) Methotrexate derivatives (Cheung other "pteridine" (Pteridines) 3 (1-2) :101-2, 1992), Biotin methotrexate derivatives (Fan and other "pteridine" (Pteridines) 3 (1-2) :131-2, 1992), D-glutamic acid or D-erythrou, threo -4 - fluoro-glutamic acid methotrexate analogues (McGuire and other "students Of chemical and pharmacology "(Biochem.Pharmacol.) 42 (12) :2400-3, 1991), β, γ-methylene Base methotrexate analogues (Rosowsky et al, "pteridine" (Pteridines) 2 (3) :133-9, 1991), 10 - deaza aminopterin (10-EDAM) analogues (Braakhuis et al, "pteridine Biochemistry - Butterfly International Symposium pyridine class of folic acid derivatives "(Chem.Biol.Pteridines, Proc.Int.Symp. Pteridines Folic Acid Deriv.) ,1027-30, 1989), γ-tetrazole analogs methotrexate (Kalman and other "pteridine Biochemistry - pteridine folic acid derivatives of the International Symposium" (Chem.Biol.Pteridines, Proc.Int.Symp.Pteridines Folic Acid Deriv.), 1154-7,1989), N-(L-α-amino acid) methotrexate derivatives (Cheung et al, "heterocycle" (Heterocycles) 28 (2) :751-8, 1989), aminopterin meta and ortho isomers (Rosowsky Et al, "Journal of Medicinal Chemistry" (J.Med.Chem.) 32 (12): 2582,1989), methotrexate hydroxymethyl Methotrexate (DE 267495), γ-fluoro methotrexate (McGuire et al, "Cancer Research" (Cancer Res.) 49 (16) :4517-25, 1989), poly-glutamyl methotrexate derivatives (Kumar and other "Cancer Research" (Cancer Res.) 46 (10) :5020-3, 1986), KAI - diphosphonate methotrexate analogues (WO 88/06158), α-and γ-substituted methotrexate analogues (Tsushima and other "tetrahedral" (Tetrahedron) 44 (17) :5375-87, 1988), 5 - methyl-5 - deaza analogs methotrexate (4,725,687), N δ-acyl-Nα-(4 - amino-4 - deoxy butterfly acyl)-L-ornithine derivatives (Rosowsky other "Journal of Medicinal Chemistry" (J.Med.Chem.) 31 (7) :1332-7, 1988), 8 - Deaza methotrexate analogues (Kuehl and other "Cancer Research" (Cancer Res.) 48 (6): 1481-8,1988), acivicin methotrexate analogues (Rosowsky other "Journal of Medicinal Chemistry" (J. Med.Chem.) 30 (8) :1463-9, 1987), polymerization cisplatin methotrexate derivatives (Carraher other "poly Compound Technology "(Polym.Sci.Technol.) (Plenum), 35 (Adv.Biomed.Polym.): 311-24,1987), methotrexate-γ-dimyristoyl phosphatidyl ethanolamine (Kinsky et al, "Biological Journal of Chemical and Biological Physics "(Biochim.Biophys.Acta) 917 (2) :211-18, 1987), Methotrexate polyglutamate analogues (Rosowsky etc., Chem.Biol.Pteridines, Pteridines Folic Acid Deriv., Proc.Int.Symp.Pteridines Folic Acid Deriv.: Chem., Biol. Clin.Aspects :985-8, 1986), poly-γ-glutamyl methotrexate derivatives (Kisliuk so Chem. Biol.Pteridines, Pteridines Folic Acid Deriv., Proc.Int.Symp.Pteridines Folic Acid Deriv.: Chem., Biol.Clin.Aspects :989-92, 1986), deoxy-uridine monophosphate Methotrexate derivatives (Webber, etc., Chem.Biol.Pteridines, Pteridines Folic Acid Deriv., Proc.Int.Symp.Pteridines Folic Acid Deriv.: Chem., Biol.Clin. Aspects :659-62, 1986), iodoacetyl lysine methotrexate analogue (Delcamp etc., Chem. Biol.Pteridines, Pteridines Folic Acid Deriv., Proc.Int.Symp.Pteridines Folic Acid Deriv.: Chem., Biol.Clin.Aspects :: 807-9,1986), containing 2ω-diamino alkanes Acid (alkanoid acid) methotrexate analogues (McGuire and other "Biochemistry and Pharmacology" (Biochem.Pharmacol.) 35 (15) :2607-13, 1986), similar methotrexate polyglutamate Matter (Kamen & Winick, "Methods in Enzymology" (Methods Enzymol.) 122 (Vitam.Coenzymes, Pt.G) :339-46, 1986), 5 - methyl-5 - deaza analogues (Piper other "Journal of Medicinal Chemistry" (J. Med.Chem.29 (6) :1080-7, 1986), quinazoline methotrexate analogue (Mastropaolo etc. J.Med.Chem.29 (1) :155-8, 1986), pyrazine methotrexate analogue (Lever & Vestal, "miscellaneous Chem ring "(J.Heterocycl.Chem.22 (1) :5-6, 1985), cysteic acid and homocysteine ​​methyl Acid methotrexate analogues (4,490,529), γ-tert-butyl esters of methotrexate (Rosowsky other "drugs Journal of chemical "(J.Med.Chem.) 28 (5) :660-7, 1985), fluorinated methotrexate analogues (Tsushima et al, "heterocyclic" (Heterocycles) 23 (1) :45-9, 1985), folate methotrexate Purine analogs (Trombe, "J. Bacteriol" (J.Bacteriol.) 160 (3) :849-53, 1984), phosphine Acyl glutamic acid analogues (Sturtz & Guillamot, "European Journal of Medicinal Chemistry - chemotherapy" (Eur.J. Med.Chem. - Chim. Ther.) 19 (3) :267-73, 1984), poly (L-lysine) methotrexate conjugate Substance (Rosowsky other "Journal of Medicinal Chemistry" (J.Med.Chem.) 27 (7) :888-93, 1984), two Lysine and three lysine methotrexate derivatives (Forsch & Rosowsky, "Journal of Organic Chemistry" (J.Org.Chem.) 49 (7) :1305-9, 1984), 7 - hydroxy methotrexate (Fabre other "Cancer Research" (Cancer Res.) 43 (10) :4648-52, 1983), poly-γ-glutamyl methotrexate analogues (Piper & Montgomery, "Advances in experimental biologic drugs" (Adv.Exp.Med.Biol.,) 163 (Folyl Antifolyl Polyglutamates) :95-100, 1983), 3 ', 5'-dichloro-methotrexate (Rosowsky & Yu, "Journal of Medicinal Chemistry" (J.Med.Chem.) 26 (10) :1448-52, 1983), diazo ketones and chlorine Methyl ketone methotrexate analogues (Gangjee other "Journal of Pharmaceutical Sciences" (J.Pharm.Sci.) 71 (6): 717-19,1982) 10 - propargyl aminopterin and alkyl methotrexate homologs (Piper and other "drugs of Journal "(J.Med.Chem.25 (7) :877-80, 1982), lectin derivatives of methotrexate (Lin Etc. JNCI 66 (3) :523-8, 1981), methotrexate polyglutamate derivatives (Galivan, "Molecular Pharmacology "(Mol.Pharmacol.) 17 (1) :105-10, 1980), methotrexate halogenated derivatives (Fox, JNCI 58 (4): J955-8, 1977), 8 - alkyl -7,8 - dihydro analogues (Chaykovsky et al, "Drug Journal of Chemistry "(J.Med.Chem.) 20 (10): J1323-7, 1977), 7 - methyl methotrexate derivatives And dichloro-methotrexate (Rosowsky & Chen, "Journal of Medicinal Chemistry" (J.Med.Chem.) 17 (12): J1308-11, 1974), lipophilic methotrexate derivatives and 3 ', 5'-dichloro-methotrexate (Rosowsky, "Journal of Medicinal Chemistry" (J.Med.Chem.) 16 (10): J1190-3, 1973), nitrogen Miscellaneous methotrexate analogues (Montgomery and other "New York Academy Yearbook" (Ann.NYAcad. Sci.) 186: J227-34, 1971), MX068 ("Japan Drugs" (Pharma Japan), 1658: 18,1999) and cysteic acid and high-cysteic acid methotrexate analogues (EPA0142220); ...

Think that these chemical compounds play the antimetabolite of folic acid.

D. Podophyllotoxin

In one aspect of the method, therapeutic agent is podophyllotoxin or derivatives thereof or analog.Such typical compound is etoposide or teniposide, and they have following structure:

The representational example of other of podophyllotoxin comprises Cu (II)-VP-16 (etoposide) complex, and (Tawa etc. " bioorganic pesticide thing chemistry " (Bioorg.Med.Chem.) 6 (7): 1003-1008,1998), etoposide analog (the Ji etc. that contain pyrroles's amidino, " bioorganic chemistry communication " (Bioorg.Med.Chem.Lett.) 7 (5): 607-612,1997), 4 beta-amino etoposide analog (Hu, University of North Carolina Dissertation, 1992), (Zhou etc. " pharmaceutical chemistry magazine " (J.Med.Chem.) 37 (2): 287-92 for the fragrant amino etoposide analog of gamma lactone ring-modification, 1994), N-glucityl etoposide analog (Allevi etc., " tetrahedron communication " (Tetrahedron Lett.) 34 (45): 7313-16,1993), etoposide A-ring analogues (Kadow etc., " bioorganic pesticide thing chemistry communication " (Bioorg.Med.Chem.Lett.) 2 (1): 17-22,1992), 4 '-dehydroxylation-4 '-methyl etoposide (Saulnier etc., " bioorganic pesticide thing chemistry communication " (Bioorg.Med.Chem.Lett.) 2 (10): 1213-18,1992), (Sinha etc. " European cancer magazine " (Eur.J.Cancer) 26 (5): 590-3 for pendular ring (pendulum ring) etoposide analog, 1990) and E-ring deoxidation etoposide analog (Saulnier etc. " pharmaceutical chemistry magazine " (J.Med.Chem.) 32 (7): 1418-20,1989).

Think that these chemical compounds play topoisomerase II inhibitor and/or dna cleavage agent.

E. Camptothecine

In one aspect of the method, therapeutic agent is camptothecine or its analog or derivant.Camptothecine has following general structure.

In this structure, X typically is O, but can be other group, for example, and the NH on the 21-lactam derivatives in the situation.R ₁Typically be H or OH, but can be other group, for example C of terminal hydroxylization _1-3Alkane.R ₂Typically be H or contain amino group, such as (CH ₃) ₂NHCH ₂, but can be other group, for example NO ₂, NH ₂, halogen (for example United States Patent (USP) 5,552,156 in disclosed) or contain the short alkane of these groups.R ₃Typically be H or short alkyl, such as C ₂H ₅R ₄Typically be H, but can be other group, for example have R ₁Methylene-dioxy.

Typical Comptothecin compounds comprises hycamtin, irinotecan (CPT-11), 9-aminocamptothecin, 21-lactams-20 (S)-camptothecine, 10,11-methylene-dioxy camptothecine, SN-38,9-nitrocamptothecin, 10-hydroxycamptothecine.Exemplary compounds has following structure:

R ₁ R ₂ R ₃

Camptothecine: H H H

Hycamtin: OH (CH ₃) ₂NHCH ₂H

SN-38： OH H C ₂H ₅

X: for most of analog is O, is NH for the 21-lactams

Camptothecine has 5 rings shown in this article.The ring that is labeled as E must be complete (lactone but not carboxylate form) so that maximum activity and minimum toxicity are arranged.

Think that camptothecine plays topoisomerase I inhibitor and/or dna cleavage agent.

F. The hydroxyl ureas

Therapeutic agent of the present invention can be hydroxyurea.The hydroxyl ureas has following general structure:

Suitable hydroxyl ureas for example is disclosed in United States Patent (USP) 6,080, in 874, and R wherein ₁For:

And R ₂Be alkyl and the R that contains 1-4 carbon ₃For one of H, acyl group, methyl, ethyl and admixture thereof, such as methyl ether.

Other suitable hydroxyl ureas for example is disclosed in United States Patent (USP) 5,665,768, in, R wherein ₁Be cycloalkenyl, for example N-[3-[5-(4-fluorobenzene sulfenyl)-furyl]-2-cyclopentenes-1-yl] the N-hydroxyurea; R ₂For H or contain the alkyl and the R of 1-4 carbon ₃Be H; X is H or cation.

Other suitable hydroxyl ureas is disclosed in, and for example United States Patent (USP) 4,299, in 778, and R wherein ₁Be the phenyl that is replaced by one or more fluorine atoms; R ₂Be cyclopropyl; And R ₃With X be H.

Other suitable hydroxyl ureas is disclosed in, and for example United States Patent (USP) 5,066, in 658, and R wherein ₂And R ₃Form with adjacent nitrogen:

Wherein m is 1 or 2, and n is that 0-2 and Y are alkyl.

In one aspect, described hydroxyurea has following structure:

The hydroxyl urea

Think that these chemical compounds work by inhibition DNA is synthetic.

G. Platinum complexes

In one aspect of the method, therapeutic agent is a platinum compounds.In general, suitable platinum complexes can be the complex of Pt (II) or Pt (IV), and contains following this basic structure:

Wherein X and Y are the anion leaving group, such as sulfate, phosphate, carboxylate and halogen; R ₁And R ₂For can further arbitrarily substituted alkyl, amine, aminoalkyl, and be essentially the group of inertia or bridging.With regard to Pt (II) complex, Z ₁And Z ₂All do not exist.With regard to Pt (IV), Z ₁And Z ₂Can be anionic group, such as halogen, hydroxyl, carboxylate, ester, sulfate or phosphate.For example, referring to United States Patent (USP) 4,588,831 and 4,250,189.

Suitable platinum complexes can contain a plurality of Pt atoms.For example, referring to United States Patent (USP) 5,409,915 and 5,380,897.For example two platinum of following type and three platinum complexes:

Typical platinum compounds is cisplatin, carboplatin, oxaliplatin and the miboplatin with following structure:

The cisplatin carboplatin

The oxaliplatin miboplatin

Other representational platinum compounds comprises (CPA) ₂Pt[DOLYM] and (DACH) Pt[DOLYM] cisplatin (Choi etc. " drug research archives " (Arch.Pharmacal Res.) 22 (2): 151-156,1999), cis-[PtCl ₂(4,7-H-5-methyl-7-oxo) 1,2,4-[triazol [1,5-a] pyrimidine] ₂] (Navarro etc. " pharmaceutical chemistry magazine " (J.Med.Chem.) 41 (3): 332-338,1998), [Pt (cis-1,4-DACH) (trans-Cl ₂) (CBDCA)] (Shamsuddin etc. " inorganic chemistry " (Inorg.Chem.) 36 (25): 5969-5971 for the 1/2MeOH cisplatin, 1997), 4-Pvridoxic Acid ester diamidogen hydroxyl platinum (pyridoxate diammine hydroxy platinum) (Tokunaga etc. " pharmaceutical science " (Pharm.Sci.) 3 (7): 353-356,1997), Pt (II) ... Pt (II) (Pt ₂[NHCHN (C (CH ₂) (CH ₃))] ₄) (Navarro etc. " inorganic chemistry " (Inorg.Chem.) 35 (26): 7829-7835,1996), 254-S cisplatin analog (Koga etc. " neurological's research " (Neurol.Res.) 18 (3): 244-247,1996), contain cisplatin analog (the Koeckerbauer ﹠amp of o-phenylenediamine part; Bednarski, " inorganic biochemistry magazine " (J.Inorg.Biochem.) 62 (4): 281-298,1996), trans, cis-[Pt (OAc) ₂I ₂(alkene)] (Kratochwil etc. " pharmaceutical chemistry magazine " (J.Med.Chem.) 39 (13): 2499-2507,1996), contain estrogen 1, (Bednarski " inorganic biochemistry magazine " (J.Inorg.Biochem.) 62 (1): 75 for the cisplatin analog of 2-diaryl ethylenediamine part (aminoacid and the glutathion that have sulfur-bearing), 1996), cis-1,4-diamino-cyclohexane cisplatin analog (Shamsuddin etc. " inorganic biochemistry magazine " (J.Inorg.Biochem.) 61 (4): 291-301,1996), cis-[Pt (NH ₃) (4-amino TEMP-O) { d (GpG) }] and 5 ' orientation isomer (Dunham ﹠amp; Lippard " Journal of the American Chemical Society " (J.Am.Chem.Soc.) 117 (43): 10702-12,1995), contain cisplatin analog (the Koeckerbauer ﹠amp of chelating diamidogen; Bednarski, " pharmaceutical science magazine " (J.Pharm.Sci.) 84 (7): 819-23,1995), contain 1, the cisplatin analog of 2-diaryl ethylenediamine part (Otto etc. " cancer research and Journal of Clinical Oncology " (J.Cancer Res.Clin.Oncol.121 (1): 31-8,1995), (ethylenediamine) platinum (II) complex (Pasini etc., J.Chem.Soc., Dalton Trans.4:579-85,1995), (Yang etc. " international oncology's magazine " (Int.J.Oncol.) 5 (3): 597-602 for CI-973 cisplatin analog, 1994), cis-diaminedichloroplatinum (II) and analog cis-1 thereof, 1-Cyclobutylcarboxylic acid (2R)-2-methyl isophthalic acid, 4-butanediamine platinum (II) and cis-diamidogen (glycolic acid) platinum (Claycamp ﹠amp; Zimbrick " inorganic biochemistry magazine " (J.Inorg.Biochem.) 26 (4): 257-67,1986; Fan etc. " cancer research " (Cancer Res.) 48 (11): 3135-9,1988; Heiger-Bernays etc., " biochemistry " (Biochemistry) 29 (36): 8461-6,1990; Kikkawa etc., " clinical experiment cancer research magazine " (J.Exp.Clin.Cancer Res.) 12 (4): 233-40,1993; Murray etc., " biochemistry " (Biochemistry) 31 (47): 11812-17,1992; Takahashi etc.; " cancer chemotherapy pharmacology " (Cancer Chemother.Pharmacol.) 33 (1): 31-5; 1993); (Yoshida etc. " biochemistry pharmacology " (Biochem.Pharmacol.) 48 (4): 793-9 for cis-amine-cyclohexylamine-dichloro platinum (II); 1994); together with-bisphosphonates cisplatin analog (FR 2683529); (meso-1; 2-two (2; 6-two chloro-4-hydroxy phenyls) dichloro platinum (II) (Bednarski etc. ethylenediamine); " pharmaceutical chemistry magazine " (J.Med.Chem.) 35 (23): 4479-85; 1992); (Hartwig etc. " Journal of the American Chemical Society " (J.Am.Chem.Soc.) 114 (21): 8292-3 to contain the cisplatin analog of tethered dansyl base; 1992); platinum (II) polyamines class (Siegmann etc.; Inorg.Met.-Containing Polym.Mater.; (Proc.Am.Chem.Soc.Iht.Symp.); 335-61; 1990); dichloro (ethylenediamine) platinum (the II) (Eastman of cis-(3H); " biochemistry yearbook " (Anal.Biochem.) 197 (2): 311-15,1991); trans-diaminedichloroplatinum (II) and cis-(Pt (NH ₃) ₂(N ₃-cytosine) (Bellon ﹠amp Cl); Lippard, " biophysics and chemistry " be 35 (2-3): 179-88 (Biophys.Chem.), 1990), 3H-cis-1,2-diamino-cyclohexane dichloro platinum (II) and 3H-cis-1,2-diamino-cyclohexane-malonic acid platinum (II) (Oswald etc., " chemistry, pathology and pharmaceutical research communication " (Res.Commun.Chem.Pathol.Pharmacol.) 64 (1): 41-58,1989), diamino monocarboxylic acid platinum (EPA296321), contain trans-(D, 1)-1, platinum analogs (the Wyrick ﹠amp of 2-diamino-cyclohexane carrier ligand; Chaney, " labelled compound and with radiopharmaceutical magazine " (J.Labelled Compd.Radiopharm.) 25 (4): 349-57,1988), amino alkylamino anthraquinone-deutero-cisplatin analog (Kitov etc., " European pharmaceutical chemistry magazine " (Eur.J.Med.Chem.) 23 (4): 381-3,1988), spiroplatin, carboplatin, iproplatin and JM40 platinum analogs (Schroyen etc. " European clinical cancer oncology magazine " (Eur.J.Cancer Clin.Oncol.) 24 (8): 1309-12,1988), the cis-platinum derivative (Orbell etc. " Chinese Journal of Inorganic Chemistry " (Inorg.Chim.Acta) 152 (2): 125-34,1988) that contains the bidentate tertiary diamine, platinum (II), platinum (IV) (Liu ﹠amp; Wang, " Shandong Medical University's journal " (Shandong Yike DaxueXuebao) 24 (1): 35-41,1986), cis-diamidogen (1, the 1-cyclobutane dicarboxylic acid-) platinum (II) (carboplatin, JM8) and (JM40) (Begg etc. of ethylenediamine-malonic acid platinum (II), " tumor radiotherapy " (Radiother.Oncol.) 9 (2): 157-65,1987), JM8 and JM9 cisplatin analog (Harstrick etc., Int.J.Androl.10 (1); 139-45,1987), (NPr4) 2 ((PtCL4). cis-(PtCl2-(NH2Me) 2)) (Brammer etc., " chemical association and chemical communication magazine " (J.Chem.Soc., Chem.Commun.) 6:443-5,1987), aliphatic tricarboxylic acids platinum complexes (EPA 185225) and cis-dichloro (aminoacid) (tert-butylamine) platinum (II) complex (Pasini ﹠amp; Bersanetti, " Chinese Journal of Inorganic Chemistry " (Inorg.Chim.Acta) 107 (4): 259-67,1985).Think that these chemical compounds by working in conjunction with DNA, promptly play the alkylating agent of DNA.

When making the medical implant of various structures and size, definite dosage changes with the different of part of size, surface area and the design of device and applied implant.Yet some principle can be applied in the application of this area.With medication dose calculation is the function of the dosage on the per unit area device of the coating (part), can determine total dosage and can measure the surface concentration of suitable active medicine.Should under following administration guideline, give the preferred anticarcinogen/anti-infective of use separately or coupling, and with medicinal application is irrelevant in the method for medical implant.

(a) anthracycline. the doxorubicin in the anthracycline is used as example, no matter be as the polymer coating coating, sneak into the polymer that constitutes implant, or do not use polymer support to use, the accumulated dose that is coated on the doxorubicin on the implant should not surpass 25mg (in the scope of 0.1 μ g-25mg).In particularly preferred embodiments, the coated drug total amount should be in 1 μ g-5mg scope.Dosage on the per unit area (medication amount of the function of the surface area of the implant part that promptly is coated with and/or sneaks into as medicine) should be at 0.01 μ g-100 μ g/mm ²The scope of surface area.In particularly preferred embodiments, should be with 0.1 μ g/mm ²-10 μ g/mm ²Dosage doxorubicin is coated on implant surface.When different polymer and non-polymer coating discharge doxorubicin with different rates, above-mentioned administration parameter should be used in combination with the rate of release of medicine from implant surface, so that keep 10 on described surface ^-7-10 ^-4The doxorubicin least concentration of M.Must guarantee that lip-deep drug level surpasses known multiple bacterioid and the lethal doxorubicin concentration of fungus of making and (promptly surpasses 10 ^-4M; But, with regard in some embodiment, lower concentration is just enough).In preferred embodiments, doxorubicin discharges so that anti-infection activity is kept several hours time limits to some months from implant surface.In particularly preferred embodiments, medicine discharges with valid density in month time limit in 1 week-6.Obviously should find out easily that from discussion provided herein analog and derivant (as mentioned above) with the active doxorubicin of identity function can be used for purpose of the present invention; The relative potency of comparing with parent compound according to analog or derivant is adjusted above-mentioned administration parameter (for example double the chemical compound of doxorubicin effect with half of above-mentioned parameter, to give effect be half chemical compound etc. of doxorubicin to double above-mentioned parameter) then.

With mitoxantrone another example as anthracycline, no matter be as the polymer coating coating, sneak into the polymer that constitutes implant, or do not use the polymer support coating, the accumulated dose of the mitoxantrone of coating should not surpass 5mg (in the scope of 0.01 μ g-5mg).In particularly preferred embodiments, the coated drug total amount should be in 0.1 μ g-1mg scope.Dosage on the per unit area (medication amount of the function of the surface area of the implant part that promptly is coated with and/or sneaks into as medicine) should be at 0.01 μ g-20 μ g/mm ²The scope of surface area.In particularly preferred embodiments, should be with 0.05 μ g/mm ²-3 μ g/mm ²Dosage mitoxantrone is coated on implant surface.When different polymer and non-polymer coating discharge mitoxantrone with different rates, above-mentioned administration parameter should be used in combination with the rate of release of medicine from implant surface, so that keep 10 ^-5-10 ^-6The mitoxantrone least concentration of M.Must guarantee that the drug level on the implant surface surpasses known multiple bacterioid and the lethal mitoxantrone concentration of fungus of making (promptly above 10 ^-5M; But, with regard in some embodiment, lower concentration is just enough).In preferred embodiments, mitoxantrone discharges so that anti-infection activity is kept several hours time limits to some months from implant surface.In particularly preferred embodiments, medicine discharges with valid density in month time limit in 1 week-6.Obviously should find out easily that from discussion provided herein analog and derivant (as mentioned above) with the active mitoxantrone of identity function can be used for purpose of the present invention; The relative potency of comparing with parent compound according to analog or derivant is adjusted above-mentioned administration parameter (for example double the chemical compound of mitoxantrone effect with half of above-mentioned parameter, to give effect be half chemical compound etc. of mitoxantrone to double above-mentioned parameter) then.

(b) fluorine pyrimidine. the 5-fluorouracil in the fluorine pyrimidine is used as example, no matter be as the polymer coating coating, sneak into the polymer that constitutes implant, or do not use the polymer support coating, the accumulated dose of the 5-fluorouracil of coating should not surpass 250mg (in the scope of 1.0 μ g-250mg).In particularly preferred embodiments, the coated drug total amount should be in 10 μ g-25mg scope.The dosage of per unit area (medication amount of the function of the surface area of the implant part that promptly is coated with and/or sneaks into as medicine) should be at 0.1 μ g-1mg/mm ²The scope of surface area.In particularly preferred embodiments, should be with 1.0 μ g/mm ²-50 μ g/mm ²Dosage 5-fluorouracil is coated on implant surface.When different polymer and non-polymer coating discharge 5-fluorouracil with different rates, above-mentioned administration parameter should be used in combination with the rate of release of medicine from implant surface, so that keep 10 at implant surface ^-4-10 ^-7The 5-fluorouracil least concentration of M.Must guarantee that lip-deep drug level surpasses known multiple bacterioid and the lethal 5-fluorouracil concentration of fungus of making and (promptly surpasses 10 ^-4M; But, with regard in some embodiment, lower concentration is just enough).In preferred embodiments, 5-fluorouracil discharges so that anti-infection activity is kept several hours time limits to some months from implant surface.In particularly preferred embodiments, medicine discharges with valid density in month time limit in 1 week-6.Obviously should find out that from discussion provided herein analog and derivant (as mentioned above) with the active 5-fluorouracil of identity function can be used for purpose of the present invention; The relative potency of comparing with parent compound according to analog or derivant is adjusted above-mentioned administration parameter (for example double the chemical compound of 5-fluorouracil effect with half of above-mentioned parameter, to give effect be half chemical compound etc. of 5-fluorouracil to double above-mentioned parameter) then.

(c) podophyllotoxin. the etoposide in the podophyllotoxin is used as example, no matter be as the polymer coating coating, sneak into the polymer that constitutes the heart implant, or do not use the polymer support coating, the accumulated dose of the etoposide of coating should not surpass 25mg (in the scope of 0.1 μ g-25mg).In particularly preferred embodiments, the coated drug total amount should be in 1 μ g-5mg scope.Dosage on the per unit area (medication amount of the function of the surface area of the implant part that promptly is coated with and/or sneaks into as medicine) should be at 0.01 μ g-100 μ g/mm ²The scope of surface area.In particularly preferred embodiments, should be with 0.1 μ g/mm ²-10 μ g/mm ²Dosage etoposide is coated on implant surface.When different polymer and non-polymer coating discharge etoposide with different rates, above-mentioned administration parameter should be used in combination with the rate of release of medicine from implant surface, so that keep 10 ^-5-10 ^-6The etoposide least concentration of M.Must guarantee that surface drug concentration surpasses known multiple bacterioid and the lethal etoposide concentration of fungus of making and (promptly surpasses 10 ^-5M; But, with regard in some embodiment, lower concentration is just enough).In preferred embodiments, etoposide discharges so that anti-infection activity is kept several hours time limits to some months from implant surface.In particularly preferred embodiments, medicine discharges with valid density in month time limit in 1 week-6.Obviously should find out that from discussion provided herein analog and derivant (as mentioned above) with the active etoposide of identity function can be used for purpose of the present invention; The relative potency of comparing with parent compound according to analog or derivant is adjusted above-mentioned administration parameter (for example double the chemical compound of etoposide effect with half of above-mentioned parameter, to give effect be half chemical compound etc. of etoposide to double above-mentioned parameter) then.

(d) conjoint therapy. should find out obviously that based on content of the discussions provided herein (for example the combination of methotrexate and/or podophyllotoxin (for example etoposide) can be used to improve the antibacterial activity of implant coating for anthracyclines (for example doxorubicin or mitoxantrone), fluorine pyrimidine (for example 5-fluorouracil), antifol.Similarly, anthracycline (for example doxorubicin or mitoxantrone), fluorine pyrimidine (for example 5-fluorouracil), antifol (for example methotrexate and/or podophyllotoxin (for example etoposide) can with the antibiotic of routine and/or antifungal agent coupling to improve effect.Anti-infective can also with antithrombotic drug and/or antiplatelet drug (heparin for example, dextran sulfate sodium, danaparoid, lepirudin, hirudin, AMP, adenosine, 2-chlorine adenosine, aspirin, Phenylbutazone, indomethacin, the meclofenamic acid ester, hydrochloroquine, dipyridamole, ciloprost, ticlopidine, clopidogrel, abciximab (abcixamab), eptifibatide, tirofiban, streptokinase and/or tissue plasminogen activator) coupling to be to improve effect.

C. Generation comprises or discharges the method for the medical apparatus of fibre modification derivant

In practice of the present invention, the medicine coating is provided, medicine floods or comprises the implant and the medical apparatus of medicine, and it induces adhesion or fibre modification in organizing around, or promotes " grappling " in position of described device/implant, thereby increases effect.In various embodiments, part by being positioned the contiguous specificity medicament of described device or implant or whole body discharge induces fibre modification.Exist many obtainable methods to optimize the fibre modification derivant to intervening sending of site, and be described below some of them.

1) comprises or discharges the device and the implant of fibre modification derivant

Medical apparatus of the present invention or implant comprise and/or are adapted to discharge the reagent of inducing fibre modification or adhering to surrounding tissue.Medical apparatus or implant can be adapted to the fibre modification derivant sneaked into their structure by the following, be adapted to have the fibre modification derivant coating the surface and/or be adapted to discharge the fibre modification derivant: (a) directly invest described implant or device and (for example, medical implant sprayed in all or part of generation film or the coating of the interior or outer surface of described device by coming with medicine and/or carrier (polymerism or non-polymerization)-pharmaceutical composition by the compositions of will required fibre modification derivant or comprising the fibre modification derivant; By described implant being immersed medicine and/or carrier (polymerism or non-polymerization) thereby-drug solution is coated with all or part of of described device or implant; Or by with therapeutic agent covalently or non-covalently (for example, the mechanical attachment by knotting or use adhesive or heat treatment, static, ion, hydrogen bond or hydrophobic interaction) be attached to described device or implant surface); (b) by coming apparatus for coating or implant with material such as hydrogel, described hydrogel can absorb required fibre modification derivant or compositions; (c) by " line " is woven into medical implant or the device in (for example, by the polymer chain of inducing fibrotic material to form (for example, silk, collagen protein, EVA, PLA, polyurethane, polymeric pharmaceutical composition) or comprise and/or from described line, discharge the polymer of fibre modification derivant), described line is made up of the fibre modification derivant or by its coating; (d) by using the sleeve pipe that comprises the fibre modification derivant, sleeve pipe or mesh cover all or part of (that is, by fibre modification derivant such as silk, collagen protein, EVA of described device or implant, PLA, polyurethane or comprise the cover that the polymer composition of fibre modification derivant is formed); (e) make up described device or implant itself (for example, with polymer such as silk, collagen protein, EVA, PLA, polyurethane or the polymer composition that comprises the fibre modification derivant make up described device) with ideal reagent or compositions; (f) or, described device or implant are immersed in required the fibre modification derivant or compositions; (g) scratch on described device or implant all or part of (that is, producing ridge or impression) thus produce the stimulation of described tissue and finally cause fibre modification; (h) described device or implant is all or part of by inducing fibrotic metal alloy (for example, copper) to form; (i) make up all or part of of described device or implant itself from degradable or the nondegradable polymer that discharges one or more fibre modification derivants; (j) use the multiple medicines thing release medical apparatus system of specialization (to be described in U.S. Patent number .6,562,065; Application No. 2003/0199970 and 2003/0167085; With in PCT publication number WO 03/015664 and WO02/32347) send the fibre modification derivant alone or in combination.

On the one hand, can by with fiber (line) thus described device is modified on the surface that is attached to described device.Described fiber can be polymeric and/or can be by the material that fibrous tissue is formed, such as silk formation or by its coating.For example, described line can form from the silk suture material.The existence of described line can cause for outside cell and/or the extracellular substrate reaction of described device.Described line can be attached to described device by any one or the combination of using subsequently method, described method comprises the use adhesive, thermal weld, roll extrusion, parcel, braiding, knotting etc.Described line can be coated with material, and described material delays line material and the time that on every side tissue or blood contact, allow thus described device settled and not since polymer line have a caused problem relevant with thrombosis.The example that can be used to prepare the material of coating comprises gelatin, polyester (for example, PLGA, PLA, MePEG-PLGA, PLGA-PEG-PLGA, and admixture), lipid, fatty acid, sugar ester, the nucleic acid ester, polyanhydride, poe and PVA, described coating can be degraded or dissolve after implantation.Described coating can also comprise fibrous tissue and form agent and/or bioactivator, they can, the probability (for example, heparin, hydrophobic quaternary amine heparin complex etc.) of thrombosis incident in the middle of for example reducing.Except polymer line, can be coated with all or part of of described device with the polymer support that comprises the fibre modification derivant.

Described fiber (line) can also comprise by applying coating or the compositions that magnetic field is affected.For example, device such as stent graft can be aggregated thing line coating, and described polymer line is formed agent (for example, silk suture) coating by fibrous tissue,, comprise it or form from it.Thereby magnetic field can be applied on the applied device relative to each other to come thereby polymer fiber is positioned and arrange the surface area that increases the fiber that contacts with the Biomedia that stimulates fibre modification to react with the surface of described device.Use several different methods, can will have active component of magnetic force and polymer fiber to link together.For example, by magnetic force active substance such as magnetic iron ore was added to before the extruding polymer fiber magnetic force active substance is sneaked in the process of preparation fiber.Use, for example, adhesive or polymer coating can be applied to magnetic force active substance component on whole fiber or the part fiber.Described polymer fiber (or its part) can be heated or make it become plastic with solvent, then rolls in the magnetic force active component, thereby makes the magnetic force material give prominence to or be encapsulated into the surface of fiber at described fiber surface.

Described line (having or do not have the magnetic force component) can be attached to described device with various configurations, and described configuration can cause the outside covering partially or completely of described device.Described polymer line can be attached to the mid portion of the terminal of device or device, and described connection can be vertical, level or diagonal manner.

2) The whole body of fibre modification derivant, regionality and local delivery

Can obtain whole body, regionality and local delivery that multiple medicine delivery technique carries out therapeutic agent.The some of them technology can be near medical apparatus or implant, be suitable for obtaining the preferably fibre modification derivant of elevated levels, described technology comprises: (a) use drug delivery tube with fibre modification derivant part, (typically, drug delivery tube is by circulation under lonizing radiation instruct or directly be inserted into and move in the tissue up to reaching required anatomical location for tissue around described device or the implant of regionality or systemic delivery; Then, thus the reagent that fibrous tissue forms can be delivered to tissue around described device or the implant from discharge medicine with therapeutic dose from tube chamber with high local concentrations; (b) the medicine location technology is such as magnetic, and the medicine that ultrasound wave or MRI instruct is sent; (c) thus the chemical modification of design fibre modification induced drug or preparation to the absorption of impaired tissue (for example increases described reagent, thereby modifying described medicine or preparation comprises directly at the impaired or component of organization for the treatment of such as macrophage, neutrophil cell, smooth muscle cell, fibroblast, extracellular matrix components, the antibody of neovascularity tissue); (d) thus the chemical modification of design fibre modification induced drug or preparation makes medicine is positioned hemorrhage zone or ruined vascular system, such as with drug encapsulation in the liposome that navigates to the site; And/or the described fibre modification derivant of direct injection reagent, for example under endoscopic observation.

3) The fibre modification derivant is to the infiltration in the tissue around device or the implant

Perhaps, can be before implantation process, among or the tissue cavity that with the fibre modification derivant described device or implant settled afterwards handle.This can finish in some modes, described mode comprises that (a) forms agent with fibrous tissue and locally apply to that (what be particularly useful in this embodiment is the application of polymer support in the dissection gap that can settle described device, described carrier forms agent with fibrous tissue and discharges-fluid in the time range of a few hours to several weeks, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, solid implant and can be delivered to the zone that described device or implant can be inserted into discharging other preparation that fibrous tissue forms agent delivery catheter or other applicator by specialization); (b) microgranule silk and/or silk chain (for example, straight line, side chain, and/or curl) are being useful in the targeted delivery of implantation site also; (c) with the sprayable preparation that comprises collagen protein such as COSTASIS (Angiotech Pharmaceuticals, Inc., Vancouver, BC) or by 4-arm mercaptan PEG (10K), 4-arm NHS PEG (10K), the material made from methylated collagen protein (following described), or by 4-arm mercaptan PEG (10K), the material that 4-arm NHS PEG (10K) and collagen protein or gel are made, independent or loading is applied to implantation site (or described implant/apparatus surface) together with the fibre modification derivant; (d) preparation that comprises PEG such as COSEAL (the Angiotech Pharmaceuticals that sprayable original position is formed, Inc., Canada), FOCALSEAL (Genzyme Corporation, Cambridge, MA), SPRAYGEL or DURASEAL are (from Confluent Surgical, Inc., Waltham, MA) independent or loading is applied to implantation site (or described implant/apparatus surface) together with the fibre modification derivant; (e) will comprise preparation such as the FLOSEAL of factor I or TISSEAL (all from Baxter Healthcare Corporation; Fremont, CA), independent or loading is applied to implantation site (or described implant/apparatus surface) together with the fibre modification derivant; (f) comprise hyaluronic preparation (noncrosslinking, crosslinked or chemical modification) such as PERLANE or RESTYLANE (all from Q-Med AB, Sweden), HYLAFORM (Inamed Corporation; Santa Barbara, CA), SYNVISC (Biomatrix, Inc.; Ridgefied, NJ), SEPRAFILM or SEPRACOAT are (from Genzyme Corporation; Cambridge, MA), it loads to be applied to the fibre modification derivant of implantation site (or implant/apparatus surface); (g) be used for polymer gel such as REPEL (Life Medical Sciences, the Inc. that surgical operation is implanted; Princeton, NJ) or FLOWGEL (IL), it loads to be applied to the fibre modification derivant of implantation site (or implant/apparatus surface) for Baxter Healthcare Corporation, Deerfield; (h) be used for prosthese and tissue maintenance orthopedics's " cement " in place, it loads to be applied to the fibre modification derivant of implantation site (or described implant/apparatus surface), such as OSTEOBOND (Zimmer, Inc., Warsaw, IN), LVC (Wright Medical Technology, Inc., Arlington, TN), SIMPLEX P (Stryker Corporation, Kalamazoo, MI), PALACOS (Smith ﹠amp; Nephew PLCCorporation, United Kingdom), and ENDURANCE (Johnson ﹠amp; Johnson, Inc., New Brunswick, NJ); (i) (for example will comprise one or more cyanoacrylates, MCA, ethyl cyanoacrylate, butyl cyanoacrylate, octyl cyanoacrylate, methoxy-propyl cyanoacrylate) surgical operation adhesive is such as DERMABOND (Johnson﹠amp; Johnson, Inc.), INDERMIL (United States Surgical; Norwalk, CT), GLUSTITCH (Blacklock Medical Products, Inc., Canada) or TISSUMENDII (Veterinary Products Laboratories; Phoenix, AZ), VETBOND (3MCompany; St.Paul, MN), TISSUEMEND (TEI Biosciences, Inc.; Boston, MA), HISTOACRYL or HISTOACRYL BLUE (Davis ﹠amp; Geck; St.Louis is MO) with ORABASE SOOTHE-N-SEAL LIQUIDPROTECTANT (Colgate-Palmolive Company; New York; NY), independent or loading is applied to implantation site (or described implant/apparatus surface) together with the fibre modification derivant; (j) (or synthetic property bone material is such as calcium sulfate to comprise the implant of hydroxyapatite, VITOSS and CORTOSS (all from Orthovita, Inc., Malvern, PA)), it loads to be applied to the fibre modification derivant of implantation site (or described implant/apparatus surface); (k) loading is with the tissue filling agent of other biocompatibility of fibre modification derivant, such as by BioCure, Inc. (Norcross, GA), 3M Company and Neomend, Inc. (it loads to be applied to the fibre modification derivant of implantation site (or described implant/apparatus surface) for Sunnyvale, CA) those of Zhi Zuoing; (I) gel (Gliatech, the Inc. of polysaccharide gel such as ADCON series; Cleveland, OH); (m) film, sponge or mesh such as INTERCEED or VICRYL mesh (Ethicon, Inc., a Johnson ﹠amp; Johnson Company, Somerville, NJ), and GELFOAM (Pharmacia ﹠amp; Upjohn Company; Kalamazoo, MI), it loads to be applied to the fibre modification derivant of implantation site (or described implant/apparatus surface); (n) form Polyethylene Glycol (for example, 4-arm four-amino PEG) [10k] from aminofunctional) and the functionalized PEG (for example, tetramethylolmethane gathers (ethylene glycol) ether four-succinimido glutarate) of 4-arm NHS (10K)) hydrogel.This hydrogel can also comprise collagen protein, methylated collagen protein and/or gelatin.This hydrogel (for example can also comprise above-mentioned fibre modification derivant, silk powder or silk thread), (o) increase bone and integrate (osteointegration) and/or osteogenesis compositions, (for example comprise by the material of forming of β-tricalcium phosphate, VITOSS by E-Interpore-Cross International making, PROOSTEON 500R), hydroxyapatite or Ca ₁₀(PO ₄) ₆OH (for example, by Ceramed Denta, Inc., Lakewood, the OSTEOGRAF that CO makes), calcium carbonate or CaCO ₃, calcium sulfate (for example, by Wright Medical Technology, OSTEOSET and ALLOMATRIX that Inc. makes), calcium phosphate is (for example by Merck ﹠amp; Co., Inc., Whitehouse Station, NJ, the CALCIBON of manufacturing and by Synthes-Strates, the NORIANSRS that Switzerland makes), and synthetic bone filler (for example, the bone filler of CORTOSS and processing is for example by Geistlich Biomaterials, Inc., the BIOOSS of Switzerland manufacturing).The representative example of these materials is described in U.S. Patent number 3,929,971,4,861,733; 6,527,810; 4,772,468; 4,882,149; 5,167,961; 6,576,015; 4,839,215; 5,614,206; 5,807,567; 6,030,636; 6,652,887; 6,206,957; 6,485,754; 4,347,234; 4,291,013; 5,129,905; 5,336,264; 5,569,442; 5,571,493; 5,683,667; 5,709,742; 5,820,632; 5,658,332; 5,681,872; 5,914,356; 5,939,039; 6,325,987; 6,383,519; 6,458,162; 6,736,799; 6,521,246; With 6,709,744.

On the one hand, described fibre modification derivant can be used as solution and sends.Described fibre modification derivant directly can be sneaked in the solution to provide all with solution or dispersion.In certain embodiments, described solution is aqueous solution.Described aqueous solution can also comprise buffer salt, and viscosity modifier (for example, hyaluronic acid, alginate, CMC etc.).In another aspect of the present invention, described solution can comprise biocompatible solvent, such as ethanol, and DMSO, glycerol, PEG-200, PEG-300 or NMP.

4) coating of the slow releasing preparation of fibre modification derivant

For many aforesaid embodiments, described fibre modification derivant can be sneaked into or is coated on the described device.For example, can mix required fibre modification derivant, fusion is puted together, thereby or modifies in addition and comprise polymer composition (it can be biodegradable or not biodegradable) or non-polymer compositions.Polymerization or non-polymer compositions (that is carrier) can be used to be coated with described device or as the component that is used for the material of preparation facilities.In other embodiments, the localized sustained of fibre modification derivant is sent may need.For example, can mix required fibre modification derivant, fusion is puted together, thereby or modifies in addition and comprise polymer composition (it can be biodegradable or not biodegradable) or non-polymer compositions to discharge described fibre modification derivant in the cycle at certain hour.For above-mentioned embodiment, can be with biodegradable and not biodegradable polymer, polymeric conjugates and non-polymeric material be used for finishing the fibre modification derivant on described device or combination.

The representational example of biodegradable compositions comprises albumin, collagen protein, gelatin, hyaluronic acid, starch, cellulose and cellulose derivative (methylcellulose for example, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose, Cellacefate, cellulose acetate succinate, Hydroxypropyl Methylcellulose Phathalate), casein, glucosan, polysaccharide, fibrinogen, poly-(ether-ether) segmented copolymer based on poly-(ethylene glycol) and poly-(terephthalic acids butene esters), (for example United States Patent (USP) 6 for tyrosine-derived polycarbonate-based, 120,491), poly-(hydroxy acid), poly-(D, the L-lactide), poly-(D, the L-lactide-co-glycolide), poly-(Acetic acid, hydroxy-, bimol. cyclic ester), poly-(butyric ester) Ju diethyleno dioxide ketone, poly-(alkyl carbonate) and poly-(ortho esters), polyesters, poly-(hydroxypentanoic acid) Ju diethyleno dioxide ketone, poly-(ethylene terephthalate), poly-(maleic acid), poly-(hydroxymalonic acid), poly-(acrylamide), polyanhydrides, poly-(ester-acid amide), poly-(ester-urea), poly-(ester-urethanes-urea), poly-(acid anhydride-ester), poly-(acid anhydride-imidodicarbonic diamide), group of polyphosphazenes, poly-(aminoacid), poly-(alkylene oxide)-poly-(ester) block copolymer (X-Y for example, X-Y-X or Y-X-Y, wherein X is a polyalkylene oxide, and Y is polyester (PLGA for example, PLA, PCL Ju diethyleno dioxide ketone and copolymer thereof) and copolymer and admixture.[generally referring to Illum, L., Davids, S.S. (eds.) " polymer in the medicine controlled releasing " (＂ Polymer in Controlled DrugDelivery ＂) Wright, Bristol, 1987; Arshady-" controlled release magazine " be 17:1-22 (J.ControlledRelease), and 1991; Pitt " International Journal of Pharmaceutical Medicine " is 59:173-196 (Int.J.Phar.), and 1990; Holland etc.-" controlled release magazine " (J.Controlled Release) 4:155-0180,1986].

That the representational example that is suitable for sending the nondegradable polymer of fibre modification derivant comprises is poly-(ethylene-altogether-vinylacetate) (＂ EVA ＂) copolymer, silicone rubber, acrylate copolymer [for example, polyacrylic acid, polymethylacrylic acid, polymethyl methacrylate, poly-(butyl methacrylate)], [for example gather (alkyl cyanoacrylate), poly-(ethyl cyanoacrylate), poly-(butyl cyanoacrylate), poly-(hexyl cyanoacrylate) and poly-(octyl cyanoacrylate)], polyethylene, polypropylene, polyamide-based (nylon 6,6), polyurethane (comprising hydrophilic polyurethane), poly-(ester-urethane), poly-(ether-urethane), poly-(ester-urea), polyethers [poly-(oxirane), poly-(propylene oxide), polyoxyalkylene ether sealing copolymer such as PLURONICs and PLURONICs R and poly-(butanediol) based on oxirane and propylene oxide, polymer (the polystyrene of styrene-based, poly-(styrene sulfonic acid), poly-(styrene)-block-poly-(isobutene .)-block-poly-(styrene), gather (styrene)-poly-(isoprene) block copolymer) and polyvinyl (polyvinylpyrrolidone, poly-(vinyl alcohol), poly-(vinylacetate phthalic acid ester) and copolymer and admixture.The polymer that is developed can also for anionic (for example alginate, carrageenan, carboxymethyl cellulose, poly-(acrylamido-2-methyl propane sulfonic acid) and copolymer thereof, poly-(methacrylic acid) and copolymer thereof and poly-(acrylic acid) and copolymer and admixture) or cationic (for example chitosan, poly-L-Lysine, polyaziridine and poly-(allyl amine)) and admixture thereof (generally referring to Dunn etc., " application polymer science magazine " (J.Applied Polymer Sci.) 50:353-365,1993; Cascone etc., " material science magazine: medicinal materials " (J.Materials Sci.:Materialsin Medicine) 5:770-774,1994; Shiraishi etc., " bio-pharmaceutical bulletin " (Biol.Pharm.Bull.) 16 (11): 1164-1168,1993; Thacharodi and Rao, " International Journal of Pharmaceutical Medicine " (Int ' l J.Pharm.) 120:115-118,1995; Miyazaki etc., " International Journal of Pharmaceutical Medicine " (Int ' l J.Pharm.) 118:257-263,1995).

Particularly preferred polymer support comprises poly-(ethylene-be total to-vinylacetate), cellulose esters (NC Nitroncellulose), poly-(methacrylic acid hydroxyl ester), poly-(methyl methacrylate), poly-(ethylene-altogether-acrylic acid), poly-(vinyl pyrrolidone), polyurethanes (for example, CHRONOFLEX AL and CHRONOFLEX AR are (from Cardio Tech International, Inc., Emeryville, CA) and BIONATE (polymer Technology Group, Inc., Emeryville, CA), poly-(D, L-lactic acid) oligomer and polymer, poly-(L-lactic acid) oligomer and polymer, poly-(glycolic), the copolymer of lactic acid and glycolic, poly-(caprolactone), poly-(valerolactone), polyanhydrides, poly-(acid anhydride ester), poly-(ester-acid amide), poly-(ester-urea), the copolymer of poly-(caprolactone) or poly-(lactic acid) and Polyethylene Glycol (for example MePEG), silicone rubber, poly-(styrene) block-poly-(isobutene .)-block-poly-(styrene), poly-(acrylate) polymer and admixture, the admixture of above-mentioned arbitrary substance or copolymer.Other preferred polymer comprises: collagen protein; Polymer based on poly-(alkylene oxide); Polysaccharide, such as the copolymer of hyaluronic acid, chitosan and fucosan and polysaccharide and degradable polymer, and above-mentioned cross-linked composition.

Other representational polymer that can continue local delivery fibre modification derivant comprises carboxylic acid polyalcohol, poly-acetate esters, polyacrylamide, polycarbonate-based, polyethers, the polyethylene kind that replaces, the polyvinyl butyral resin class, polysilanes, polyureas, the polyoxide class, polystyrene type, polysulfide, polysulfones, polysulfonides, the polyvinylhalide class, pyrrolidinone compounds, isoprene rubber, thermoset polymer, crosslinkable acrylic acid and methacrylate polymer, ethylene acrylic acid co polymer, styrene acrylic copolymer, vinyl acetic acid ester polymer and copolymer, vinyl acetal polymer and copolymer, epoxy, melamine, other amino resins, phenol polymer and copolymer thereof, the water-insoluble cellulose ester polymer (comprises cellulose-acetate propionate, cellulose acetate, NC Nitroncellulose, cellulose acetate-butyrate, celluloid, Cellacefate and admixture thereof), polyvinylpyrrolidone (pvp), polyethylene glycols, poly(ethylene oxide), polyvinyl alcohol, polyethers, acrylic polyol, glucosan, xanthan gum, hydroxypropyl cellulose, methylcellulose and N-vinyl pyrrolidone, the N-vinyl lactam, the N-vinyl butyrate lactam, the N-caprolactam, other has the homopolymer and the copolymer of the vinyl compound of polarity side group, the acrylate and the methacrylate that have hydrophilic esterification group, hydroxy acrylate and acrylic acid and combination thereof; The homopolymer of cellulose esters and ethers, ethyl cellulose, NC Nitroncellulose, hydroxyethyl-cellulose, celluloid, cellulose acetate, cellulose acetate-butyrate, cellulose-acetate propionate, polyacrylate, natural and synthetic elastomer, acetal, styrene polybutadiene, acrylic resin, polyvinylidene chloride, Merlon, vinyl compound and copolymer, polrvinyl chloride and polyvinyl chloroacetate (polyvinylchloride acetate).

The representational example of the patent relevant with release polymer and preparation thereof comprises: PCT publication number WO 98/19713, WO 01/17575, WO 01/41821, WO 01/41822 and WO01/15526 (and corresponding U. S. application); With United States Patent (USP) 4,500,676,4,582,865,4,629,623,4,636,524,4,713,448,4,795,741,4,913,743,5,069,899,5,099,013,5,128,326,5,143,724,5,153,174,5,246,698,5,266,563,5,399,351,5,525,348,5,800,412,5,837,226,5,942,555,5,997,517,6,007,833,6,071,447,6,090,995,6,106,473,6,110,483,6,121,027,6,156,345,6,214,901,6,368,611,6,630,155,6,528,080, RE37,950,6,46,1631,6,143,314,5,990,194,5,792,469,5,780,044,5,759,563,5,744,153,5,739,176,5,733,950,5,681,873,5,599,552,5,340,849,5,278,202,5,278,201,6,589,549,6,287,588,6,201,072,6,117,949,6,004,573,5,702,717,6,413,539 and 5,714,159,5,612,052; With Application No. 2003/0068377,2002/0192286,2002/0076441 and 2002/0090398.

Polymer as described herein can also be carried out fusion or copolymerizationization according to sending fibre modification inhibitor for treating dosage to the required difference composition of the blood vessel in treatment site, this should be conspicuous to those skilled in the art.

According to the device that uses, compositions or implant can be made the polymer support that is used for the fibre modification inhibitor various forms that has required release characteristics and/or have special properties.For example, the form that polymer support can be formed in contact certain trigger situation, can discharge the fibre modification derivant during such as pH (for example, referring to Heller etc. the medicine-releasing system of main regulation " chemically from " (＂ Chemically Self-Regulated Drug Delivery Systems ＂)-" polymer in the medicine " (Polymer in Medicine) III, Elsevier Science Publishers B.V., Amsterdam, 1988, pp.175-188; Kang etc., " application polymer science magazine " (J Applied PolymerSci.) 48:343-354,1993; Dong etc. " controlled release magazine " (J.Controlled Release) 19:171-178,1992; Dong and Hoffman, R Controlled Release.15:141-152,1991; Kim etc. " controlled release magazine " (J.Controlled Release) 28:143-152,1994; Cornejo-Bravo etc., " controlled release magazine " (J.Controlled Release) 33:223-229,1995; Wu and Lee " drug research " (Pharm.Res.) 10 (10): 1544-1547,1993; Serres etc. " drug research " (Pharm.Res.) 13 (2): 196-201,1996; Peppas " ultimate principle of pH-and thermal sensitivity delivery system " (＂ Fundamentals of pH-and Temperature-Sensitive DeliverySystems ＂)-(eds.) such as Gumy " beat and pass medicine " (Pulsatile Drug Delivery), Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1993, pp.41-55; Doelker " cellulose derivative " (＂ Cellulose derivatives ＂) 1993-at (Biopolymer) I of Peppas and Langer (eds.) " biopolymer ", Springer-Verlag, Berlin) in.The example of representational pH-sensitive polymer comprises: poly-(acrylic acid) and derivant thereof (comprise that homopolymer for example is such as poly-(amino carboxylic acid); Poly-(acrylic acid); Poly-(methacrylic acid); The copolymer of this class homopolymer; With poly-(acrylic acid) with such as the copolymer of aforesaid acryl monomer.Other pH sensitive polymer comprises: polysaccharide, such as Cellacefate; Hydroxypropyl Methylcellulose Phathalate; HPMC-AS; Acetic acid benzenetricarboxylic acid cellulose; And chitosan.Other pH sensitive polymer comprises any admixture of pH sensitive polymer and water-soluble polymer.

Equally, can (for example send the fibre modification derivant by the thermosensitive polymer carrier, referring to (Proceed.Intern.Symp.Control.Rel.Bioact.Mater.) 22:167-168 of Chen etc. " the new hydrogel that is used for the thermal sensitivity Pluronic vagina release and the grafting of biocementation powder and polypropylene acid main chain " (＂ Novel Hydrogels of a Temperature-Sensitive PluronicGrafted to a Bioadhesive Polyacrylic acid Backbone for Vaginal DrugDelivery ＂)-" inner seminar journal of control release biological active material ", Controlled Release Society, Inc., 1995; Okano " MOLECULE DESIGN that is used for the S-R hydrogel of temporary transient controlled release " (＂ Molecular Design of Stimuli-Responsive Hydrogels for Temporal ControlledDrug Delivery ＂)-" the inner seminar journal of control release biological active material " be 22:111-112 (Proceed.Intern.Symp.Control.Rel.Bioact.Mater.), Controlled Release Society, Inc., 1995; Johnston etc. " drug research " (Pharm.Res.) 9 (3): 425-433,1992; Tung " International Journal of Pharmaceutical Medicine " (Int ' l J.Pharm.) 107:85-90,1994; Harsh and Gehrke, " controlled release magazine " (J.Controlled Release) 17:175-186,1991; Bae etc. " drug research " (Pharm.Res.) 8 (4): 531-537,1991; Dinarvand and D ' Emanuele " controlled release magazine " be 36:221-227 (J.ControlledRelease), and 1995; Yu and Grainger " new thermal sensitivity amphiphilic gel: poly--the N-N-isopropylacrylamide-altogether-sodium acrylate-altogether-N-alkyl acrylamide network structure is synthesized and materialization characterizes ", (＂ Novel Thermo-sensitive Amphiphilic Gels:Poly-N-isopropylacrylamide-co-sodium acrylate-co-N-alkylacrylamideNetwork Synthesis and Physicochemical Characterization ＂)-" chemistry and bioscience development ", (Dept.ofChem ical ﹠amp; Biological Sci.), Oregon Graduate Institute ofScience ﹠amp; Technology, Beaverton, OR, pp.820-821; Zhou and Smid " physical hydrogel of association star polymer " (＂ Physical Hydrogels of Associative Starpolymer ＂), Polymer Research Institute-" chemical developer " (Dept.of Chemistry), College of Environmental Science and Forestry, State Univ.of New York, Syracuse, NY, pp.822-823; Hoffman etc. " irritant reaction hydrogel mesopore size and water ' structure ' sign " (＂ Characterizing Pore Sizes and Water ' Structure ' inStimuli-Responsive Hydrogels ＂), Center for Bioengineering, Univ.ofWashington, Seattle, WA, p.828; Yu and Grainger " the cancellated thermal sensitivity swelling character of crosslinked N-N-isopropylacrylamide: cation, anion and both sexes hydrogel " (＂ Thermo-sensitive Swelling Behavior in Crosslinked N-isopropylacrylamideNetworks:Cationic, Anionic and Ampholytic Hydrogels ＂)-" chemistry and bioscience development " (Dept.of Chemical ﹠amp; Biological Sci.), Oregon Graduate Institute ofScience ﹠amp; Technology, Beaverton, OR, pp.829-830; Kim etc. " drug research " (Pharm.Res.) 9 (3): 283-290,1992; Bae etc. (drug research) (Pharm.Res.) 8 (5): 624-628,1991; Kono etc. " controlled release magazine " (J.Controlled Release) 30:69-75,1994; Yoshida etc. " controlled release magazine " (J.Controlled Release) 32:971-102,1994; Okano etc. " controlled release magazine " (J.Controlled Release) 36:125-133,1995; Chun and Kim " controlled release magazine " (J.Controlled Release) 38:39-47,1996; D ' Emanuele and Dinarvand " International Journal of Pharmaceutical Medicine " (Int ' l J.Pharm.) 118:237-242,1995; Katono etc. " controlled release magazine " (J.Controlled Release) 16:215-228,1991; Hoffman " the hot reversible hydrogel that contains the bioactivator kind " (＂ Thermally Reversible Hydrogels Containing BiologicallyActive Species ＂)-(eds.) such as Migliaresi " polymer in the medicine " (Polymer inMedicine) III, Elsevier Science Publishers B.V., Amsterdam, 1988, pp.161-167; Hoffman " application in treatment and diagnosis of thermally reversible polymer and hydrogel " (＂ Applications of Thermally Reversible Polymer and Hydrogels inTherapeutics and Diagnostics ＂)-" international symposiums of the 3rd relevant medicine-releasing system latest developments " (Third International Symposium on Recent Advances in Drug DeliverySystems), Salt Lake City, UT, Feb.24-27,1987, pp.297-305; Gutowska etc. " controlled release magazine " (J.Controlled Release) 22:95-104,1992; Palasis and Gehrke " controlled release magazine " (J.Controlled Release) 18:1-12,1992; Paavola etc. " drug research " (Pharm.Res.12 (12): 1997-2002,1995).

The representational example of hot glue cohesion compound and gelation temperature thereof [LCST (℃)] comprising: homopolymer, such as poly-(N-methyl-N-n-propyl group acrylamide), 19.8; Poly-(N-n-propyl group acrylamide), 21.5; Poly-(N-methyl-N-isopropyl propyl group acrylamide), 22.3; Poly-(N-n-propyl methyl amide), 28.0; Poly-(N-N-isopropylacrylamide), 30.9; Poly-(N, n-diethyl acrylamide), 32.0; Poly-(N-isopropyl methyl acrylamide), 44.0; Poly-(N-cyclopropyl acrylamide), 45.5; Poly-(N-ethyl-methyl acrylamide), 50.0; Poly-(N-methyl-N-ethyl acrylamide), 56.0; Poly-(N-cyclopropyl Methacrylamide), 59.0; With poly-(N-ethyl acrylamide), 72.0.In addition; copolymer between above-mentioned by preparing (wherein) monomer or by with this class homopolymer and other water-soluble polymer, such as acryl monomer (for example acrylic acid and derivant thereof; such as methacrylic acid, acrylate and derivant thereof, such as butyl methacrylate, acrylamide and N-n-butyl acrylamide) merge and to prepare hot glue cohesion compound.

Other representational example of hot glue cohesion compound comprises: cellulose ether derivative, and such as hydroxypropyl cellulose, 41 ℃; Methylcellulose, 55 ℃; Hydroxypropyl emthylcellulose, 66 ℃; With poly(ethylene oxide)-polyester block copolymer of ethylhydroxyethylcellulose, structure X-Y, Y-X-Y and X-Y-X, wherein X is that poly(ethylene oxide) and Y are biodegradable polyester (for example PLG-PEG-PLG); With PLURONIC such as F-127,10-15 ℃; L-122,19 ℃; L-92,26 ℃; L-81,20 ℃; And L-61,24 ℃.

The representational example that relates to the patent of hot glue cohesion compound and preparation thereof comprises: U.S. Patent number 6,451,346; 6,201,072; 6,117,949; 6,004,573; 5,702,717; With 5,484,610; With PCT publication number WO 99/07343; WO 99/18142; WO 03/17972; WO01/82970; WO 00/18821; WO 97/15287; WO 01/41735; WO 00/00222; With WO 00/38651.

The fibre modification derivant can be connected in the substrate of described polymer by inaccessible (occlusion), and it can pass through covalent bonds, or is encapsulated in the microcapsule.In some preferred embodiment of the present invention, therapeutic combination is made non-capsule, such as line, film and the spray of microsphere (nanometer-micron size), paste, all size.

Aspect some, therapeutic combination can be made any size between the 50nm-500 μ m of the present invention, this depends on concrete application.These compositionss can be the form of microsphere (porous or imporosity), microgranule and/or nanoparticle.Can form these compositionss by spray drying method, polishing, coacervation, W/O (water/oil) emulsion process, W/O/W emulsion process and solvent evaporated method.In certain embodiments, these compositionss can comprise microemulsion, Emulsion, liposome and micelle.Alternatively, also be easy to this based composition is used as ＂ spray ＂, it can film-forming or organizes lining (line) as the coating of device/implant surface coating or to implant site.Can prepare this class spray by the microsphere of various grade sizes, comprise: for example 0.1 μ m-3 μ m, 10 μ m-30 μ m and 30 μ m-100 μ m.

Therapeutic combination of the present invention can also be prepared into various ＂ and stick with paste ＂ or gel form.For example, in one embodiment of the invention, be formed under a kind of temperature therapeutic combination for liquid (for example temperature is higher than 37 ℃, such as 40 ℃, 45 ℃, 50 ℃, 55 ℃ or 60 ℃) and be solid or semisolid (for example at environment body temperature or be lower than under 37 ℃ the arbitrary temp) under the another kind of temperature.Be easy to use various technology to prepare this class ＂ heat and stick with paste ＂ (for example referring to PCT publication number WO 98/24427).Other paste can be used as liquid, it is gone into aqueous body environment because of the water soluble ingredient stripping of paste and encapsulation drug precipitation in vivo and solidifies in vivo.These ＂ paste ＂ that contain the fibre modification derivant are particularly useful in ＂ gel ＂ and are coated on the tissue surface that can contact implant or device.

On the one hand, fibrous tissue forms agent or comprises the compositions that fibrous tissue forms agent and can or can exist with the form of film or mesh with film or mesh combination.

Film or mesh can be taked various ways, include, but not limited to the surgical operation mesh, film (for example, barrier film), surgical patch, surgical patches, the surgical operation parcel, binder, liquid binder, surgical operation dressing, gauze, fabric, band, surgical operation film, polymeric matrix, shell, tunicle, organize the surgical operation substrate of covering and other type, and support.

On the one hand, described device comprises or can exist with form membrane.Described film can be made one of many geometries.Depend on and use that described film can be made tubulose maybe can be the thin flexure strip of polymer.Film generally be lower than 5,4,3,2 or 1mm is thick, thick more preferably less than 0.75mm, 0.5mm, 0.25mm or 0.10mm.Can also produce the film of the thickness that is lower than 50 μ m, 25 μ m or 10 μ m.Film generally have pliability and good tensile (for example greater than 50, be preferably greater than 100 and more preferably greater than 150 or 200N/cm ²), good cohesive (promptly with moistening or moist surface adhesion) and have controlled permeability.Polymeric film (it can be a porous or non-porous) is used in particular for being coated on device or implant surface and tissue, chamber or organ surface.

Can make film by certain methods, or it can be in the original position formation of treatment site, described method comprises, for example by casting mold with by spraying.For example, sprayable preparation can be administered on the treatment site, it then forms solid film.

On the other hand, described device can comprise or exist with the mesh form.When being used for this paper, the material that mesh is made up of multiple fiber or fibril (being fibrous material), wherein fiber or fibril are arranged (for example interweave, knotting weaves, and is overlapping, and ring formation is knitting, intersects, and tangles, and reticulates felt etc.) in the mode that forms loose structure.Typically, mesh is a flexible material, so it has enough flexibilities and is wrapped in around the device.In some aspects, thus described mesh has enough flexibilities can be wrapped in a part of outer surface of body passage or chamber or its.Described mesh can provide support for structure (for example blood vessel or chamber wall).In some aspects, mesh can be adapted to discharge a certain amount of therapeutic agent.

Mesh can be taked various ways.For example, described mesh can be with woven, and knitting or non-woven form exists and maybe can comprise directed arbitrarily toward each other or with the fiber or the fibril of oldered array or arranged in patterns.In one embodiment, for example, mesh can be a form of fabric, such as, (for example melt spray (melt-blown) or wet shop (wet-laid)) or the fabric that net is knitted of for example knitting, braiding, crocheting, woven, nonwoven.In one embodiment, mesh can comprise natural or synthetic biodegradable polymer, and it can form knitting mesh, woven mesh, spraying mesh, mesh screen, braiding mesh, ring-type mesh etc.Preferably, mesh or wrappage have the line of the entanglement that forms loose structure, and it can be for example knitting, and woven or net is knitted.

Be used for the structure of mesh of device and performance and depend on and use and expectation Mechanics of Machinery (i.e. flexibility, hot strength, and elasticity), degradation property and for the expectation load and the release performance of selected therapeutic agent.Described mesh should have mechanical performance, heals until surrounding tissue so that device can keep fully firm.The factor that influences the flexibility of mesh and mechanical strength comprises for example porosity, fabric thickness, fibre diameter, polymer composition (for example type of monomer and initiator), processing conditions and is used to prepare the additive of material.

Typically, described mesh has sufficient porosity and flows through fibroreticulate hole and promote tissue ingrowth to allow fluid.Usually, the gap of mesh should enough widely be separated by to allow the eyes visible light, and perhaps fluid passes through the hole.Yet, also can use to have the more material of compressing structure.Multiple factor can be depended in the gap that fluid flows through mesh, comprises for example pin number or line density.For example by filling the mesh gap with another kind of material (for example granule or polymer) or can further regulating the porosity of mesh, so that reduce the aperture and produce non-zone of fiber by handling mesh (for example by heating).Fluid flow by mesh of the present invention will be according to fluidic performance such as viscosity, hydrophilic/hydrophobic, ion concentration, temperature, elasticity, pseudoplastic behavior, granule content etc. and changing.The space of described mesh can enough discharge from mesh with therapeutic agent that do not prevent to flood or coating greatly, and described gap does not preferably prevent the exchange of tissue fluid at practical site.

Mesh material should be enough flexible so that can be adapted to the shape on apparatus surface or anatomy surface.In some cases, described mesh material should be enough flexible so that can be wrapped in all or part external surface peripheral in body passage or chamber.The flexible typically woven or knitting form of flexible mesh material, thickness are about 25 microns to about 3000 microns; Preferably from about 50 microns to about 1000 microns.The mesh material that is suitable for the present invention practice typically thickness is about 100 to 400 microns.

The diameter of fiber or fibril and length can be according to the form (for example knitting, woven or nonwoven) of material and required elasticity, porosity, surface area, flexibility and hot strengths and varying dimensions.Fiber can be any length, from staple to long line (being that length is several microns to hundreds of meters).Depend on application, fiber can have monofilament or multifilament structure.

Described mesh can comprise the fiber of same size or different size, and fiber can be formed by the biodegradable polymer of identical or different type.Woven material for example can comprise the rule or the irregular array of warp thread and weft strands, and can comprise the polymer (having and first kind of degradation curve that polymer is identical or different) of the another kind of type of one type polymer of weft direction and warp thread direction.The degradation curve of parallel polymer can be similar and different with the degradation curve of warp polymer.Similarly, knit materials can comprise the fiber of one or more types (for example monofilament, multifilament) and size and can comprise the fiber of being made by the biodegradable polymer of identical or different type.

The structure of mesh (for example fibre density and porosity) can influence the amount that can be loaded into the therapeutic agent in the device or on it.For example, what be characterised in that low fibre density and high porosity has loose woven fabric and can have lower thread count, causes the total fiber volume and the surface area that reduce.As a result, at fixed carrier: can be loaded under the therapeutic agent ratio among the fiber or on the amount of reagent will be lower than fabric with high fibre density and low porosity.Usually preferred mesh also should not cause biologically deleterious inflammation or toxic reaction, and metabolism fully in vivo has acceptable shelf-life (at least one approximately year or longer) and sterilization easily.

Described device can comprise the multiple mesh material of any combination or arrangement.For example, the part of device can be that knit materials and another part can be woven materials.In another embodiment, device can be more than one deck (for example the woven material of one deck be fused to one deck knit materials or another layer same type or dissimilar woven materials).In some embodiments, can use for example multi-ply construction (device that for example has two-layer or multilayer material) so that the performance performance of intensifier (for example be used for the rigidity of intensifier or change porosity, elasticity or hot strength) or be used to improve the medicine useful load.

Described mesh or film can or comprise polymer by polymer formation.Described polymer can be biodegradable or not biodegradable polymer, or its combination.

The Biodegradable compositions that can be used to prepare the mesh of film comprises polymer, this polymer comprises albumin, collagen protein, hyaluronic acid and derivant, sodium alginate and derivant, chitosan and derivant, gelatin, starch, cellulosic polymer (methylcellulose for example, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose, Cellacefate, cellulose acetate succinate, Hydroxypropyl Methylcellulose Phathalate), casein, glucosan and derivant, polysaccharide, poly-(caprolactone), fibrinogen, poly-(hydroxy acid), poly-(L-lactide), poly-(D, the L lactide), poly-(D, the L-lactide-co-glycolide), poly-(L-lactide-co-glycolide), the copolymer of lactic acid and hydroxyacetic acid, the copolymer of 6-caprolactone and lactide, the copolymer of Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone, lactide and 1, the copolymer of 4-diox-2-ketone, comprise one or more group unitary polymer of monomer residue and copolymers down: the D-lactide, the L-lactide, D, the L-lactide, Acetic acid, hydroxy-, bimol. cyclic ester, 6-caprolactone, propylene carbonate, 1,4-diox-2-ketone or 1,5-dioxepan-2-one, poly-(Acetic acid, hydroxy-, bimol. cyclic ester), poly-(butyric ester), poly-(alkyl carbonate) and poly-(ortho acid esters), polyesters, poly-(hydroxypentanoic acid), polydioxanone, polyethylene terephthalate, poly-(malic acid), poly-(hydroxymalonic acid), polyanhydrides, group of polyphosphazenes, poly-(aminoacid).These compositionss comprise that the admixture of the copolymer of above polymer and above polymer and combination are (generally referring to Illum, L, Davids, S.S. (eds.) " polymer in the controlled release drug transhipment " (＂ Polymers in Controlled Drug Delivery ＂) Wright, Bristol, 1987; Arshady, " controlled release magazine " (J.Controlled Release) 17:1-22,1991; Pitt, " International Journal of Pharmaceutical Medicine " be 59:173-196 (Int.J.Phar.), and 1990; Holland etc. " controlled release magazine " (J.Controlled Release) 4:155-0180,1986).

On the one hand, described mesh or film comprise biodegradable or absorbable polymer, and it forms from one or more monomers, described monomer is selected from by in the following group of forming: lactide, Acetic acid, hydroxy-, bimol. cyclic ester, e-caprolactone, propylene carbonate, 1,4-diox-2-ketone, 1,5-dioxepan-2-ketone, 1,4-dioxepan-2-ketone, hydroxyl valerate, and butyric ester.On the one hand, described polymer can comprise, for example the copolymer of lactide and Acetic acid, hydroxy-, bimol. cyclic ester.On the other hand, described polymer comprises poly-(caprolactone).On the other hand, described polymer comprises poly-(lactic acid), poly-(L-lactide)/poly-(D, L-lactide) admixture or L-lactide and D, the copolymer of L-lactide.In yet another aspect, described polymer comprises the copolymer of lactide and e-caprolactone.On the other hand, described polymer comprises polyester (for example, poly-(lactide-co-glycolide).Described poly-(lactide-co-glycolide) can have the lactide of the about 2:98 of about 20:80-: Acetic acid, hydroxy-, bimol. cyclic ester ratio ranges, the lactide of about 10:90: the ratio of Acetic acid, hydroxy-, bimol. cyclic ester, or the lactide of about 5:95: Acetic acid, hydroxy-, bimol. cyclic ester ratio.On the one hand, described poly-(lactide-co-glycolide) is poly-(L-lactide-co-glycolide).Other example of biodegradable material comprises polyglactin, polyglycolic acid, autogenetic, allosome and xenogeneic tissue (for example, pericardium or submucous layer of small intestine) and oxidation, regenerated cellulose.These meshes can be knitting, woven or non-woven meshes.Other example of non-woven mesh comprises the material of electrospinning silk.

Be used in the representative example that forms the not biodegradable compositions in film and the mesh and comprise ethylene-common-vinyl acetate copolymer, based on acrylic acid with based on the polymer of methacrylic acid (polyacrylic acid for example, polymethylacrylic acid, polymethyl methacrylate, poly-(hydroxyethyl meth acrylate), poly-(alkyl cyanoacrylate), poly-(alkyl acrylate), poly-(alkylmethacrylate)), polyolefin such as poly-(ethylene) or poly-(propylene), it is polyamide-based that (for example nylon 6,6), polyurethane (for example poly-(ester urethane), poly-(ether urethane), poly-(carbonic ester urethane), poly-(ester-urea)), polyester (for example, PET, polybutylene terephthalate (PBT), with poly terephthalic acid hexylene glycol ester), polyethers (for example poly-(oxirane), poly-(expoxy propane), poly-(oxirane)-poly-(expoxy propane) copolymer, diblock and triblock copolymer, poly-(butanediol), the polymer and the polyvinyl [polyvinylpyrrolidone that contain siloxanes, poly-(vinyl alcohol), poly-(vinylacetate phthalic acid ester)], poly-(styrene-altogether-isobutene .-altogether-styrene), the ethylene, propylene (FEP) that fluorine-containing polymer (fluoropolymer polymer) is changed such as fluorine or poly-(tetrafluoroethene) (for example, PTFE of extension).

Described many film mesh materials, it can be used in combination with the cicatrization agent.For example, described film or mesh can be to be adapted to organize and with the biodegradable polymer matrix of the method release reagent of controlled release.See, for example, U.S. Patent number 6,461,640.Described film or mesh can be self-adherent siloxane sheets, and it floods with antioxidant and/or antimicrobial.See that for example U.S. Patent number 6,572,878.Described film or mesh can be the flexible shieldings with attachment portion and perforation, and its boniness that is adapted to cover in the spine is dissected.See that for example U.S. Patent number 5,868,745 and Application No. 2003/0078588.Described film or mesh can be absorbable mocromembranes, and it has the monolayer imporosity polymer-matrix metallic substance of polylactide.See, for example, U.S. Patent number 6,531,146 and U. S. application number 2004/0137033.Described film or mesh can be the wound dressing coats, and it adheres to the inner gel lining by outside flexible layer with the oneself who serves as the dressing that contacts wound and forms.See that for example U.S. Patent number 6,548,728.Described film or mesh can be to have the binder that cicatrization is handled pad, and described spacer has silicone elastomer or layer of silicone gel.See that for example U.S. Patent number 6,284,941 and 5,891,076.Described film or mesh can be crosslinkable systems, and it has at least three reactive compounds, and each has the polymer molecule core with at least one functional group.See, for example, U.S. Patent number 6,458,889.Described film or mesh can be made up of the prosthese fabric, and described prosthese fabric has the 3 dimension structures of separating two surfaces, and it is open that the cell of one of them surface after for surgical operation settled down, and the material symphysis of surface and collagen connects.See that for example U.S. Patent number 6,451,032.Described film or mesh can be made up of two crosslinked synthetic polymers, and one has nucleophilic group and another has electrophilic group, thereby make their form the substrate that can be used to merge bioactive compound.For example see U.S. Patent number 6,323,278; 6,166,130; 6,051,648 and 5,874,500.Described film or mesh can be that oxidized regenerated cellulosic suitable warp-knit goods or other can biological resorbent materials, and the effect of described material is similar to the physical barriers that stops postoperative intestinal adhesion.See, for example, U.S. Patent number 5,007,916.The mesh that is used in the present invention's practice also is described in U.S. Patent number 6,575,887, in the application of common pending trial, described application is entitled as ＂ Perivascular Wraps, ＂ is filed in JIUYUE 26 days (U.S. serial (U.S. serial 10/673,046)) in 2003, and it is incorporated herein by reference in full hereby.

On the one hand, fibrous tissue can be formed agent and merge in biodegradable or soluble film or the mesh, then before or after prosthese/implant implantation, it is applied to the treatment site.The exemplary material for preparing these films or mesh is hyaluronic acid (crosslinked or noncrosslinking), cellulose derivative (for example, hydroxypropyl cellulose), PLGA, collagen protein and crosslinked poly-(ethylene glycol).

Can mix and comprise according to the film of one or more cicatrization agent of the present invention or mesh and to be purchased product.Wherein can mix the film of fibrous tissue formation agent or the example of mesh and comprise INTERCEED (Johnson ﹠amp; Johnson, Inc.), PRECLUDE (W.L.Gore), with POLYACTIVE (poly-(ether-ether) segmented copolymer (Osteotech, Inc., Shrewsbury based on poly-(ethylene glycol) and poly-(mutual-phenenyl two acid bromide two alcohol ester), NJ), and from Johnson ﹠amp; The absorbable hemorrhage gauze of the SURGICAL of Johnson print.Another kind of mesh be have be called SEPRAMESH BiosurgicalComposite biology again the prosthese polypropylene mesh of absorber coatings (Genzyme Corporation, Cambridge, MA).Side that can biological absorbed layer again be coated with described mesh with hyaluronate sodium and carboxymethyl cellulose provides tissue and organ surface and the isolating temporary physical barriers of mesh with infra.Other side of described mesh is not coated, allows the tissue ingrowth completely that is similar to naked polypropylene mesh.In one embodiment, agent be can only fibrous tissue be formed and the uncoated side of SEPRAMESH rather than a side that is coated with by hyaluronate sodium/carboxymethyl cellulose are applied to.Other film and mesh comprise: (a) BARD MARLEX mesh (C.R.Bard, Inc.), it is the knit goods structure with very dense of low porosity; (b) monofilament body polypropylene mesh is such as can be from Ethicon, Inc.Somerville, the PROLENE (seeing that for example U.S. Patent number 5,634,931 and 5,824,082) that NJ obtains); (c) (all from Cook Surgical, Inc.), it is used for strengthening soft tissue with open and laparoscopic procedures repairing inguinal hernia by the device that specificity is set for SURGISIS GOLD and SURGISIS IHM soft tissue graft thing; (d) thin-walled polypropylene surgical operation mesh is such as at trade (brand) name PROLITE, and (Hudson NH) obtains from Atrium Medical Corporation under PROLITE ULTRA and the LITEMESH; (e) COMPOSIX hernia mesh (C.R.Bard, Murray Hill, NJ), (described paster comprises that two-layer inertia synthesizes mesh in conjunction with the mesh paster for it, usually make by polypropylene, and be described in U.S. Patent number 6,280, in 453), it comprises makes the device hardening and it is maintained filament in the plane configuration; (f) (from C.R.Bard, Inc.), it is the polypropylene mesh that is made up by monofilament body polypropylene to the VISILEX mesh; (g) can be available from C.R.Bard, other mesh of Inc., it comprises PERFIX Plug, KUGEL hernia paster, 3D MAX mesh, LHI mesh, DULEX mesh and VENTRALEX hernia paster; (h) the polypropylene monofilament body hernia mesh of other type and insertion product comprise the USA from Herniamesh, Inc. (Great Neck, HERTRA mesh 1,2 NY), and 2A, HERMESH 3,4 ﹠amp; 5 and HERNIAMESH insert T1, T2, and T3.

Can comprise as follows with other example that fibrous tissue forms the commercially available mesh of agent combination.Boston Scientific Corporation sells TRELEX NATURAL Mesh, and it is made up of knitting polypropylene material.Ethicon, Inc. make absorbable VICRYL (polyglactin 910) mesh (knitting and woven) and MERSILENE polyester fiber mesh.(Midland, MI) sale forms the mesh material of the silicone elastomer of the SILASTIC Rx Medical Grade Sheeting (Platinum Cured) that calls oneself to Dow Corning Corporation.United StatesSurgical/Syneture (Norwalk, CT) the mesh of vending articles DEXON Mesh Products by name by absorbable polyglycolic acid making.Membrana Accurel Systems (Germany) sells CELGARD microporous polypropylene fibers and film.Gynecare Worldwide, a division ofEthicon, Inc. sell be called INTERCEED TC7 by oxidized, the mesh material that regenerated cellulose is made.

The mesh of many types described above and film and the polymer that uses with mesh and film.With become fiber composition to be incorporated on described film or the mesh or among method comprise that (a) (directly or indirectly) will become fiber composition to be attached to described film or mesh (for example, with or not with carrier, by aforesaid spraying process or infusion process); (b) will become fiber composition to mix or be impregnated in described film or the mesh (for example, with or not with carrier, by aforesaid spraying process or infusion process); (c) by being coated with described film or mesh with material such as hydrogel, it can absorb into fiber composition again, (d) use the part that makes up described film or mesh itself or described film or mesh into fiber composition, or (e) will become fiber agent directly to be covalently bound to the surface or the joint (micromolecule or polymer) of described film or mesh, described joint is applied or be attached to described film or meshed surface.For applied device, can implement coating process by this way, (a) only be coated with surface of described film or mesh or (b) the described film of coating or two in mesh are lateral all or part of.

Therapeutic agent can be the major part (integral part) (that is, can be arranged in the fiber of described mesh) of described film or mesh.As mentioned above, described fibre modification inhibitor can directly be attached in described film or the mesh or be can be incorporated in the secondary carrier (polymeric or non-polymeric), then is incorporated in described film or the mesh.

Perhaps, or in addition, can form agent or comprise that the compositions that fibrous tissue forms agent is coated with described film or mesh with fibrous tissue.Described coating can be taked the coating of surface adhering, mask, film, gel, the form of foam or model.

Many polymer compositions that can be used in combination with film of the present invention and mesh have been described.These compositionss can be with, example gel, spray, and the form of liquid and paste exists maybe and can form from monomer or prepolymerized component in-situ polymerization.For example, described compositions can be the polymer tissue coating, it forms by polymerization initiator being applied to tissue and then covering with the water solublity macromonomer, and described water-soluble macromolecule monomer uses the radical initiator polymerizable under the influence of UV light.See that for example U.S. Patent number 6,177,095 and 6,083,524.Described compositions can be a waterborne compositions, comprises surfactant, BL-191 and polyoxyalkylene polyethers.See, for example, U.S. Patent number 6,399,624.Described compositions can be to form hydrogel, from solvation (self-solvating), absorbable polyester copolymer, its behind the contact aqueous environments, can with the water-setting blob of viscose that adapts to optionally, the combining of part (association).See, for example, U.S. Patent number 5,612,052.Described compositions can be made up of material before the mobile polymerization, before the described polymerization material be placed in (emit) thus tissue surface and then contact the transformation of material that initiation is applied in position with activation energy to noncurrent polymer form.See U.S. Patent number 6,004,547 and 5,612,050.Described compositions can be made up of admixture of gas, and in described admixture of gas, oxygen exists with the volume ratio of 1-20%.See U.S. Patent number 6,428,500.Described compositions can be made up of anionic polymer, and described polymer has bisulfate and greater than 5% sulfur content, it acts on and suppresses mononuclear cell or macrophage invasion.See U.S. Patent number 6,417,173.Described compositions can be made up of the non-gelling polyoxyalkylene compositions that has or do not have therapeutic agent.See U.S. Patent number 6,436,425.Described compositions can be applied to tissue surface and can be by hydrophilic, the polymerism material (for example, polypeptide or polysaccharide) aqueous solution form, described polymerism material has greater than 50,000 molecular weight and 0.01 weight % in the concentration range of 15 weight %.See that for example U.S. Patent number 6,464,970.

Other representative example that can be applied to the polymerizable composition, polymerizable composition on described film or the mesh comprises the system based on poly-(ethylene glycol), hyaluronic acid and crosslinked hyaluronic acid compositions.These compositionss can be used as that whole compositions is applied or they can be used as the material that original position forms crosslinked gel and are applied.

Can include, but are not limited to (a) sprayable preparation that comprises PEG such as COSEAL, SPRAYGEL, FOCALSEAL or DURASEAL together with film and bonded other compositions of mesh with the cicatrization agent; (b) comprise hyaluronic preparation such as RESTYLANE, HYLAFORM, PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT, INTERGEL, (c) polymerism gel such as REPEL or FLOWGEL, (d) dextran sulfate gel such as the product of ADCON scope and (e) based on compositions such as the ADSURF (BrittaniaPharmaceuticals) of lipid.

Before implantation, thereby the hole that adaptation is widened is pruned or cut to described film or mesh from the sheet of bulkrage, conduit, or the structure of anatomic region, or at least, cover the tissue regions that is touched.Thereby can carry out the concrete configuration that bending or shaping adapt to put area to described film or mesh.Can also carry out the periphery that roll extrusion forms cover type or column type and is placed in the outside of required tissue to described film or mesh.Described film or mesh can be provided with the sheet of relatively large volume and then be cut into shape to be molded as the tissue that is wrapped or the concrete structure and the topographical surface of device.Perhaps, described film or mesh can be formed one or more patterns in advance to be used for application subsequently.Typically, described film and mesh can be rectangular shapes and can place or be placed on desired location in the surgical sites by endoscopic technique by direct surgical operation.Go up (that is, autohension) by it being wrapped in itself, or by using suture, follow closely, sealant etc. are fixed it, and described film or mesh can be determined and be placed on the position.Perhaps, described film or mesh can easily be adhered to tissue and therefore may not need additional mechanism of ammonium fixation.In another aspect of the present invention, polymer support is provided, it is adapted to comprise and discharges hydrophobic fibre degeneration inducing compounds, and/or comprises combination with carbohydrate, the carrier of the hydrophobic compound of protein or polypeptide.In certain embodiments, described polymer support comprises, or comprises the zone of one or more hydrophobic compounds, bag or granule.For example, in one embodiment of the invention, hydrophobic compound can be incorporated in the substrate that comprises hydrophobic fibre degeneration inducing compounds, subsequently substrate be incorporated in the polymer support.Many substrate can be used in this aspect, comprise, for example, carbohydrate and polysaccharide, such as starch, cellulose, glucosan, methylcellulose, sodium alginate, heparin, chitosan and hyaluronic acid and protein or polypeptide be such as albumin, collagen protein and gelatin.In alternative embodiment, hydrophobic compound can be included in the hydrophobic core, and this core is included in the hydrophilic shell.

In another aspect of the present invention, polymer support can be the material that original position forms.In one embodiment, precursor can polymerization or the monomer or the macromonomer of crosslinked unsaturated group for containing.For example, these monomers or macromonomer can be injected area for treatment then or be injected on the area for treatment surface and use radiation source (for example visible light or UV light) or free radical system (for example potassium peroxydisulfate and ascorbic acid or ferrum and hydrogen peroxide) to carry out in-situ polymerization or crosslinked.Can be before reagent being injected the treatment site, simultaneously or carry out polymerization or cross-linking step afterwards immediately.The representational case description of compositions that carries out radical polymerization or cross-linking reaction is at WO01/44307, WO01/68720, WO 02/072166, WO 03/043552, WO 93/17669 and WO 00/64977; U.S. Patent number 5,900,245; 6,051,248; 6,083,524; 6,177,095; 6,201,065; 6,217,894; 6,639,014; 6,352,710; 6,410,645; 6,531,147; 5,567,435; 5,986,043; With 6,602,975; In U.S. Patent Publication No. 2002/012796,2002/0127266,2002/0151650,2003/0104032,2002/0091229 and 2003/0059906.

In another embodiment, described reagent can carry out electrophilic-necleophilic reaction and generate crosslinked substrate.End have nucleophilic group such as amine, sulfydryl, hydroxyl ,-PH ₂Or CO-NH-NH ₂Polymer can be used as nucleopilic reagent, the polymer that end has electrophilic group can be used as electrophilic reagent, described electrophilic group such as succinimido, carboxylic acid, aldehyde, epoxide, isocyanates (ester), vinyl, ethylene sulfoxide, maleimide ,-S-S-(C ₅H ₄N) or activatory ester, for example use in peptide is synthetic.For example, can be under alkali condition (pH〉about 8) make the deutero-Polyethylene Glycol of 4-arm mercaptan (for example, poly-(ethylene glycol) ether four-sulfydryl of tetramethylolmethane) and 4 deutero-Polyethylene Glycol of arm NHS-(for example poly-(ethylene glycol) ether four-succinimido glutarate of tetramethylolmethane) reaction.The representational case description of compositions that carries out this electrophilic-necleophilic reaction is for example: United States Patent (USP) 5,752,974; 5,807,581; 5,874,500; 5,936,035; 6,051,648; 6,165,489; 6,312,725; 6,458,889; 6,495,127; 6,534,591; 6,624,245; 6,566,406; 6,610,033; 6,632,457; U.S. Patent Application Publication No. 2003/0077272A1; With title is " tissue reactive compounds and compositions and application thereof " (＂ Tissue Reactive Compounds and Compositionsand Uses Thereof) (U.S. serial US60/437 of December in 2002 submission on the 30th, the U.S. serial 60/44 that on January 17th, 384 and 2003 submitted to, 924) and " from the fast gelation polymer composition, passing medicine " (＂ Drug Delivery from Rapid Gelling PolymerComposition ＂) (U.S. serial US 60/437 that December in 2002 was submitted on the 30th, the U.S. serial US 60/440,875 that on January 17th, 471 and 2003 submitted to) unexamined patent application.

In another embodiment, the polymer that has electrophilic or a nucleophilic end can also comprise that can increase original position forms the machinery of compositions and/or the polymer of adhesive property.This polymer can be degradable nondegradable polymer.For example, described polymer can be collagen protein or collagen derivative, for example, and methylated collagen protein.Poly-(ethylene glycol) ether four-sulfydryl of an exemplary application tetramethylolmethane of the compositions that original position forms] (4-arm mercaptan PEG), tetramethylolmethane gathers (ethylene glycol) ether four-succinimido glutarate] (4 arm NHS PEG) and methylated collagen protein be as reactive reagent.When mixing with suitable reducing, said composition can produce crosslinked hydrogel.(see, for example, U.S. Patent number 5,874,500; 6,051,648; 6,166,130; 5,565,519 and 6,312,725).

In another embodiment, the material polymers of described original position formation can be a polyester.Can comprise poly-(hydroxyl ester) with the polyester in the compositions that forms in position.In another embodiment, described polyester can comprise one or more residues of monomers, and described monomer is selected from lactide, lactic acid, Acetic acid, hydroxy-, bimol. cyclic ester, hydroxyacetic acid, e-caprolactone, γ-caprolactone, hydroxypentanoic acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolacton, gamma-valerolactone, γ-decalactone, δ-Gui Neizhi, propylene carbonate, 1,4-diox-2-ketone or 1,5-dioxepan-2-ketone.The representative example of the compositions of these types is described in U.S. Patent number 5,874,500; 5,936,035; 6,312,725; 6,495,127 and PCT publication number WO 2004/028547 in.

In another embodiment, have the polymer of electrophilic end can be partially or completely by micromolecule or comprise that the oligomer of electrophilic group (for example, two succinimido glutarates) replaces.

In another embodiment, have the polymer of nucleophilic end can be partially or completely by micromolecule or comprise that the oligomer of nucleophilic group (for example, dicysteine, two lysines, three lysines etc.) replaces.

Other example that operable original position forms material comprises based on proteinic crosslinked those and (being described in, for example U.S. Patent number RE38158; 4,839,345; 5,514,379,5,583,114; 6,310,036; 6,458,147; 6,371,975; U.S. Patent Application Publication No. 2004/0063613A1,2002/0161399A1, and 2001/0018598A1, and PCT publication number WO 03/090683, WO 01/45761, among WO 99/66964 and the WO 96/03159), and those (seeing, for example PCT publication number WO 04/021983) of adding the polymer of medicated cap based on isocyanates or isothiocyanate.

Other example of the material that original position forms comprises reagent, and described reagent comprises one or more alpha-cyanoacrylate ester groups.These reagent can be used for preparation poly-(alkyl cyanoacrylate) or (for example gather (carboxyalkyl cyanoacrylate), poly-(ethyl cyanoacrylate), poly-(butyl cyanoacrylate), poly-(isobutyl cyanoacrylate), poly-(basic cyanoacrylate), poly-(methoxy-propyl cyanoacrylate) and poly-(octyl cyanoacrylate)).

The example of operable commercially available cyanoacrylate comprises DERMABOND, INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND, TISSUMEND II, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEALLIQUID PROTECTANT.

In another embodiment, described cyanoacrylate compositions can also comprise additive to stablize described reagent or to change the response speed of described cyanoacrylate.For example, can mix with 2-alkoxyalkyl cyanoacrylate (for example, 2-methoxy-propyl cyanoacrylate) based on the oxalate polymer of the polymer of propylene carbonate or poly-(ethylene glycol) or based on the copolymer of ε-caprolactone.The representative example of these compositionss is described in U.S. Patent number 5,350, in 798 and 6,299,631.

In another embodiment, can prepare described cyanoacrylate compositions by heterochain polymer being added medicated cap with the alpha-cyanoacrylate ester group.The described heterochain polymer that is added medicated cap by cyanoacrylate preferably every chain has at least two cyanoacrylate ester groups.Described heterochain polymer can comprise absorbable poly-(ester), poly-(ester-carbonic ester), poly-(ether-carbonic ester) and poly-(ether-ester).Can also will be described in U.S. Patent number 5,653, poly-(ether-ester) in 992 and 5,714,159 is as heterochain polymer.Three poly-(ε-caprolactones-be total to-propylene carbonate) are the examples of adaptable poly-(ester-carbonic ester).Described heterochain polymer can be a polyethers.The example of operable polyethers comprises poly-(ethylene glycol), the block copolymer (for example, including, but are not limited to the PLURONICS group of PLURONIC F127 or F68) of poly-(propylene glycol) and poly-(ethylene glycol) and poly-(propylene glycol).The representative example of these compositionss is described in U.S. Patent number 6,699, in 940.

As mentioned above, can use above-mentioned polymer coating that described fibrous tissue is formed agent is coated on the part of whole device or device.This can pass through, for example, dipping, spraying, the electrospinning silk is smeared or is finished by vacuum moulding machine.Except that above-mentioned coating composition and method, also there are various other coating composition as known in the art and method.The representational case description of these coating compositions and method is in following document: U.S. Patent number 6,610,016; 6,358,557; 6,306,176; 6,110,483; 6,106,473; 5,997,517; 5,800,412; 5,525,348; 5,331,027; 5,001,009; 6,562,136; 6,406,754; 6,344,035; 6,254,921; 6,214,901; 6,077,698; 6,603,040; 6,278,018; 6,238,799; 6,096,726; 5,766,158; 5,599,576; 4,119,094; 4,100,309; 6,599,558; 6,369,168; 6,521,283; 6,497,916; 6251964; 6,225,431; 6,087,462; 6,083,257; 5,739,237; 5,739,236; 5,705,583; 5648442; 5645883; 5,556,710; 5,496,581; 4,689,386; 6,214,115; 6,090,901; 6,599,448; 6,054,504; 4,987,182; 4,847,324; With 4,642,267; U.S. Patent Application Publication No. 2003/0129130; 2001/0026834; 2003/0190420; 2001/0000785; 2003/0059631; 2003/0190405; 2002/0146581; 2003/020399; 2003/0129130; 2001/0026834; 2003/0190420; 2001/0000785; 2003/0059631; 2003/0190405; 2002/0146581; With 2003/020399; With PCT publication number WO 02/055121; WO 01/57048; WO 01/52915; With WO 01/01957.

In another aspect of the present invention, can use non-polymer reagent to send bioactivator.These non-polymer reagent comprise: sucrose derivative (for example SAIB, sucrose oleate); Sterin is such as cholesterol, stigmasterol, cupreol and estradiol; Cholesterol ester is such as cholesteryl stearate; C ₁₂-C ₂₄Fatty acid is such as lauric acid, myristic acid, Palmic acid, stearic acid, arachidic acid, behenic acid and tetracosanoic acid; C ₁₈-C ₃₆One-, two-and triacylglycerol ester, such as glycerin mono-fatty acid ester, glycerol list linoleate, glyceryl monolaurate, glycerol list docosane acid esters, monomyristin, glycerol list decenoate, dipalmitin, glycerol two (docosane acid esters), glycerol two myristinates, glycerol two decylenic acid esters, glycerol three (docosane acid esters), myristin, glycerol tridecylene acid esters, glycerol tristearate and composition thereof; Sucrose fatty acid ester is such as sucrose distearate and sucrose palmitate; Sorbitan fatty ester is such as anhydrosorbitol monostearate, sorbitan-monopalmityl ester and anhydrosorbitol tristearate; C ₁₆-C ₁₈Aliphatic alcohol is such as spermol, myristyl alcohol, octadecanol and cetostearyl alcohol; The ester of aliphatic alcohol and fatty acid is such as cetin and cetearylpalmitate; The acid anhydride of fatty acid is such as stearic anhydride; Phospholipid comprises phosphatidylcholine (lecithin), Phosphatidylserine, PHOSPHATIDYL ETHANOLAMINE, phosphatidylinositols and lysoderivatives thereof; Sphingol and derivant thereof; Sphingomyelins (spingomyelins) is such as hard ester acyl sphingomyelins, palmityl sphingomyelins class and tricosyl sphingomyelins class; Ceramide is such as stearoyl and palmityl ceramide type; Glycosyl sphingolipid; Lanoline and lanolin alcohol, calcium phosphate, sintering and unsintered hydroxyapatite, zeolite, and combination and mixture.

The representational example that relates to the patent of non-polymer delivery system and preparation thereof comprises U.S. Pat 5,736,152,5,888,533,6,120,789; 5,968,542 and 5,747,058.

Can be used to comprise and transport other carrier that fibrous tissue as herein described forms agent equally comprises: hydroxypropyl (Cserhati and Hollo, " International Journal of Pharmaceutical Medicine " be 108:69-75 (Int.J.Pharm.), 1994), liposome (for example, referring to Sharma etc., " cancer research " be 53:5877-5881 (CancerRes.), and 1993; Sharma and Straubinger, " drug research " (Pharm.Res.) 11 (60): 889-896,1994; WO 93/18751; U.S. Patent number 5,242,073), liposome/gel (WO 94/26254), nanocapsule (Bartoli etc., " microencapsulation magazine " (J.Microencapsulation) 7 (2): 191-197,1990), micelle (Alkan-Onyuksel etc., " drug research " (Pharm.Res.) 11 (2): 206-212,1994), nano-particle (Violante and LanzafamePAACR), modified nanoparticles (U.S. Patent number 5,145,684), nano-particle (surface modification) (u.s. id 5,399,363), micelle (surfactant) (U.S. Patent number 5,403,858), synthetic phosphatide cpd (U.S. Patent number 4,534,899), aerogenesis dispersion (gas borne dispersion) (U.S. Patent number 5,301,664), liquid emulsion, foam, spray, gel, lotion, cream, ointment, disperse vesicle, granule or droplet solid or liquid aersol, microemulsion (U.S. Patent number 5,330,756), polymerization housing (nanocapsule and micron capsule) (U.S. Patent number 5,439,686), Emulsion (Tarr etc. " drug research " (Pharm Res.) 4:62-165,1987), nanometer spheroid (Hagan etc., " control release biological active material international symposium journal " (Proc.Intern.Symp.Control Rel.Bioact.Mater.) 22,1995; Kwon etc., " drug research " (Pharm Res.) 12 (2): 192-195; Kwon etc., " drug research " (Pharm Res.) 10 (7): 970-974; Yokoyama etc., " controlled release magazine " be 32:269-277 (J.Contr.Rel.), and 1994; Gref etc., " science " be 263:1600-1603 (Science), and 1994; Bazile etc., " pharmaceutical science magazine " be 84:493-498 (J.Pharm.Sci.), 1994) and implant (Invest.Ophthalm.Vis.Science 34 (11): 3076-3083,1993 for U.S. Pat 4,882,168, Jampel etc.; Walter etc., Cancer Res.54:22017-2212,1994).

In another embodiment, the fibre modification derivant can be impregnated in increases in bone integration and/or the osteogenetic compositions.The example of these compositionss comprises by bata-tricalcium phosphate (for example, VITOSS, PROOSTEON 500R), hydroxyapatite or Ca ₁₀(PO ₄) ₆OH (for example, OSTEOGRAF, calcium carbonate or CaCO ₃, the material that calcium sulfate (for example, OSTEOSET and ALLOMATRIX), calcium phosphate (for example, CALCIBON or NORIAN SRS) are formed, and synthetic property bone filler (for example, CORTOSS) and processed bone filler (for example, BIOOSS).The representative example of these materials is described in U.S. Patent number 3,929,971,4,861,733; 6,527,810; 4,772,468; 4,882,149; 5,167,961; 6,576,015; 4,839,215; 5,614,206; 5,807,567; 6,030,636; 6,652,887; 6,206,957; 6,485,754; 4,347,234; 4,291,013; 5,129,905; 5,336,264; 5,569,442; 5,571,493; 5,683,667; 5,709,742; 5,820,632; 5,658,332; 5,681,872; 5,914,356; 5,939,039; 6,325,987; 6,383,519; 6,458,162; 6,736,799; 6,521,246; With 6,709, in 744.

In another aspect of the present invention, the fibre modification derivant may further include secondary carrier.This secondary carrier can (block copolymer of SDS, X-Y, X-Y-X or Y-X-Y form, wherein X be the form of polyester (for example PLGA, PLLA, PDLLA, PCL, poly-diethyleno dioxide ketone), zeolites or cyclodextrin for poly-(alkylene oxide) or its alkyl ether and Y for microsphere (for example PLGA, PLLA, PDLLA, PCL, gelatin, poly-diethyleno dioxide ketone, poly-(alkyl cyanoacrylate)), nanometer spheroid (PLGA, PLLA, PDLLA, PCL, gelatin, poly-diethyleno dioxide ketone, poly-(alkyl cyanoacrylate)), liposome, Emulsion, microemulsion, micelle.

In another aspect of the present invention, these fibre modification derivant/secondary carrier compositionss can a) directly be attached among the described device or on, b) mix in the solution, c) mix in gel or the viscosity solution, d) mix the compositions that is used for being coated with described device, or e) after being coated with described device with coating composition, be attached among the described device or on.

For example, the fibre modification derivant that has loaded the PLGA microsphere can be mixed in the polyurethane coating solution, then it is coated on the described device.

In another example, with polyurethane coated described device, thereby allow that then the part drying makes the surface remain sticking.The particle form of fibre modification derivant or fibre modification derivant/secondary carrier then can be administered on viscous coating all or part of, subsequently that described device is dry.

In another example, can come described device is coated with one of above-mentioned coating.Then, heat treatment method can be used for softening coating, subsequently, fibre modification derivant or fibre modification derivant/secondary carrier be administered on the part of whole device or described device (for example, outer surface).

In another aspect of the present invention, suppress or the applied device that reduces fibre modification reaction (fibroticreaction) in the body is further delayed the release of fibre modification derivant and/or active chemical compound or compositions and is coated with.The representative example of these reagent comprises the biologically inert material such as gelatin, PLGA/MePEG film, PLA, polyurethane, silicone rubber, surfactant, lipid or Polyethylene Glycol, and bioactive substance such as heparin (for example, induce condense).

For example, in one embodiment of the invention, the activating agent on the described device is pushed up by physical barriers and is coated with (top-coated).These barriers can comprise the material of Nondegradable or biodegradable material such as gelatin, PLGA/MePEG film, PLA, Polyethylene Glycol, or analog.In one embodiment, the speed that spreads in barrier coatings of therapeutic agent is slower than the speed that therapeutic agent spreads in coat layer.In the situation of PLGA/MePEG, in case described PLGA/MePEG contacts with blood flow, MePEG can stripping from PLGA, stay from PLGA to (for example comprising the fibre modification derivant, silk or Ciclosporin A) the passage of lower floor, described fibre modification derivant then is diffused in the blood vessel wall and causes its biologic activity.

In another embodiment of the invention, for example, use polymer (for example, PLG, PLA, or polyurethane) particle form of activating agent (for example silk or Ciclosporin A) can be applied on the described device.Dissolving slowly or degraded (for example, MePEG-PLGA or PLG) and second polymer that do not comprise activating agent can be coated on the ground floor.In case upper strata dissolving or degraded, the coating of its contact infra, this makes activating agent contact with the treatment site or discharges from coating.

In another aspect of the present invention, the skin of the applied device of fibre modification reaction in the inductor is further handled skin with cross-linked coating.This can finish by applied device being carried out Cement Composite Treated by Plasma (plasma treatment) method.The crosslinked degree and the character of finishing can be set by changing RF power, and about isoionic location, the duration of processing and the gas composition that is introduced into plasma chamber change.

Can also be by being coated with the surperficial of described device or implant with inert molecule or coming coating surface by the form of passivation of using the fibre modification derivant that was activated afterwards; use the protection to bioactivity surface, described inert molecule is approaching by sterically hindered prevention and avtive spot.For example, be coated with described device with enzyme, it causes the release of fibre modification derivant or activates described fibre modification derivant.

Another example of suitable device surface coatings comprises anticoagulant such as heparin, thereby its top that can be coated on the fibre modification derivant makes the existence of heparin or other anticoagulant delay condensing in the treatment site.When heparin or other anticoagulant stripping, anticoagulant active may slow down or stop, and the fibre modification derivant that exposes (for example, silk or Ciclosporin A) can suppress or reduce fibre modification and occurs in contiguous tissue.

In another strategy, can be coated with described device with the form of passivation of fibre modification derivant, in case device is used, it then is activated.Be used or be applied in the area for treatment at the fibre modification derivant at described device (as described below) (by, for example injection, spraying, washing, drug delivery tube or air bag) after, can successfully carry out this activation in the area for treatment by other material is expelled to.For example, can be coated with described device with the form of passivation of fibre modification derivant.In case use described device, with activating substance injection be administered among the treatment site or on, in described treatment site, used the fibre modification derivant of form of passivation.

For example, bioactive fiber degeneration derivant can be applied on the device with usual way.Then, can cover the coating that (for example, coating) comprises activated fibre degeneration derivant with Polyethylene Glycol.Can carry out PEG and comprise the coating combination that fibrous tissue forms agent by forming key between the reactive group on two-layer.For example, use condensation reaction can form ester bond.Before using described device, esterase is expelled to the treatment site of implanted device exterior circumferential.Described esterase can the key of cracking between ester and fibre modification derivant, makes reagent cause fibre modification thus.

In yet another aspect, medical apparatus can comprise multiple storage vault in its structure, and each storage vault has certain form to store and the protection medicine.Described storage vault can form from installing the divets in the surface or installing intravital micropore or passage.On the one hand, described storage vault can form the space in apparatus structure.Described storage vault can be stored the medicine of single type or surpass one type medicine.Described medicine can be prepared together with carrier (for example, polymeric or non-polymeric material), and it is loaded in the described storage vault.The storage vault that is filled can be used as medicine and sends the storehouse and work, and depends on the kinetics that medicine discharges from carrier, and it can discharge medicine within a certain period of time.In certain embodiments, described storage vault can load with multilamellar.Every layer can comprise the different pharmaceutical with concrete amount (dosage) medicine, and every layer of amount that can have different compositions with the medicine that further is fit to be discharged by lower floor.The multiwalled carrier of tool can also comprise the barrier layer that stops drug release.For example, can use barrier layer with control medicine effusive direction from the space.

In certain embodiments of the invention, therapeutic combination can also comprise other composition, such as surfactant (for example, PLURONICS, such as F-127, L-122, L-101, L-92, L-81, and L-61), anti-inflammatory agent, antithrombotic drug, anti-infective, antiseptic, antioxidant and/or antiplatelet drug.

In certain embodiments of the present invention, therapeutic agent or carrier can also comprise radiopaque, produce (echogenic) material of echo and nuclear magnetic resonance (MRI) responsive materials (being the MRI contrast agent) and make it possible to will install development under ultrasonic, fluoroscopy and/or MRI.For example, device can by produce echo radiopaque compositions manufacturing or with the said composition coating (for example with produce echo or radio-opaque material such as powdery tantalum, tungsten, brium carbonate, bismuth oxide, barium sulfate, metrazimide, iopamidol, iohexol, iopromide, iobitridol, iomeprol, iopentol, ioversol, ioxilan, iodixanol, iotrolan, the acetrizoic acid derivant, amidotrizoic acid derivant, iotalamic acid derivant, ioxithalamic acid derivant, the metrizoic acid derivant, iodamide, lypophylic agents, the microsphere or the bubble at sound wave interface are made or had by adding to adipiodone and ioglycamic acid).The coating of use generation echo can obtain the development by the device of ultra sonic imaging.The coating that produces echo for example is described in, and U.S. Patent number 6,106 is in 473 and 6,610,016.In order under MRI, to develop, contrast agent (for example chelating gadolinium (III) or iron oxides chemical compound) can be attached among the device or on, as for example as the component in the coating or the device voidage in (for example in inner chamber, storage, or in being used to form the structural material of device).In some embodiments, medical apparatus can comprise radiopaque or MRI visable indicia (for example, band), and it can be used at method for implantation described device being carried out orientation and guidance.

Perhaps or in addition, use fluorescence, or by other spectrophotography, medical implant can develop under visible light.Can be comprised that the developing agent that satisfies this purpose comprises dyestuff, pigment and other coloring agent.On the one hand, described medical implant may further include coloring agent with in vivo and/or ex vivo (ex vivo) increase the development of implant.Usually, implant may be difficult to develop after insertion, particularly at the edge of implant.Thereby colorant combination can be reduced or removes the incidence rate or the seriousness of this problem to medical implant.Described coloring agent provides unique color, increases contrast, or provides unique fluorescent characteristic to described device.On the one hand, provide the solid implant that comprises coloring agent, thereby easily develop (under visible light or use fluorescent technique) and easily it is distinguished from its implantation site.In yet another aspect, coloring agent can be included in liquid or the semi-solid combination.For example, can carry out the one-component in two component mixtures painted, thereby when ex vivo (ex vivo) or when making up in vivo, described mixture is by fully painted.

Described coloring agent is passable, for example is that interior source compound (for example, aminoacid or vitamin) or nutrient or food material can be hydrophobicity or hydrophilic compounds also.Preferably, on employed concentration, described coloring agent has low-down toxicity or does not have toxicity.Further preferably coloring agent normally safety and enter in the body by absorption usually, such as bata-carotene.The representative example of painted nutrient (under visible light) comprises fatsoluble vitamin such as vitamin A (yellow); Water soluble vitamins such as vitamin B12 (pink-red) and folic acid (yellow-orange); Carotenoid such as beta-carotene (yellow-purple) and lycopene (redness).Other example of coloring agent comprises natural product (berry and fruit) extract such as anthrocyanin (purple) and Stigma Croci extract (dark red).Described coloring agent can be fluorescence or phosphorescent compounds such as α-tocopherolquinol (vitamin e derivative) or L-tryptophan.Can also use any derivant, analog and isomer of above-mentioned coloring compound.The method that coloring agent is mixed in implant or the therapeutic combination can depend on that the character of coloring agent changes with its desired position.For example, can select the hydrophobicity coloring agent to be used for hydrophobic base.Described coloring agent can be mixed carrier matrix, in micelle.In addition, thus the pH that can control environment further controls described color and intensity.

On the one hand, compositions of the present invention comprises that one or more are also referred to as the coloring agent of dyestuff, and it will be to give described compositions, and example gel exists with observable painted effective dose.The example of coloring agent comprises that the dyestuff that is suitable for food is such as being known as F.D.﹠amp; C. those of dyestuff and natural colorant be such as Pericarpium Vitis viniferae extract, beet red powder, beta-carotene, annato, fuchsin, Rhizoma Curcumae Longae, Fructus Capsici powder etc.Can also use any derivant, analog and isomer of above-mentioned coloring compound.The method that coloring agent is mixed in implant or the therapeutic combination can depend on that the character of coloring agent changes with its desired position.For example, can select the hydrophobicity coloring agent to be used for hydrophobic base.Described coloring agent can be mixed carrier matrix, in micelle.In addition, thus the pH that can control environment further controls described color and intensity.

In one aspect, compositions of the present invention comprises one or more antiseptic or antibacterial, its effective dose with the bacterial growth in and/or the composite inhibiting anticorrosion to compositions exists, for example, bismuth tribromophenate, methyl hydroxybenzoate, bacitracin, nipagin A, nipasol, erythromycin, chlorocresol, benzalkonium chloride etc.The other example of antiseptic comprises p-methoxybenzoic acid ester (paraoxybenzoic acid esters), chlorobutanol, benzylalcohol, phenethanol, dehydroactic acid, sorbic acid etc.In one aspect, compositions of the present invention comprises that one or more kill antibacterial (being also referred to as antibacterial) reagent.

On the one hand, compositions of the present invention comprises the antioxidant that one or more exist with effective dose.The example of antioxidant comprises sulphite, alpha-tocopherol and ascorbic acid.

In related fields of the present invention, generator and may or can not with the bonded compositions of device, after using described device or applying said compositions, it discharges induces fibrotic reagent in vivo.In some aspects, with the fibre modification derivant and comprise the fibre modification derivant compositions local or regionally be delivered to the treatment site from device or compositions.

Of the present invention aspect some in, therapeutic combination should be biocompatibility and in a few hours, discharge one or more fibrous tissue in the period of a couple of days or several months and form agent.

Thereby device of the present invention can have certain configuration discharges the cicatrization agent in one or more stages, and described one or more stages have similar or different performance (for example, discharging) pattern.Described therapeutic agent can be on the amount supported, intermittently or that continue; In one or more stages; And/or delivery rate; Being effective in increases or promotes any of fibre modification (or cicatrization) or multicomponent more, comprise: the formation of neovascularity (angiogenesis), the migration and the propagation of connective tissue cell (such as fibroblast or smooth muscle cell), the deposition of extracellular matrix (ECM) and to reinvent (fibre modification tissue ripe and form) aspect be obtainable for tissue; Or described reagent can serve as the blood vessel wall stimulant.

Therefore, thus thereby can design fibrotic at least a kind of composition is promoted or increase and influence fibre modification (or cicatrization) rate of release by discharge the cicatrization agent at certain hour.And therefore predetermined rate of release can reduce reagents loaded and/or concentration and provide minimum medicine to remove effectively also increases pharmaceutically-active efficient.Any one of at least a cicatrization agent can be brought into play one or more functions, comprise the formation (angiogenesis) that promotes neovascularity, promote the migration and the propagation of connective tissue cell (such as fibroblast or smooth muscle cell), promote the deposition and the promotion of extracellular matrix (ECM) to reinvent (the ripe and composition of fibre modification tissue); And/or serve as the blood vessel wall stimulant.In one embodiment, rate of release can provide the cicatrization agent of sustainable (sustainable) level to the treatment site.In another embodiment, rate of release is sustained.Described speed can reduce and/or increase in time, and it can randomly comprise non-release substantially period.Described rate of release can comprise multiple speed.In one embodiment, multiple rate of release can comprise and being selected from by constant substantially, reduces, and increases and does not discharge speed in the group of composition substantially.

On described device, among or near the total amount of the cicatrization agent that exists can from about 0.01 μ g (microgram) in about 2500mg (milligram) scope.Usually, the amount of described cicatrization agent can from 0.01 μ g in about 10 μ g scopes; Or from 10 μ g in the scope of about 1mg; Or in the scope from 1mg to about 10mg; Or in the scope from 10mg to about 100mg; Or in the scope from 100mg to about 500mg; Or from 500mg in about 2500mg scope.

On described device, among or near the dose,surface of cicatrization agent can be at every mm of apparatus surface area ²Be less than 0.01 μ g in about 250 μ g scopes.Usually, the amount of described cicatrization agent can be less than 0.01 μ g/mm ²Scope in; Or from 0.01 μ g to about 10 μ g/mm ²Scope in; Or from 10 μ g to about 25 μ g/mm ²Scope in; Or from 25 μ g to about 250 μ g/mm ²Scope in.

On described device, among or near cicatrization agent can from described compositions and/or device, discharge over a period to come, can begin to measure described period from the implantation time, it is in being less than 1 day to about 180 days scope.Usually, described release time can also be from being less than 1 day to about 7 days approximately; From 7 days to about 14 days; From 14 days to about 28 days; From 28 days to about 56 days; From 56 days to about 90 days; From 90 days to about 180 days.

On the one hand, provide ＂ rapid release ＂ or ＂ ＂ (burst) therapeutic combination that breaks, it discharges in 7 to 10 days period and surpasses 10%, 20%, or the fibre modification derivant of 25% (w/v).In certain embodiments, these " rapid release " compositionss should be able to discharge the required fibrous tissue formation agent of treatment level (it can be used).In other embodiments, provide the therapeutic combination of " slowly discharging ", it discharges the fibre modification derivant that is less than 1% (w/v) in 7 to 10 days period.In other embodiments, therapeutic combination is provided, it is being less than the fibre modification derivant of 1% (w/v) or is not discharging therapeutic combination at all surpassing to discharge in 10 days period, but keeps the whole duration that described compositions is settled in vivo such as device very long period.

The amount of the cicatrization agent that discharges from described compositions and/or device can be determined based on the extracorporeal releasing characteristic of described reagent from compositions as the function of time.By placing the phosphate buffer (pH7.4) of suitable buffer such as 0.1M to determine in-vitro release rate in 37 ℃ in the described cicatrization agent in compositions or the device.Then, the sample of buffer solution regularly removed by HPLC or by the gravimetric analysis mode analyzes, thereby and described buffer be replaced and avoid any saturation effect.

Based on in-vitro release rate, the amount of the release of cicatrization agent every day can be from about 0.0 μ g (microgram) to about 2500mg (milligram).Usually, the amount of the cicatrization agent that can discharge at a day can be in the scope of 0.0-0.01 μ g; 0.01 μ g-about 10 μ g; Or from 10 μ g to about 1mg; Or from 1mg to about 10mg, or from 10mg to about 100mg; Or from 100mg to about 500mg; Or from 500mg to about 2500mg.In one embodiment, prepare the cicatrization agent so that responsive tissue site obtains in stable still constant substantially mode, thereby described reagent is remained unchanged in tissue substantially.In another embodiment, the agent of preparation cicatrization, so that sensitive organization obtains in the mode that continues and/or be controlled, this has caused the efficient and/or the effect that increase.In addition, rate of release can all change in any or two processes in initial sum release stage subsequently.Can also exist the other stage to carry out the release of same substance and/or different material.

In addition, therapeutic combination of the present invention should preferably have the stable pot-life that is at least the several months, and can be produced under aseptic condition and keep.By the described compositions of preparation under gnotobasis, and/or can use the obtainable method in this area that they are carried out final sterilization, described compositions can be aseptic.Many medicines are made into aseptic and this standard is by USP XXII＜1211〉defined.Term ＂ USP ＂ refer to American Pharmacopeia (see www.usp.org, Rockville, MD).By multiple that in industry, accepted and list in USP XXII＜1211〉in method can realize sterilization, comprise gaseous sterilization, ionizing radiation, perhaps when suitable, filtration.Can be by also being in USPXXII＜1211〉in the operation handled of the defined asceptic of being called keep aseptic.The acceptable gas that is used for gaseous sterilization comprises oxirane.The acceptable ray type that is used for the ionizing radiation method for example comprises the γ from cobalt 60 and electron beam.Gamma-ray typical doses is 2.5MRad.By radiation of final use gamma-rays or electron beam sterilization method, also can take place aseptic.Utilize the appropriate bore size, for example 0.22 μ m and suitable material, for example politef (for example, realize filtering by filter TEFLON).The combination of these methods can also be used to prepare the compositions of sterile form.

On the other hand, compositions of the present invention and device are included in the container, and this allows them to be used as the purpose of expectation.Important container characteristics is to allow to add the composition medium, such as water or for example brinish spatial content of other aqueous medium, acceptable light transmission, thereby prevent that luminous energy from damaging compositions in the described container (referring to USPXXII＜661 〉), the acceptable restriction (referring to USPXXII) of extractable in the container material is for humidity (referring to USPXXII＜671 〉) or the acceptable barrier ability of oxygen.For oxygen infiltration, can be by in container, including a kind of noble gas of malleation, such as highly purified nitrogen, or noble gas, control as argon.

The typical material that is used to produce the container that is used for medicine comprises that USPI is to III type and NP type glass (referring to USP XXII＜661 〉), polyethylene, TEFLON, siloxanes and grey fourth glue.For parenteral, preferred USPI is to the glass and the polyethylene of III type.

Should it will be apparent to one skilled in the art that aforementioned fibers degeneration derivant, any of or derivatives thereof and analog can be used to produce the variant of above-mentioned composition under the prerequisite that does not deviate from spirit and scope of the invention.Also should it is evident that described reagent can with or be not used in the compositions and change described carrier and do not depart from scope of the present invention with polymer support.

For all previous embodiments, the example that suitable fibrous tissue forms agent comprises tissue stimulating agent such as silk, fine hair (wool), asbestos, Silicon stone, bleomycin, neomycin, the Talcum powder, metallic beryllium, and copper is particularly suitable for practice of the present invention.Can be incorporated among described implant or the device or on or other reagent of from described implant or device, discharging comprise that extracellular matrix components such as fibrous structure albumen (for example, fibrillar collagen albumen, non-fiber collagen protein and elastin laminin), viscous glycoprotein (for example, laminin and fibronectin), Dan Baijutang (for example, heparin sulfate, chondroitin sulfate, dermatan sulfate), hyaluronan (for example hyaluronic acid), be rich in the acidic secretion protein (SPARC) of cysteine, thrombospondin, the inhibitor of tenacin and matrix metalloproteinase, (for example TIMPs and synthetic property TIMPs, such as, marimistat, batimistat, doxycycline, tetracycline, minocycline, TROCADE, Ro-1130830, CGS27023A, BMS-275291) and polylysine.The somatomedin and the inflammatory cytokine that relate to the synthetic and tissue remodeling of blood vessel generation, fibroblast migration, fibroblast proliferation, ECM, such as epidermal growth factor (EGF) family, transforminggrowthfactor-(TGF-α), transforming growth factor-beta (TGF-9-1, TGF-9-2, TGF-9-3, platelet-derived somatomedin (PDGF), fibroblast growth factor (acidity-aFGF; And alkalescence-bFGF), bone morphogenetic protein, activator protein, VEGF (VEGF, VEGF-B, VEGF-C, placental growth factor-PIGF), angiogenin, insulin like growth factor (IGF), hepatocyte growth factor (HGF), Connective Tissue Growth Factor (CTGF), bone marrow colony stimulating factor (CSFs), granulocyte-macrophage colony stimutaing factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), M-CSF (M-CSF), erythropoietin, interleukin (IL-1 particularly, IL-8, IL-6), tumor necrosis factor-alpha (TNF9), nerve growth factor (NGF), interferon-' alpha ', interferon-beta and growth hormone (GH) also are adapted to be incorporated into and discharge from the specificity endovascular device.Can be applied to that described implant or device are gone up or comprise binding agent such as cyanoacrylate or by 4-arm mercaptan PEG (10K) by other reagent of its release, the material that 4-arm NHS PEG (10K) and methylated collagen protein make.

5) with fibre modification derivant apparatus for coating

As mentioned above, the material of polymerism and non-polymerization can be used for the fibre modification derivant is combined on the device or among.With the compositions that comprises these fibre modification derivants or with the fibre modification derivant be coated with described device only be can be used for the fibre modification derivant is attached among the described device or on a kind of method.

A) dip-coating

Dip-coating is an example that can be used to make fibre modification derivant and the bonded coating process of described device.In one embodiment, the fibre modification derivant is dissolved in the solvent of fibre modification reagent and then it is applied on the described device.

Fibre modification derivant and atent solvent

In one embodiment, thus described solvent is a atent solvent for described device to be made described solvent can not dissolve medical apparatus on any bigger degree and can not absorb any going up largely by described device.Described device can partially or even wholly be immersed in reaches certain period in fibre modification derivant/solvent solution.Can change the speed that immerses fibre modification derivant/solvent solution (for example, 0.001cm/ second to 50cm/ second).Then, can from described solution, remove described device.Can change the speed that from described solution, shifts out described device (for example, 0.001cm/ second to 50cm/ second).Can carry out air-dry to applied device.Depend on concrete application, described dip-coating process can be repeated one or many.Thereby described device can carry out drying and reduce remaining solvent levels under vacuum.This method can make the fibre modification derivant be applied to the surface of described device.

Fibre modification derivant and sweller

In one embodiment, described solvent is can not dissolve described device but the solvent that can be absorbed by described device.Therefore these solvents can swell to described device to a certain degree.Described device can partially or even wholly be immersed in reaches certain period (several seconds is to a couple of days) in fibre modification derivant/solvent solution.Can change the speed that immerses fibre modification derivant/solvent solution (for example, 0.001cm/ second to 50cm/ second).Then, can from described solution, remove described device.Can change the speed that from described solution, shifts out described device (for example, 0.001cm/ second to 50cm/ second).Can carry out air-dry to applied device.Depend on concrete application, described dip-coating process can be repeated one or many.Thereby described device can carry out drying and reduce remaining solvent levels under vacuum.This method can make the fibre modification derivant be absorbed in the described medical apparatus.Described fibre modification derivant can also appear on the described apparatus surface.With the amount of the fibre modification derivant of surface combination can be by being reduced to applied device in the solvent that applied device is dipped into the fibre modification derivant or by solvent spray with the fibre modification derivant.

Fibre modification derivant and solvent

In one embodiment, described solvent is the solvent that can be absorbed and can dissolve described device by described device.Described device can partially or even wholly be immersed in reaches certain period (several seconds is to a few hours) in fibre modification derivant/solvent solution.Can change the speed that immerses fibre modification derivant/solvent solution (for example, 0.001cm/ second to 50cm/ second).Then, can from described solution, remove described device.Can change the speed that from described solution, shifts out described device (for example, 0.001cm/ second to 50cm/ second).Can carry out air-dry to applied device.Depend on concrete application, described dip-coating process can be repeated one or many.Thereby described device can carry out drying and reduce remaining solvent levels under vacuum.This method can make the fibre modification derivant be absorbed in the described medical apparatus and and surface combination.Preferably, the time that described device contacts with solvent is such, and it can not cause the obvious persistent change in size of described device.Described fibre modification derivant can also appear on the described apparatus surface.With the amount of the fibre modification derivant of surface combination can be by being reduced to applied device in the solvent that applied device is dipped into the fibre modification derivant or by solvent spray with the fibre modification derivant.

In one embodiment, described fibre modification derivant and polymer dissolution are forming in the solvent of agent at polymer and fibrous tissue, and then are applied on the described device.

In above-mentioned description, described device can be the device that is not modified before the coating process or by further improved device, described improvement is passed through with polymer-coated, come treatment surface by Cement Composite Treated by Plasma, flame treatment, sided corona treatment, surface oxidation or reduction, surface etching, machinery flatten or polishing, or transplant and carry out.

In any of above-mentioned dip-coating method, come described apparatus surface is handled with plasma polymerisation method before can or comprising the compositions of cicatrization agent in coating cicatrization agent, thereby thin polymeric layer is deposited on the described apparatus surface.The example of these methods comprises the parylene coating of device and uses various monomers such as hydrogenation cyclisation siloxanyl monomers.If the part of described device or device is made up of the material (for example, rustless steel, nitinol) that uses one of said method not allow that therapeutic agent is attached in the surface layer, the parylene coating can be particularly advantageous.Use parylene coater (for example from Cookson Electronics PDS2010 LABCOTER2) and (for example as the suitable agent of coating feed material, two-p-xylylene or two chloro-, two-p-xylylene), parylene priming paint (primer) can be deposited upon on the device.The parylene chemical compound can be purchased certainly, SpecialtyCoating Systems for example, Indianapolis, IN), comprise PARYLENE N (two-p-xylylene), PARYLENE C (monochloroization of PARYLENE N (monchlorinate) derivant and PARYLENE D, the dichloride derivant of PARYLENE NJ).

Fibre modification derivant/polymer and atent solvent

In one embodiment, thus described solvent is a atent solvent for described device to be made described solvent can not dissolve medical apparatus on any bigger degree and can not absorb any going up largely by described device.Described device can partially or even wholly be immersed in reaches certain concrete period in fibre modification derivant/polymer/solvent solution.Can change the speed that is immersed in fibre modification derivant/polymer/solvent solution (for example, 0.001cm/ second to 50cm/ second).Then, can from described solution, shift out described device.Can change the speed that from described solution, shifts out described device (for example, 0.001cm/ second to 50cm/ second).Can carry out air-dry to applied device.Depend on concrete application, described dip-coating process can be repeated one or many.Thereby described device can carry out drying and reduce remaining solvent levels under vacuum.This method can make fibre modification derivant/polymer be applied on the surface of described device.

Fibre modification derivant/polymer and sweller

In one embodiment, described solvent is can not dissolve described device but the solvent that can be absorbed by described device.Therefore these solvents can swell to described device to a certain degree.Described device can partially or even wholly be immersed in reaches certain concrete period (several seconds is to a couple of days) in fibre modification derivant/polymer/solvent solution.Can change the speed that is immersed in fibre modification derivant/polymer/solvent solution (for example, 0.001cm/ second to 50cm/ second).Then, can from described solution, shift out described device.Can change the speed that from described solution, shifts out described device (for example, 0.001cm/ second to 50cm/ second).Can carry out air-dry to applied device.Depend on concrete application, described dip-coating process can be repeated one or many.Thereby described device can carry out drying and reduce remaining solvent levels under vacuum.This method can cause fibre modification derivant/polymer to be applied on the surface of described device and the fibre modification derivant is absorbed into probability in the described medical apparatus.Described fibre modification derivant can also be present on the described apparatus surface.With the amount of the fibre modification derivant of surface combination can be by being reduced to applied device in the solvent that applied device is dipped into the fibre modification derivant or by solvent spray with the fibre modification derivant.

Fibre modification derivant/polymer and solvent

In one embodiment, described solvent is the solvent that can be absorbed and can dissolve described device by described device.Described device can partially or even wholly be immersed in reaches certain period (several seconds is to a few hours) in fibre modification derivant/solvent solution.Can change the speed that is immersed in fibre modification derivant/solvent solution (for example, 0.001cm/ second to 50cm/ second).Then, can from described solution, remove described device.Can change the speed that from described solution, shifts out described device (for example, 0.001cm/ second to 50cm/ second).Can carry out air-dry to applied device.Depend on concrete application, described dip-coating process can be repeated one or many.Thereby described device can carry out drying and reduce remaining solvent levels under vacuum.In preferred embodiments, the time that described device contacts with solvent can be such, its can not cause the obvious persistent change in size of described device (except with coating itself bonded those).Described fibre modification derivant can also appear on the described apparatus surface.With the amount of the fibre modification derivant of surface combination can be by being reduced to applied device in the solvent that applied device is dipped into the fibre modification derivant or by solvent spray with the fibre modification derivant.

In above-mentioned description, described device can be the device that is not modified before the coating process or by further improved device, described improvement is by being coated with polymer (for example parylene), come treatment surface by Cement Composite Treated by Plasma, flame treatment, sided corona treatment, surface oxidation or reduction, surface etching, machinery flatten or polishing, or transplant and carry out.

In another embodiment, can prepare the suspension of fibre modification derivant in polymer solution.Can be by select can dissolve polymer, but can not dissolve the fibre modification derivant solvent or can dissolve polymer and therein the solvent of fibre modification derivant on its solubility limit prepare described suspension.In above-mentioned similar process, thereby can be coated with described device with polymer in the suspension with device immersion fibre modification derivant and polymer solution, described polymer has the fibrous tissue that is suspended in wherein and forms agent.

B) Spraying

Spraying is the coating process of operable another kind of type.In spraying process, will have or not have the solution of fibre modification derivant of polymer or non-polymeric carriers or suspension atomizing and be directed to applied device by air-flow.Can use sprayer unit such as air-brush (for example, from Badger Air-brush Company, Franklin Park, the model 2020,360 of IL, 175,100,200,150,350,250,400,3000,4000,5000,6000), spary device, TLC reagent sprayer (for example, Part # 14545 and 14654, Alltech Associates, Inc.Deerfield, IL) and ultrasonic atomization device (for example can be from Sono-Tek, Milton, those that NY obtains).Can use powder sprayer and electrostatic atomiser.

In one embodiment, the fibre modification derivant being dissolved in fibrous tissue forms in the solvent of agent and then is sprayed on the described device.

Fibre modification derivant and atent solvent

In one embodiment, thus described solvent is a atent solvent for described device to be made described solvent can not dissolve medical apparatus on any bigger degree and can not absorb any going up largely by described device.Described device can be placed in suitable position or described device can be placed on axle or the bar strip, and described axle or bar strip have at X, Y or Z plane or the ability of moving in these planar combination.Use one of above-mentioned sprayer unit, described device can partially or even wholly be coated with fibre modification derivant/solvent solution thereby can spray to be coated with to described device.The speed (for example, 0.001ml/ second to 10ml/ second) that can change spraying fibre modification derivant/solvent solution is to guarantee to obtain the good coat of fibre modification derivant.Then, can carry out air-dry to applied device.Depend on concrete application, described spraying process can be repeated one or many.Thereby described device can carry out drying and reduce remaining solvent levels under vacuum.This method can make the fibre modification derivant be applied on the surface of described device.

Fibre modification derivant and sweller

In one embodiment, described solvent is can not dissolve described device but the solvent that can be absorbed by described device.Therefore these solvents can swell to described device to a certain degree.Described device can be partially or completely by the spraying coating in fibre modification derivant/solvent solution.Can change the spray rate (for example, 0.001ml/ second to 10ml/ second) of fibre modification derivant/solvent solution thus guarantee to obtain the good coat of fibre modification derivant.Can carry out air-dry to applied device.Depend on concrete application, described spraying process can be repeated one or many.Thereby described device can carry out drying and reduce remaining solvent levels under vacuum.This method can make the fibre modification derivant be absorbed in the described medical apparatus.Described fibre modification derivant can also be present on the described apparatus surface.With the amount of the fibre modification derivant of surface combination can be by being reduced to applied device in the solvent that applied device is dipped into the fibre modification derivant or by solvent spray with the fibre modification derivant.

Fibre modification derivant and solvent

In one embodiment, described solvent is the solvent that can be absorbed and can dissolve described device by described device.Described device can partially or even wholly be sprayed in fibre modification derivant/solvent solution.The spray rate (for example, 0.001ml/ second to 10ml second) that can change fibre modification derivant/solvent solution is to guarantee to obtain the coating of good fibre modification derivant.Can carry out air-dry to applied device.Depend on concrete application, described spraying process can be repeated one or many.Thereby described device can carry out drying and reduce remaining solvent levels under vacuum.This method can make the fibre modification derivant be absorbed in the described medical apparatus and and surface combination.Preferably, the time that described device contacts with solvent is such, and it can not cause the obvious persistent change in size of described device.Described fibre modification derivant can also be present on the described apparatus surface.With the amount of the fibre modification derivant of surface combination can be by being reduced to applied device in the solvent that applied device is dipped into the fibre modification derivant or by solvent spray with the fibre modification derivant.

In one embodiment, described fibre modification derivant and polymer dissolution are forming in the solvent of agent at polymer and fibrous tissue, and then are sprayed onto on the described device.In above-mentioned description, described device can be not have improved device and by further improved device before coating process, described improvement comes treatment surface by with polymer (for example, parylene) coating by Cement Composite Treated by Plasma, flame treatment, sided corona treatment, surface oxidation or reduction, surface etching, machinery flattens or polishing, or transplants and carry out.

Fibre modification derivant/polymer and atent solvent

In one embodiment, thus described solvent is a atent solvent for described device to be made described solvent can not dissolve medical apparatus on any bigger degree and can not absorb any going up largely by described device.Described device can partially or even wholly be sprayed in fibre modification derivant/polymer/solvent solution reaches the regular period.The spray rate (for example, 0.001ml/ second to 10ml/ second) that can change fibre modification derivant/solvent solution is to guarantee to obtain the coating of good fibre modification derivant.Can carry out air-dry to applied device.Depend on concrete application, described spraying process can be repeated one or many.Thereby described device can carry out drying and reduce remaining solvent levels under vacuum.This method can make fibre modification derivant/polymer be applied on the surface of described device.

Fibre modification derivant/polymer and sweller

In one embodiment, described solvent is can not dissolve described device but the solvent that can be absorbed by described device.Therefore these solvents can swell to described device to a certain degree.Described device can partially or even wholly be sprayed in fibre modification derivant/polymer/solvent solution.The spray rate (for example, 0.001ml/ second to 10ml/ second) that can change fibre modification derivant/solvent solution is to guarantee to obtain the good coat of fibre modification derivant.Can carry out air-dry to applied device.Depend on concrete application, described spraying process can be repeated one or many.Thereby described device can carry out drying and reduce remaining solvent levels under vacuum.This method can cause fibre modification derivant/polymer to be applied on the surface of described device and the fibre modification derivant is absorbed into probability in the described medical apparatus.Described fibre modification derivant can also be present on the described apparatus surface.With the amount of the fibre modification derivant of surface combination can be by being reduced to applied device in the solvent that applied device is dipped into the fibre modification derivant or by solvent spray with the fibre modification derivant.

Fibre modification derivant/polymer and solvent

In one embodiment, described solvent is the solvent that can be absorbed and can dissolve described device by described device.Described device can partially or even wholly spray in fibre modification derivant/solvent solution.The spray rate (for example, 0.001ml/ second to 10ml/ second) that can change fibre modification derivant/solvent solution is to guarantee to obtain the good coat of fibre modification derivant.Can carry out air-dry to applied device.Depend on concrete application, described spraying process can be repeated one or many.Thereby described device can carry out drying and reduce remaining solvent levels under vacuum.Preferably, the time that described device contacts with solvent can be such, its can not cause the obvious persistent change in size of described device (except with coating itself bonded those).Described fibre modification derivant can also be present on the described apparatus surface.With the amount of the fibre modification derivant of surface combination can be by being reduced to applied device in the solvent that applied device is dipped into the fibre modification derivant or by solvent spray with the fibre modification derivant.

In above-mentioned description, described device can be the device that is not modified before coating process and by further improved device, described improvement is by being coated with polymer (for example parylene), come treatment surface by Cement Composite Treated by Plasma, flame treatment, sided corona treatment, surface oxidation or reduction, surface etching, machinery flatten or polishing, or transplant and carry out.

(c) Directly adhere to

In certain embodiments, the fibre modification derivant can directly be attached to described device.This can be by using binding agent (for example, cyanoacrylate, polymer/solvent solution), use heat treatment and by with fibre modification reagent stitching (sew) among described device or on finish.In one embodiment, the fibre modification derivant can be with granule (irregular, rule, porous, sphere), line, and fiber, the braiding knot, fabric or electrospinning silk (electrospun) material form exist.For example, silk can be prepared as knitting, woven or electrospinning silk material.Then, this material can be placed on the surface of described device.Then, suture and/or binding agent can be used for the silk material is fixed in described device.

In another embodiment, the fibre modification derivant can be dissolved in the suitable solvent.Then, use electrospray or electrical spinning method this solution can be applied to described device.Help out or in the adhesion of fibre modification derivant and device, help out in electrospray or electrospinning silk process thereby polymerism or non-polymerization additive can be added in this solution.For example, silk can be dissolved among the HFIP and then, can be with its electrospray or electrospinning silk to described device (for example, Si Tengte fixedly film).

In another embodiment, can in described device preparation process or after the preparation fibre modification derivant be attached in the described device.For example, provide a kind of product in the hernia mesh thereby silk fiber can be woven into, described product comprises the fibre modification derivant that is combined in the described device.

D uses the method for medical implant

Can be used to induce the fibre modification around described device/implant to react medical apparatus of the present invention and implant, it causes the combination between tissue and prosthese to increase.These medical apparatus are provided solution with implant to the following FAQs relevant with many clinical interventions.

1. degeneration disc disease (degenerative disc disease) treatment (DDD)

Backache is that the U.S. occupy primary health care cost reason and annual cost surpasses 50,000,000,000 dollars (being 1,000 hundred million dollars in the world wide).The U.S. surpass 1,200 ten thousand people have the degeneration disc disease (DDD) of certain form and wherein 10% (1,200,000) may need surgical operation to correct their problem.

In the individuality of health, spinal column is made up of the vertebra dish, and described vertebra dish is formed strong joint and born spinal compression at the volley by disc separation.Intervertebral disc is formed by being called the inside gel-like substance of examining pulposus, and it is centered on by the tough and tensile fibrous cartilage capsule that is called as fibrous ring.Described nucleus pulposus is made up of the loose framework and the water of collagen protein fibril in the gel substrate that is embedded in glucosaminoglycan and connective tissue cell (similar fibroblast and chondrocyte).The fibre modification ring is made up of many concentric rings that anchor to the fibrocartilaginous ring in the vertebral body.The common cause of DDD occurs in when fibrous ring and tears when producing local weak zone, described zone makes protruding the increasing (bulging) of nucleus pulposis and fibrous ring, and outstanding (herniation) or sequestrum form and occur in spinal canal and/or the vertebral foramen.The described protruding dish that increases or give prominence to often compresses nervous tissue such as spinal cord fiber or spinal cord and nerve roots fiber.To causing neuronal function unusual (paralysis, weakness, tingling) from the spinal cord of impaired intervertebral disc or the pressure of nerve root, bitterly wounded or disabled, intestinal or bladder are disorderly and can frequently cause long-term anergy.Although the case of many DDD can spontaneously solve, but obviously there are many patients can need operating intervention, the form of described surgical intervention has the operation of intrusion degree minimum, micro-diskectomy, the major surgical excision of dish, vertebra perfusion (using various technology and device to pour into contiguous vertebra dish), and/or implant artificial dish.The invention provides adhesion or fibre modification derivant are applied in the surgical operation therapy of DDD.

(i) treatment of the DDD of intrusion degree minimum

The fibrous tissue formation agent that the invention provides the injectable compositions that comprises extender or filler and be used for being injected directly into impaired intervertebral disc.Can be injected into the injectable substance that comprises the fibre modification derivant in the intervertebral disc space (makes up separately or with polymer support, described polymer support can be with example gel, paste or spray form exist) annular distance (annular ring) that is used to increase cicatrization and support disc is (for example, by inducing fibrous tissue and fibrocartilaginous generation), so minimizing is coiled the function of disruptive risk and recovery dish and do not need surgical operation (embodiment of using is described below) in the dish surgical procedures.In another embodiment, lasting fixing (immobilization) of adjacent vertebrae if desired, the Injectable composition that comprises the fibre modification derivant can also comprise the reagent of promote osteogenesis.

In the method, insert a needle in the intervertebral disc, lead (guidewire) is stretched in the tissue and with double channel catheter (for many hydrogels that describe below such as COSEAL, COSTASIS, FLOSEAL, TISSEAL, VITOSS and by 4-arm mercaptan PEG (10K), the material that 4-arm NHSPEG (10K) and methylated collagen protein make, such as above-mentioned, or single lumen catheter (for material such as cyanoacrylate, CORTOSS, bone cement, apatite hydroxyl apatite, calcium phosphate, calcium sulfate, hyaluronic acid, protein, carbohydrate, sclerosing agent etc.) stretch in the dish.When direct injection is carried out in intervertebral disc, technology can be used for making the pin (or conduit) that places dish to develop, described technology comprises, but be not limited to use (Angiotech Pharmaceuticals, the Inc.) pin of bag quilt, or (for example add the contrast agent that is used for by the X-ray localization with ultrasonic development coating agent such as ECHO-COAT, barium, tantalum, technitium, gadolinium etc.).Behind verified correct location, remove lead and will together with or not together with bone morphogenetic protein, and/or osteogenic growth factor is (such as transforming growth factor, platelet-derived somatomedin, fibroblast growth factor) the compositions that comprises the fibre modification derivant is expelled in the dish by pipeline.Can also be before being injected into fiber composition, such as collagenase, chymopapain or other tissue degradation enzyme are used for the dish tissue of chemical degradation remnants with chemical nucleic acid-degrading agent.Passage in time, the fibre modification derivant, with or not with bone morphogenetic protein, and/or osteogenic growth factor can promote fibrous ankylosis, the sclerotin ankylosis of the intervertebral space stability and the pain that cause increasing reduces subsequently.

Injectable material can comprise polymer system, and described system can provide the fibre modification derivant, bone morphogenetic protein, thereby and/or the lasting release of skeletal growth factor increase effect and reduce the needs of repetitive administration activating agent.Be suitable for sending the fibre modification derivant, the polymerism injection mass of the somatomedin of bone morphogenetic protein and/or promote osteogenesis can be nondegradable or degradable material.The non-degradable material that is fit to comprises crosslinked compositions, or bone cement (for example, SIMPLEX P by Stryker Howmedica making, ZIMMER REGULAR and ZIMMERLOW VISCOSITYCEMENT, PALACOS, CMW-1 and CMW-2, ENDURANCE), synthetic cancellous bone infilling (for example, CORTOSS), pHEMA, poly-(vinyl PEG), poly-(styrene sulfonate), poly-(acrylic acid), poly-(methacrylic acid), and the polymer of other known formation hydrogel, described crosslinked compositions comprises PVA, PVP, polyacrylamide, methyl methacrylate (MMA) and methyl methacrylate-styrene (MMA-styrene), when mixing, form polymethyl methacrylate (PMMA) cement.Other compositions comprises the admixture and the copolymer of the reagent of listing above.Suitable degradable substance include, but not limited to by bata-tricalcium phosphate form can resorbent Inorganic Non-metallic Materials (for example VITOSS and PROOSTEON 500R), hydroxyapatite or Ca ₁₀(PO ₄) ₆OH (for example, BIOOSS and OSTEOGRAF), calcium carbonate or CaCO ₃, calcium sulfate is (for example, by Wright MedicalTechnology, Inc. OSTEOSET of Zhi Zaoing and ALLOMATRIX), calcium phosphate (for example CALCIBON or NORIAN SRS), the crosslinked material of PEG, gelatin, collagen protein, (for example, ALLOGRO (the Allosource Corporation of bone allograft, Centennial, CO), ORTHOBLAST (GenSci Regeneration Sciences, Inc., Canada), OPTEFORM (Exactech, Inc., Gainesville, FL), GRAFTON (Osteotech, Inc., Eatontown, NJ), mescenchymal stem cell, hyaluronic acid, derivatives of hyaluronic acids, polysaccharide, carbohydrate, protein (for example, albumin, casein, lactalbumin, phytoprotein and fish protein), from the body bone, the bone matrix that demineralizes, cellulose derivative (for example, HPC), chitosan, chitosan derivative, polyester-polyalkylene oxide block copolymer (for example, PLGA-PEG-PLGA and MePEG-PLGA, etc.) and other can be by excretory low-molecular weight polymers.Interested especially injectable substance is by 4-arm mercaptan PEG (10K), and 4-arm NHS PEG (10K) and methylated collagen protein prepare such as above-mentioned.

In a preferred embodiment, injectable material also comprises can induce fibre modification and ankylopoietic bioactivator in the crack of circling or whirl in the air.In one embodiment, injectable material is loaded with the fibre modification derivant and be injected into the outstanding formation to help repairing described ring and to stop nucleus pulposis in the intervertebral disc.In another embodiment, injectable material comprise can induction of bone growth bioactivator such as bone morphogenetic protein and somatomedin (transforming growth factor, platelet-derived somatomedin, fibroblast growth factor) to promote the fusion of the strong and adjacent vertebrae of osteoarthrosis.

In addition, or at the fibre modification derivant, in the situation of bone morphogenetic protein and somatomedin, injectable material can be used to send sclerosant and give the joint space.Sclerosant comprises chemical compound such as ethanol, DMSO, surfactant, sucrose, NaCl, dextrose, glycerol, minocycline, tetracycline, doxycycline, Polidocanol, sodium tetradecyl sulfate, sodium morrhuate, Sotradecol and other.Injectable material can also comprise reagent such as glycerol, glycerol, and PEG200, triethyl citrate and triacetin are as plasticizer.

Thereby can also modify the line that makes its line form or comprise polymer to above-mentioned injectable material by polymer.Polymer line has the ability of inducing the fibroplasia reaction from surrounding tissue.These polymer lines are degradable or nondegradable.Degradable line can be by degradable polyester, polyanhydride, poly-(acid anhydride ester), poly-(ester-amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine (polyphosphazines), cyanoacrylate polymer, collagen protein, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose, cellulose esters, its admixture and copolymer, and other known degradable polymer is formed.Operable non-degradable polymer include, but not limited to polyester (for example, PET), polyurethane, siloxanes, PE, PP, PS, PAA, PMA, the silk, its admixture, copolymer and other known polymer.Described line can be made up of the admixture of single compositions or different components.Can come polymer line itself is further modified by the polymer coating that interpolation is applied on the described line.Be used to be coated with described line polymer can on to regard to described line itself described similar.Described polymer coating can also comprise bioactivator, and it has the ability of fibroplasia of inducing or osteogenic response.Operable reagent further is described in following part (vi).

Above-mentioned injectable substance can be used for the delivery of particles material, it has induces fibrotic ability in intervertebral disc.These granules are degradable or nondegradable and similar to the above-mentioned description at line.The other particulate matter useful for putting into practice of the present embodiment comprises silk, Talcum, starch, glass, silicate, Silicon stone, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic property mineral (for example, VITOSS and CORTOSS, PMMA, silver nitrate, Inorganic Non-metallic Materials granule and other inorganic particle of inducing the fibroplasia reaction to carry out mineralising subsequently known in the art).The granule that is used in the present embodiment can be all same combinations or the admixture of different components.As mentioned above, can also be with these granules as the coating that is applied on the polymer chain.

Thereby can also make up injectable material makes it by polymer line and granulometric composition.The line that uses and granule are to above-mentioned those are similar and can be uniform composition or mixed compositions.In fact, particulate any combination of the line of different components and different components can be used in the present embodiment.As described below, can be with hydrogel, polymer line and granule all are used to send one or more bioactivators.

A kind of concrete compositions comprises poly-(ethylene glycol) compositions by methylated collagen protein-crosslinked, such as above-mentioned, and the bar of preparation, it added pulverous granule and/or mineral particle in the compositions before solidifying.In case use, described bar can absorb water, filling dish gap also is attached on the bone of any fibrous cartilage or exposure.This expansion can stop described bar migration, and simultaneously pulverous silk and/or mineral particle can start makes ankylopoietic reaction.When described material begins degraded, described material can support starting of described granule and the osseous tissue of strengthening inwardly to grow.Bone morphogenetic protein and/or somatomedin (front and back is described) also are used in and are included in this compositions.In order further to increase the initial speed of this fibroplasia reaction, can add sclerosing agent such as surfactant (SDS), ethamolin (ester) or DMSO.In addition, can also add or replace the 4-arm mercaptan PEG of all (or part) with the amino PEG of 4-arm.Described amino PEG can provide the gel that can need the longer time degraded and can provide some positive charges to the other porous material that attractability is arranged (cellular material).

Another embodiment is made up of injectable implant, and the polymerized form (that is, fibrous tissue forms the recurring unit that agent condenses together) of agent itself is made of or is formed from fibrous tissue to described implant silk fiber.Bone morphogenetic protein and/or somatomedin (front and back is described) can also be added said composition.

Except hydrogel, bone cement and comprising outside the material of above-mentioned calcium phosphate, exist some other be suitable for use in Injectable composition in intervertebral disc operation of invasive degree minimum.All comprising is used in biomaterial among the nucleus pulposis, follows or do not follow the fibre modification derivant, bone morphogenetic protein, and/or the interpolation of suitable somatomedin.Compositions subsequently can be passed through special delivery catheter, endoscope, pin or other applicator, drainage tube or entry port that operation is settled, or other transdermal access to plant is delivered to intervertebral disc, comprises and uses (a) fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the preparation of solid implant and other delivery of biologically active fibre modification derivant; (b) independent or load with additional fibers degeneration derivant, bone morphogenetic protein, and/or the microgranule silk of somatomedin and/or silk chain (linearity, side chain, and/or curl) they also are useful in the intervertebral disc for being injected directly into; (c) be injected into that injectable in the intervertebral disc comprises preparation such as the COSTASIS of collagen protein or by 4-arm mercaptan PEG (10K), the material of 4-arm NHS PEG (10K) and methylated collagen protein such as above-mentioned composition, described preparation is independent or loads with the fibre modification derivant, bone morphogenetic protein, and/or somatomedin; (d) preparation that is injected into the injectable PEG of comprising in the intervertebral disc is such as COSEAL, FOCALSEAL, and SPRAYGEL or DURASEAL, it is independent or loads with the fibre modification derivant bone morphogenetic protein, and/or somatomedin; (e) be injected into the preparation that comprises fibrinogen such as FLOSEAL or TISSEAL in the intervertebral disc, it is independent or loads with the fibre modification derivant bone morphogenetic protein, and/or somatomedin; (f) be injected into and comprise hyaluronic preparation such as RESTYLANE, HYLAFORM, PERLANE in the intervertebral disc, SYNVISC, SEPRAFILM, SEPRACOAT, it is independent or loads with the fibre modification derivant bone morphogenetic protein, and/or somatomedin; (g) be injected into polymer gel such as the REPEL or the FLOWGEL that implant at surgical operation in the intervertebral disc, it is independent or loads with the fibre modification derivant bone morphogenetic protein, and/or somatomedin; (h) be injected into orthopedics's " cement " in the intervertebral disc such as OSTEOBOND, low viscosity cement (LVC), SIMPLEX P, PALACOS, CORTOSS and ENDURANCE, described " cement " is independent or loads with the fibre modification derivant bone morphogenetic protein, and/or somatomedin; (i) be injected into the surgical operation binding agent that comprises cyanoacrylate in the intervertebral disc such as DERMABOND, INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND, TISSUMEND II, HISTOACRYL BLUE and ORABASESOOTHE-N-SEAL LIQUID PROTECTANT or as mentioned above, described binding agent are independent or load with the fibre modification derivant, bone morphogenetic protein, and/or somatomedin; (j) be injected into the hydroxyapatite that comprises in the intervertebral disc, calcium phosphate (such as VITOSS), or the surgical implants of calcium sulfate, it is independent or loads with the fibre modification derivant bone morphogenetic protein, and/or somatomedin; (k) be injected into other biocompatible tissue filler in the intervertebral disc, such as by BioCure, those that 3M Company and Neomend make, it is independent or loads with the fibre modification derivant bone morphogenetic protein, and/or somatomedin; (1) be injected into the gel of polysaccharide gel such as the ADCON series in the intervertebral disc, described polysaccharide gel is independent or loads with the fibre modification derivant bone morphogenetic protein, and/or somatomedin; (m) be injected into film in the intervertebral disc, sponge, or mesh is such as INTERCEED, VICRYL mesh, and GELFOAM, and it is independent or loads with the fibre modification derivant bone morphogenetic protein, and/or somatomedin; And/or (N) form Polyethylene Glycol from amino-functional (for example, 4-arm tetramino PEG[10k] and the hydrogel of the functionalized PEG (for example, tetramethylolmethane gathers (ethylene glycol) ether four-succinimido glutarate [10K]) of 4-arm NHS.This hydrogel also can comprise collagen protein, methylated collagen protein and/or gelatin.This hydrogel also can comprise above-mentioned fibre modification derivant (for example, silk powder or silk thread).In many these embodiments, add radiopaque material (for example, tantalum, barium, other metal or developing materials) thus make that injected material can by radiography or to develop by MRI also be useful.

Tackling in those skilled in the art is to it is evident that potentially, above-mentioned any fibre modification derivant can be used alone or in combination in the practice of the present embodiment.The exemplary fibrous tissue formation agent that is used in the spinal prostheses (for example device and filler) comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF and above-mentioned analog and derivant.

Randomly, described device can comprise inflammatory cytokine (for example, TGF β, PDGF in addition, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, or growth hormone) and/or bone morphogenetic protein (BMP) is (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant).

In addition, described device can comprise the medicament that stimulates cellular proliferation.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, all-trans retinoic acid (ATRA), and analog and derivant.(vi) be described with in these embodiments using of these reagent with dosage part below.

(ii) open surgery dish excision and micro-diskectomy

When there being tangible neurological handicap; Particularly when intestinal or vesical dysfunction, the spinal disc excision is necessary with urgent in cauda equine syndrome.Also carry out it alternatively to ease the pain and to eliminate still less nervous symptoms.

(laminectomy (laminectomy) under general anesthesia, places the patient ground position that is modified in excision for the open surgery of disruptive lumbar disc.In postmedial line, cut, and tissue is cut to expose suitable space; Excision ligament flavum and in some cases allows enough manifesting thereby the part of hone lamella removed.Carefully nerve root is withdrawn to expose outstanding fragment and the defective in ring.Typically, the chamber of described dish from the ring break and with the loose fragment of hypophyseal forceps (pituitary forceps) removal nucleus pulposus.Also careful segregate (sequestered) that removes the crack of circling or whirl in the air thus the fragment of inner or outside any additional dish and effectively the space of washing tray remove the fragment of any remnants.Be present in the dura mater if break, with the closed described dura mater of suture, it is reinforced through fibrin commonly used.Then with the closed described tissue of absorbable suture.

Microplate (Microlumbar) dish excision (micro-diskectomy) can be used as outpatient's method and has replaced laminectomy in a large number as the selection for the intervention of outstanding dish.Handling (spinous process) thorn-like below being subjected to by thorn-like handles and forms one inch otch on the dish that influences.Use the microscope of operation, described tissue is switched to ligament flavum place downwards, and bone is removed up to can easily recognizing nerve root from described plate.Carefully regain described nerve root and under amplification, observe tearing in the described ring.Described little dish (Microdisc) pincers are used for removing disc segment and having removed any hidden (sequestered) disc segment by ring breakage.As for laminectomy, the described crack of circling or whirl in the air is washed to remove any disc segment, repair that any dura mater breaks and with the closed described tissue of absorbable suture.It should be noted, preceding road (abdominal part) method can also be used for open and endoscope's lumbar discectomy art.Cervical intervertebral disk is similar to lumbar discectomy art method with the thoracic disk excision and also can be undertaken or carry out as preceding excision fusion by the method (about laminectomy) of back.

Thereby the invention provides the cicatrization that injectable compositions promotes ring, the cicatrization of dura mater defective and contiguous vertebra stable.Under direct observation, in open or endoscope's dish excision process, send the compositions that comprises fibre modification agent or fibrous tissue formation agent.Here, the compositions that will comprise the fibre modification derivant directly or the lateral parts by endoscope be applied on ring or the dura mater defective (in the open surgery method).Described fibre modification derivant can help out in the generation of outstanding or the strong fibre modification tissue of site, disruptive front in the anchor ring fibre modification.This can strengthen the weak part of intervertebral disc and reduce disruptive once more subsequently probability.In the dura mater defective, described fibre modification derivant can in the healing of dura mater, help out and complication prevention such as the CSF seepage.

Thereby described material can also be formed the lasting release that the fibre modification derivant is provided by polymer system.Satisfying the material that the object of the invention is suitable for sending the fibre modification derivant can be made up of non-degradable or degradable material.The non-degradable material that is fit to comprises crosslinked compositions, or bone cement (for example, SIMPLEX P, ZIMMER REGULAR or ZIMMER LOWVISCOSITY CEMENT, PALACOS, CMW-1, CMW-2, or ENDURANCE), synthetic cancellous bone infilling (for example, CORTOSS), pHEMA, poly-(vinyl PEG), poly-(styrene sulfonate), poly-(acrylic acid), poly-(methacrylic acid), and the polymer of other known formation hydrogel, described crosslinked compositions comprises PVA, PVP, polyacrylamide, methyl methacrylate (MMA) and methyl methacrylate-styrene (MMA-styrene) when being mixed in a time-out, form polymethyl methacrylate (PMMA) cement.Other compositions comprises the admixture and the copolymer of the reagent of listing above.Suitable degradable substance include, but not limited to by bata-tricalcium phosphate form can resorbent Inorganic Non-metallic Materials (for example VITOSS and PROOSTEON 500R), hydroxyapatite or Ca ₁₀(PO ₄) ₆OH (for example, BIOOSS, OSTEOGRAF), calcium carbonate or CaCO ₃, calcium sulfate (for example, OSTEOSET and ALLOMATRIX), calcium phosphate (for example CALCIBON or NORIAN SRS), the crosslinked material of PEG, gelatin, collagen protein, (for example, the ALLOGRO of bone allograft, ORTHOBLAST, OPTEFORM, GRAFTON), mescenchymal stem cell, hyaluronic acid, derivatives of hyaluronic acids, polysaccharide, carbohydrate, protein are (for example, albumin, casein, lactalbumin, phytoprotein and fish protein), from the body bone, the bone matrix that demineralizes, cellulose derivative (HPC etc.), chitosan, chitosan derivative, polyester-polyalkylene oxide block copolymer (for example, PLGA-PEG-PLGA and MePEG-PLGA, etc.) and other can be by excretory low-molecular weight polymers

The interested especially a kind of material that is used to encircle with the dura mater repairing in the intervertebral disc surgical operation is a kind of injectable substance, and it is by 4-arm mercaptan PEG (10K), and 4-arm NHS PEG (10K) and methylated collagen protein such as above-mentioned, prepare.In a preferred embodiment, injectable material also comprises bioactivator, thereby it can induce fibre modification reinforcing fibre ring (minimizing repeats outstanding or disruptive danger) or help out (seepage that stops CSF) in the repairing of dura mater defective.The preferred bioactivator that uses with injectable combinations of substances (for example comprises fibre modification derivant and somatomedin, transforming growth factor, platelet-derived somatomedin, fibroblast growth factor), its dosage and release dynamics are all described below part in detail (vi).

Also can improve above-mentioned material so that it is made up of polymer line or comprises it.Polymer line has the ability of inducing the fibroplasia reaction in fibrous ring or dura mater.These polymer lines can be degradable or nondegradable.Degradable line can be by degradable polyester, polyanhydride, poly-(acid anhydride ester), poly-(ester-amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, cyanoacrylate polymer, collagen protein, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose, cellulose esters, its admixture and copolymer, and other known degradable polymer is formed.Operable non-degradable polymer include, but not limited to polyester (for example, PET), polyurethane, siloxanes, PE, PP, PS, PAA, PMA, the silk, its admixture, copolymer.The line that uses can be made up of the admixture of single compositions or different components.Can come polymer line itself is further modified by the polymer coating that interpolation is applied on the described line.Be used to be coated with described line polymer can on to regard to described line itself described similar.Described polymer coating can also comprise bioactivator, and it has the ability of inducing the fibroplasia reaction.Operable reagent further is described in following part (vi).

Above-mentioned material can also be used for the delivery of particles material, it has the fibrotic ability of inducing.These granules can be degradable or nondegradable and to above-mentioned described those are similar at line.Except those, the particulate matter useful for putting into practice of the present embodiment comprises silk, Talcum, starch, glass, silicate, Silicon stone, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic property mineral is (for example, VITOSS and CORTOSS), PMMA, silver nitrate, Inorganic Non-metallic Materials granule and other inorganic particle of inducing the fibroplasia reaction to carry out mineralising subsequently known in the art).The granule that is used in the present embodiment can be all same combinations or the admixture of different components.As mentioned above, can also be with these granules as the coating that is applied on the polymer chain.

Obviously, thus can also make up material used in this invention makes it be made up of polymer line and granule.The line that uses and granule are to above-mentioned those are similar and can be uniform composition or mixed compositions.In fact, particulate any combination of the line of different components and different components can be used in the present embodiment.As described below, can be with hydrogel (for example, by 4-arm mercaptan PEG (10K), the injectable substance of 4-arm NHS PEG (10K) and methylated collagen protein ester preparation), polymer line and granule all are used to send one or more bioactivators.

Other compositions is suitable for use in open surgery dish excision and micro-formula diskectomy.Thereby all comprising used biomaterial and fibre modification derivant reinforcing fiber ring or helped out in dura mater is repaired.Compositions subsequently can be used special delivery catheter directly, by endoscope, or pin or other applicator, send in open surgery dish excision and micro-formula diskectomy: (a) fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, solid implant and other discharge the preparation of fibre modification derivant; (b) independent or load with the fibre modification derivant, and/or the microgranule silk of somatomedin and/or silk chain (linearity, side chain, and/or curl); (c) comprise preparation such as the COSTASIS of collagen protein or by 4-arm mercaptan PEG (10K), 4-arm NHS PEG (10K) and methylated collagen protein, such as above-mentioned, the material that makes, described preparation is independent or loads with the fibre modification derivant, and/or somatomedin; (d) the injectable preparation that comprises PEG is such as COSEAL, FOCALSEAL, and SPRAYGEL or DURASEAL, it loads with the fibre modification derivant, and/or somatomedin; (e) comprise preparation such as the FLOSEAL or the TISSEAL of fibrinogen, it loads with the fibre modification derivant, and/or somatomedin; (f) comprise hyaluronic preparation such as RESTYLANE, HYLAFORM, PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT, it loads with the fibre modification derivant, and/or somatomedin; (g) be expelled to polymer gel such as the REPEL or the FLOWGEL that implant at surgical operation of joint hole, it loads with the fibre modification derivant, and/or somatomedin; (h) orthopedics's " cement " is such as OSTEOBOND, LVC, and SIMPLEX P, PALACOS, CORTOSS and ENDURANCE, described " cement " loads with the fibre modification derivant, and/or somatomedin; (i) comprise the surgical operation binding agent of cyanoacrylate such as DERMABOND, INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND, TISSUMEND II, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUIDPROTECTANT or as mentioned above, described binding agent loads with the fibre modification derivant, and/or somatomedin; (j) comprise hydroxyapatite, calcium phosphate (such as VITOSS, Orthovita), or the surgical implants of calcium sulfate, it loads with the fibre modification derivant, and/or somatomedin; (k) other biocompatible tissue filler, such as by BioCure, those that 3M Company and Neomend make, it loads with the fibre modification derivant, and/or somatomedin; (1) polysaccharide gel is such as the gel of ADCON series, and described polysaccharide gel loads with the fibre modification derivant, and/or somatomedin; (m) be injected in the intervertebral disc, independent or load with the fibre modification derivant, bone morphogenetic protein, and/or the film of somatomedin, sponge, or mesh is such as INTERCEED, VICRYL mesh, and GELFOAM; And/or (n) form the hydrogel of the functionalized PEG (for example, tetramethylolmethane gathers (ethylene glycol) ether four-succinimido glutarate [10K]) of Polyethylene Glycol from amino-functional (for example, 4-arm tetramino PEG[10k]) and 4-arm NHS.This hydrogel also can comprise collagen protein, methylated collagen protein and/or gelatin.This hydrogel (for example also can comprise above-mentioned fibre modification derivant, silk powder or silk thread) and/or independent or load with the fibre modification derivant, and/or (m) film, sponge, or mesh is such as INTERCEED, VICRYL mesh, and GELFOAM, its separately or load with the fibre modification derivant, and/or somatomedin.

Tackling in those skilled in the art is to it is evident that potentially, above-mentioned any fibre modification derivant can be used alone or in combination in the practice of the present embodiment.The exemplary fibrous tissue formation agent that is used in the spinal prostheses (for example device and filler) comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF and above-mentioned analog and derivant.

Randomly, described device can comprise inflammatory cytokine (for example, TGF β, PDGF in addition, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) and/or bone morphogenetic protein (BMP) is (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant).

In addition, described device can individualism or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, all-trans retinoic acid (ATRA), and analog and derivant.(vi) be described with in these embodiments using of these reagent with dosage part below.

(iii) treat the vertebra compression fracture

Osteoporosis is a kind of sexual involution osteopathia of carrying out, and it is characterized in that the inorganic matter density of bone reduces the degraded of bone micro-structure and the minimizing of bone strength.The bone that dies down usually can not withstanding pressure, or even be subjected to taskwork moving normally, and be in the danger of increase of frequent fracture.Fracture is that the modal clinical manifestation of osteoporosis and this disease often are asymptomatic up to the fracture generation.In the U.S., osteoporosis is the reason of annual 1300000 fracture and estimates that it has caused the annual health care system cost that surpasses 10,000,000,000 dollars.Hip, the fracture of wrist and other long bone is common in the osteoporosis, but as their consequence of disease, has patient's (having 700,000 in the world wide) of 550,000 to suffer the vertebra compression fracture approximately in the U.S..Here, the cancellous bone that dies down of spinal column withers when weight is placed on it (compression) in normal activity and described vertebra lose height (, the center of vertebra wither and two soleplates migration of vertebra closed together).The compression of vertebra causes pain, highly reduces, and rachiocamposis (hunchback), and in some cases, owing to placing the pressure on thoracic cavity and the lung to cause breathing problem.

Traditionally, the vertebra compression fracture is carried out expectant treatment with period of recumbence.In serious situation, also the spinal fusion and/or the open reduction of fracture (with the orthopedics's plate and the screw repair of bone fractures of surgical operation placement) are used in the treatment vertebra compression fracture.Recently, developed the method-vertebroplasty (vertebroplasty) of two kinds of intrusion degree minimums and kyphoplasty art (kyphoplasty) with treatment because osteoporosis or more singularly because the vertebra compression fracture that bone tumor causes.Vertebroplasty is under the X-ray instructs, and (polymethyl methacrylate-PMMA) with stable fracture provides support and reduces pain to use the bone cement that is injected under pressure in the fracture.This method is often carried out for the outpatient, and provide almost immediately sx and early stage activity.The kyphoplasty art comprises inserts air bag (by Kyphon Inc., Sunnyvale, the KYPHX Inflatable Bone Tamp that CA makes) in fracture, it is expanded in bone to produce the space, and stable fracture is also stretched bone and spinal column (promptly recovering because compression fracture causes the vertebral levels that loses).Then the surgeon passes through special access to plant (by Kyphon, Inc. (Sunnyvale, CA) the Inflation Syringe and Bone Access System of Zhi Zaoing) is expelled to the vertebra to support to be fractured in the space with bone filler (typically PMMA or based on the material of calcium phosphate) under the fluoroscopy of C-arm image-guidance.Bone cement is expelled to can make in the chamber that air bag produces is injected at that low-pressure carries out and the incidence rate of the nerve injury that minimizing is relevant with the cement seepage.The cement seepage takes place under pressure in the injected vertebroplasty in described therein cement in the patient of 30-73%, and treat with the kyphoplasty art those 8-9% is only arranged.

In vertebroplasty and kyphoplasty art, by the bone that bone cement is strengthened and replacement is fractured.Unfortunately, bone cement obviously be better than contiguous bone and can to around vertebra apply incompressible mass effect (mass effect) thus cause by the compression and the fracture of the vertebra up and down at the position of being treated.The invention provides the injectable compositions as vertebroplasty and kyphoplasty art part, it comprises extender or filler and the fibrous tissue formation agent that is injected directly in the vertebra compression fracture.The material that will comprise the fibre modification derivant is (alone or in combination with polymer support, described carrier can be with example gel, paste, or spray form exists) thus be expelled to the growth filling vertebral body defective that can be used to promote endogenous cicatrization tissue in the vertebra compression fracture, therefore closer imitate normal structure kinetics and reduce the incidence rate that adjacent vertebrae is fractured.In another embodiment, the Injectable composition that comprises the fibre modification derivant can also comprise the reagent of promote osteogenesis (for example, bone morphogenetic protein, somatomedin etc.).When the injection implemented the vertebra compression fracture, adding compositions also is essential with the visuality that increases pin (or conduit).Reagent that is fit to that is used in combination with fibre modification derivant (having or do not have the reagent of promote osteogenesis) and method include, but not limited to use by the pin of ECHO-COAT bag quilt or (for example add contrast agent, barium, tantalum, technitium, gadolinium) to carry out location by X-ray or MRI.

Injectable material can also comprise polymer system, described system can provide the fibre modification derivant (with or not with the bone morphogenetic protein of following, and/or osteogenic growth factor together) thereby lasting release increase effect and reduce the needs of repetitive administration activating agent.Be suitable for sending injectable fibre modification derivant (with or not with the somatomedin of bone morphogenetic protein and/or promote osteogenesis) thus the preferred polymer support of treatment vertebra compression fracture is degradable material, it is replaced by the cicatrization tissue of health itself after initial tissue support is provided gradually.Be used in suitable degradable substance in the present embodiment include, but not limited to by bata-tricalcium phosphate form can resorbent Inorganic Non-metallic Materials (for example VITOSS and PROOSTEON 500R), hydroxyapatite or Ca ₁₀(PO ₄) ₆OH (for example, BIOOSS and OSTEOGRAF), calcium carbonate or CaCO ₃, calcium sulfate (for example, OSTEOSET and ALLOMATRIX), calcium phosphate (for example CALCIBON or NORIAN SRS), the crosslinked material of PEG, gelatin, collagen protein, (for example, the ALLOGRO of bone allograft, ORTHOBLAST, OPTEFORM, GRAFTON), mescenchymal stem cell, and hyaluronic acid (as RESTYLANE, HYLAFORM, PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT), derivatives of hyaluronic acids, polysaccharide, carbohydrate comprises the preparation (such as FLOSEAL or TISSEAL) of fibrinogen, and protein (for example, albumin, casein, lactalbumin, phytoprotein and fish protein etc.), from the body bone, the bone matrix that demineralizes, cellulose derivative is (for example, HPC etc.), chitosan, chitosan derivative, polyester-polyalkylene oxide block copolymer are (for example, PLGA-PEG-PLGA and MePEG-PLGA, etc.) and other can be by excretory low-molecular weight polymer.Also can be with the injectable preparation that comprises PEG such as COSEAL, FOCALSEAL, SPRAYGEL or DURASEAL are used for being expelled to the vertebra compression fracture, and described preparation loads with the fibre modification derivant, bone morphogenetic protein, and/or somatomedin.With the material of fibre modification derivant (with or not with bone morphogenetic protein, and/or the somatomedin of promote osteogenesis is together) load these materials and can produce injectable material, it can provide alleviating of initial support and symptom, but when the cicatrization tissue growth of health itself during with correction of the defect, it is degraded in time.

The interested especially injectable substance that is used for being expelled to the vertebra compression fracture is by 4-arm mercaptan PEG (10K), and 4-arm NHS PEG (10K) and methylated collagen protein are such as above-mentioned preparation.In a preferred embodiment, injectable material also comprise bioactive fiber degeneration derivant (with or not with bone morphogenetic protein, and/or the somatomedin of promote osteogenesis together).In one embodiment, load injectable material with the fibre modification derivant and be injected in the vertebra compression fracture so that stability and sx to be provided, form Muller's fibers and the ingrown support of bone, send and to promote the activating agent repaired, in case and degraded when finishing in tissue repairing.In another embodiment, injectable material comprise can induction of bone growth bioactivator such as bone morphogenetic protein and somatomedin (transforming growth factor, platelet derived growth factor, fibroblast growth factor) to promote the fusion of the strong and adjacent vertebrae of osteoarthrosis.In some cases, injectable material can comprise the somatomedin of fibre modification derivant and bone morphogenetic protein and/or promote osteogenesis.

(for example, in how unsettled treatment of fractures) in certain embodiments can be ideal thereby use bone cement to send the fibre modification derivant in the vertebra compression fracture.The non-degradable material that is fit to comprises crosslinked compositions, and described crosslinked compositions comprises PVA, PVP, polyacrylamide, methyl methacrylate (MMA) and methyl methacrylate-styrene (MMA-styrene) when they are mixed in a time-out, (for example form polymethyl methacrylate (PMMA) or bone cement, SIMPLEX P, ZIMMER REGULAR and ZIMMER LOW VISCOSITYCEMENT, PALACOS, CMW-1, CMW-2, or ENDURANCE).Be used in the synthetic property cancellus bone infilling (for example CORTOSS) that also has in the present embodiment, pHEMA gathers (vinyl PEG), poly-(styrene sulfonate), poly-(acrylic acid), poly-(methacrylic acid), and the polymer of other known formation hydrogel.Loading is with the fibre modification derivant, bone morphogenetic protein, and/or the surgical operation binding agent that comprises cyanoacrylate of somatomedin is such as DERMABOND, INDERMIL, GLUSTITCH, TISSUEMEND, VETBOND, HISTOACRYLBLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT also are suitable for being expelled in the vertebra compression fracture.Other compositions comprises the admixture and the copolymer of the reagent of listing above.In every kind of situation, described material be loaded with the fibre modification derivant (with or not with bone morphogenetic protein, and/or the somatomedin of promote osteogenesis together) and be injected into (as the part of vertebroplasty or kyphoplasty art) in the vertebral compression fracture thus stable fracture and promote the inside growth of tissue.The interpolation of fibrous tissue around nondegradable implant neutralization can make the characteristic of material and natural tissues is similar and the incidence rate of the fracture that minimizing is contiguous.

Thereby can also further modify the line that makes its line form or comprise polymer to above-mentioned all injectable materials by polymer.Polymer line has the ability of inducing the fibroplasia reaction from surrounding tissue.These polymer lines can be degradable or nondegradable.Degradable line can be by degradable polyester, polyanhydride, poe, poly phosphate, poly-phosphazine, cyanoacrylate polymer, collagen protein, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose, cellulose esters, its admixture and copolymer, and other known degradable polymer is formed.Operable non-degradable polymer include, but not limited to polyester (for example, PET), polyurethane, siloxanes, PE, PP, PS, PAA, PMA, the silk, its admixture, copolymer and other known polymer.Employed line can be made up of the admixture of single compositions or different components.Can come polymer line itself is further modified by the polymer coating that interpolation is applied on the described line.Be used to be coated with described line polymer can on to regard to described line itself described similar.Described polymer coating can also comprise bioactivator, and it has the ability of fibroplasia of inducing or osteogenic response.Operable fibre modification derivant is further described below part (vi).

Above-mentioned injectable substance can be used for the delivery of particles material, it has in the intervertebral disc fracture induces fibrotic ability.These granules are degradable or nondegradable and similar to above-mentioned at line those.Separately or load with additional fibers degeneration derivant, bone morphogenetic protein, and/or the microgranule silk of somatomedin and/or silk chain (linearity, side chain and/or curl) to be expelled to the vertebra compression fracture for orientation also be useful.The other particulate matter useful for putting into practice of the present embodiment comprises Talcum, starch, glass, silicate, Silicon stone, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic property mineral is (for example, VITOSS and CORTOSS), PMMA, silver nitrate, Inorganic Non-metallic Materials granule and other inorganic particle of inducing the fibroplasia reaction to carry out mineralising subsequently known in the art).The granule that is used in the present embodiment can be all same combinations or the admixture of different components.As mentioned above, can also be with these granules as the coating that is applied on the polymer chain.

Thereby can also make up injectable material makes it the two is formed by polymer line and granule.The line that uses and granule are to above-mentioned those are similar and can be uniform composition or mixed compositions.In fact, particulate any combination of the line of different components and different components can be used in the present embodiment.As described below, can be with hydrogel, polymer line and granule all are used to send one or more bioactivators.

A kind of concrete compositions comprises by 4-arm mercaptan PEG (10K), 4-arm NHS PEG (10K) and methylated collagen protein such as above-mentioned preparation and comprise pulverous granule (or silk thread) and/or be added to mineral particle in the compositions before treatment.In case use, described compositions can absorb water, the filling fracture gap also is attached on the contiguous bone.This expansion can stable fracture and is recovered vertebral levels, and simultaneously pulverous silk and/or mineral particle can start makes ankylopoietic reaction.As 4-arm mercaptan PEG (10K), 4-arm NHS PEG (10K) and methylated collagen composition begin degraded, and described material can be supported the inside growth by the osseous tissue of granule starting and reinforcement.Bone morphogenetic protein and/or somatomedin (front and back is described) also are used in and are included in this compositions.In addition, can also add or replace the 4-arm mercaptan PEG of all (or part) with the amino PEG of 4-arm.Described amino PEG can provide the gel that can need the longer time degraded and can provide some positive charges to the other porous material that attractability is arranged.

Second specific embodiments is made up of injectable implant, and described implant is made up of the polymerized form (that is, fibrous tissue forms the recurring unit that agent condenses together) that silk fibre or fibrous tissue form agent itself.Bone morphogenetic protein and/or somatomedin (front and back is described) can also be added said composition.

Tackling in those skilled in the art is to it is evident that potentially, above-mentioned any fibre modification derivant can be used alone or in combination in the practice of the present embodiment.The exemplary fibrous tissue formation agent that is used in the spinal prostheses (for example device and filler) comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF and above-mentioned analog and derivant.

Randomly, described device can comprise inflammatory cytokine (for example, TGF β, PDGF in addition, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) and/or bone morphogenetic protein (BMP) is (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant).

In addition, described device can be individually or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, all-trans retinoic acid (ATRA), and analog and derivant.

(vi) be described with the using of these reagent in the embodiment in the above with dosage part below.

(vi) spinal fusion device

In some cases, may be necessary be that the bone that promotes the adjacent vertebrae part merges (on biology effectively with described part " welding " together).The fusion of one or more vertebra parts is moved by impaired intervertebral disc by the restriction vertebra and is slowed down pain.Use several different methods, implant and device can be finished the surgical operation spinal fusion.

Typically, canalis spinalis is removed rope or the nerve root decompression that is affected fully to allow by open surgery (the preceding road and/or the way of escape) exposure and with part or all of damaged disc.Be used to promote vertebra to merge bone graft (autograft or allograft) or bone substituent, fixture makes the fixing fixedly generation up to bone in described zone simultaneously.As the operating part of spinal fusion, what often need is by when bone graft or bone substituent merge with standing part, inserts the implant or the device of the spine portion of stablizing fusion and strengthens this program.Be designed to clamp the implant of described part and the example of device comprises in therapeutic process: fusing device (comprises the fusion basket, merge support (cage) device, support between vertebral body, implant between vertebral body, merge the support anchoring device, merge equalization chamber, merge the support anchor plate), bone anchoring device (hone lamella that comprises grappling, bone screw and other mounting hardware) and tissue filler/implant (comprise bone cement, allograft material, the autotransplantation material, collagen protein and other biocompatible tissue filler).These all implants are suitable for the coating of fibre modification derivant or send it to promote healing and to quicken the fusion of vertebral body.

The spinal fusion support is the interbody that is adapted in intervertebral space and/or the zone, the preceding road of spinal column.The fusion support has different shape and comprises rectangle or cylindrical and a plurality of open and screw type screw threads (threading).Merge support and be made up of ectosome and hole usually, it can maybe cannot be used to insert bone growth promoting substance and merge to stimulate bone.For example, prosthese can be to merge support between vertebral body, and its profile that has that end stretches out outside convex is doing of wire, uses a series of plates, is that solid thing and solid screw are fixed it.See U.S.6 for example, 156,037.Described prosthese can be the fusion support with wire outer surface, when bone-when the growth inducing material is wrapped in the stake body, its be suitable for promoting and bone structure between fusion.See U.S.4 for example, 961,740; 5,015,247; 4,878,915; With 4,501,269.Described prosthese can normally have the piped shell of helical form filament, and it stretches out a plurality of pillars with hole and (sees, for example to promote inside growth of bone and mechanical anchor, U.S.6,071,310 and 5,489,308) or its can be bioactive and promote with the lamina of vertebra that is close between fusion (see, U.S.5 for example, 489,308 and 6,520,993).Other United States Patent (USP) of describing the wire spinal implant comprises U.S. Patent number 5,263,953; 5,458,638; With 5,026,373.

In yet another aspect, described prosthese can be a bone anchoring device, thereby it is designed to promote that vertebra merges the migration that is limited between the adjacent vertebrae.For example, can be with nail, bar, hook, tinsel (wire), wedge, plate, screw and other composition are used for vertebra is fixed to the position.Described fixture can be installed in the intervertebral space or it can only can be around the zone, preceding road of spinal column around the zone, preceding road of intervertebral space and spinal column or its.Thereby bone anchoring device can use in that device is stabilized in the intervertebral zone and helps out with merging support.For example, described prosthese can exist with solid ring bodies form, described ring bodies thereon surface and the outstanding a plurality of discontinuous bones of lower surface engage teeth and have can be with the centre bore of bone growth promoting substance filling.See U.S.6 for example, 520,993.Described prosthese can have the dish sample body that is placed in the apparent surface to increase the lateral stability of original position, and described dish sample body has the part of weld seam sample projection.See U.S.4 for example, 917,704.Described prosthese can partly be made up of opposing ends, and it keeps the height of interbody space with the littler complete center part of diameter, wherein the skeletonization material is placed in the ring-type bag between the end portion.See U.S.6 for example, 146,420.Described prosthese can be made up of first and second side surfaces that extend in parallel towards each other with upper surface and lower surface, and it engages contiguous vertebra.See, for example, U.S.5,716,415.Described prosthese can and have the fusion equalization chamber that at least one hole is formed with the end portion in the bone around being fixed to by the intervertebral space of hollow.See U.S.6 for example, 066,175.Described prosthese can be made up of metallic object, and described metallic object is held into coniform being tapered from the abdomen end to the back of the body, and has a plurality of fish platees (fishplate) that extend from the opposite flank, and described relative side has the hole of bone screw.See U.S.4 for example, 955,908.Described prosthese can be made up of a pair of plate, and described plate can have the projection that engages contiguous vertebra and be placed in collating unit between the fish plate, arranges thereby described plate separated they are maintained at lordosis.See U.S.6 for example, 576,016.Described prosthese can be a plurality of quilts implants to promote that bone merges by intervertebral space in the insertion dish gap side by side.See U.S.5 for example, 522,899.The anchoring device that described prosthese can be made up of anchor plate with core and end portion, described core has a definite form (for example to be attached to vertebral implant, merge support), described end portion is adapted to be fixed in fixed form the bone parts of vertebra.See, for example, 6,306,170.Described prosthese can be the bone anchoring device of being made up of hone lamella and fixture (for example, bone screw).See U.S.6 for example, 342,055; 6,454,769; 6,602,257; With 6,620,163.

Can comprise commercially available product with spinal prostheses according to one or more fibre modification derivant combinations of the present invention.Example comprises: INTERFIX wire fusing device is (by MedtronicSofamor Danek, Memphis, TN makes), BAK/C cervical vertebra mesosome emerging system and CERVI-LOK neck fixed system (by Centerpulse SPINE-TECH, Minneapolis, MN makes), the preceding road of SC-ACUFIX jugularia system is (by Spinal Concepts, Austin, TX makes), ACROFLE TDR prosthese and CHARIT

Artificial dish is (by DePuy Spine, Inc., Raynham, MA makes), PRODISC system and PRODISC neck-C IDE dish alternative (by Synthes-Stratec, Switzerland makes) and PROSTHETIC DISC NUCLEUS (by Raymedica, Inc., Minneapolis, MN makes).

In all aforementioned spinal fusion device, adding the fibre modification derivant can help out in the spinal fusion process by the generation that promotes fibrous tissue.On the one hand, body of the present invention provides spinal fusion device (to comprise the fusion basket, merge holder device, support between vertebral body, implant between vertebral body, fusion support anchoring device, fusion equalization chamber, fusion support anchor plate; The hone lamella that comprises grappling, the bone anchoring device of bone screw and other mounting hardware; With comprise bone cement, allograft material, the autotransplantation material, collagen protein, with the tissue filler/implant of other biocompatible tissue filler, thereby described device comprises the fibre modification derivant or comprises the compositions promotion cicatrization of fibre modification derivant and described device is fixed in bone on every side.On the one hand, thus form agent or comprise the compositions coating spinal fusion device that fibrous tissue forms agent with fibrous tissue and improve healing.On the other hand, fibrous tissue can be formed agent is attached in the fixing adhesive/cement in place of spinal fusion device.On the other hand, cover spinal fusion device (all or part) with silk screen eye or grid thus promote cicatrization and be anchored to around bone.For example, thus silk screen eye or grid can be covered in the surface of merging support or other bone mounting hardware all or part of go up promote cicatrization and be anchored to around bone.

The carrier system of aforesaid many polymerization rerum naturas and non-polymeric rerum natura can be used for providing of the lasting release of fibre modification derivant from spinal fusion device.With become fiber composition to be attached on the spinal fusion device or in method comprise: (a) directly will become fiber composition be attached to described device (for example, by aforesaid spraying process or dip coating, with or not with carrier); (b) directly will become fiber composition be attached in the described device (for example, by aforesaid spraying process or dip coating, with or not with carrier); (c) by being coated with described device such as the hydrogel that can absorb into fiber composition again with material; (d) by becoming in fiber composition braiding (for example, discharging the silk chain or the other polymer line of fibre modification derivant) the auto levelizer structure; (e) by described device is inserted in sleeve pipe or the mesh, described sleeve pipe or mesh are by becoming fiber composition to form or by its coating; (f) with becoming fiber composition construction device itself, or the part of described device; Or (g) directly be covalently bound to apparatus surface by fibrous tissue being formed agent, or in the joint (micromolecule or polymer), described joint is applied or be attached to apparatus surface.For these devices, can carry out coating process by this way, described mode is the surface of the device that contact with bone of (a) coating, (b) device that do not contact with bone of coating surperficial or (c) be coated with and contact all or part of with the surface of the device that does not contact with bone with bone.

Except with becoming the fiber composition coating spinal fusion device, thus can with the fibre modification derivant be used in the material of device in making up and mix fibrous tissue formation agent is attached in the final device.

Should it is evident that to those skilled in the art, any above-mentioned adhesion or fibre modification derivant can be used alone or in combination in the practice of the present embodiment potentially.Being used in spinal fusion device (comprises the fusion basket, merges holder device, support between vertebral body, implant between vertebral body, fusion support anchoring device, fusion equalization chamber, fusion support anchor plate; The hone lamella that comprises grappling, the bone anchoring device of bone screw and other mounting hardware; With comprise bone cement, allograft material, autotransplantation material, collagen protein, tissue filler/implant with other biocompatible tissue filler) exemplary fibers texturizer comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin, and CTGF, and aforesaid analog and derivant.

Randomly, described device can comprise inflammatory cytokine (for example, TGF β, PDGF in addition, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) and/or bone morphogenetic protein (BMP) is (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant).

In addition, described device can be individually or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, all-trans retinoic acid (ATRA), and analog and derivant.

(vi) be described with in these embodiments using of these reagent with dosage part below.

(v) intervertebral disk prosthesis

In some situation of DDD, use the intervertebral disk prosthesis of keeping vertebra anatomy and vertebral joint motion can treat impaired intervertebral part.This is carrying out when the damage that surpasses a vertebra part takes place usually.When being used for this paper, term " intervertebral disk prosthesis " (or " artificial dish ") refers to be positioned among the spinal column, on, or near implant and/or device, described implant and/or device increase spinal column is brought into play its function in the patient ability.The example of intervertebral disk prosthesis comprises, but be not limited to, artificial spine dish and relevant device, described relevant device comprises vertebral implant, the vertebra disc prosthesis, the lumbar intervertebral disc implant, cervical intervertebral disk implant, transplantable intervertebral prostheses, spinal prostheses, artificial dish, prosthetic implant, prosthese spinal disc, the spinal disc built-in prothesis, spinal implant, artificial spine dish, intervertebral implant, transplantable spinal implant, the artificial lumbar vertebra intercalated disc, spinal column nucleus (spinalnucleus) implant and intervertebral disc space district.

Be fit to can be made up of one matter or some materials with the artificial dish that makes up according to fibre modification derivant of the present invention, described material includes, but are not limited to the allograft bone material (to be seen, U.S.6 for example, 143,033), metal (is seen U.S.4 for example, 955,908), and/or synthetic property material (see, for example, U.S.6,264,695; 6,419,706; 5,824,093; With 4,911,718).Described prosthese must be a biocompatibility, and depends on being intended to function and can being made up of biodegradable or not biodegradable component of described device.See U.S.4 for example, 772,287.Described intervertebral disk prosthesis can be biological inert and can be used as the mechanical system (seeing U.S.4 for example, 955,908 and 5,716,415) of stabilizing spine or as the mode that keeps spinal function.On the other hand, described prosthese can be the alternative of spinal fusion.Described prosthese can be the dish that is designed to be provided at normal migration in the lamina of vertebra.Described artificial dish can tend to simulate natural damping of shocks (shock absorbent) function of natural disc.Described artificial dish can be made up of or it tends to only replace the part (for example, vertebral pulp) of natural disc centronucleus and connector assembly, and described connector assembly support is against the dish of adjacent vertebrae.For example, described artificial dish can exist to be clipped in two elastomer portion-forms in the rigid plate.See, for example, U.S.6,162,252; 5,534,030; 5,017,437; With 5,031,437.The elongation prosthetic disc marrow that described intervertebral disk prosthesis can be made up of hydrogel marrow (core) and restrictive flexible chuck, described chuck are allowed described marrow distortion and reorganization.See U.S.5 for example, 824,093.Described artificial dish can by above inflexible and following recessed-convex assembly and nucleome form, described nucleome moves allowing between concave surface.See U.S.6 for example, 156,067.The part spinal prostheses that described artificial dish can be made up of marrow, described marrow is made by elastic material such as siloxane polymer or elastomer, and described elastomer is covered by the protective sleeve of being made by the rigidity material that contacts with adjacent vertebrae.See U.S.6 for example, 419,706.Described intervertebral disk prosthesis can only replace nucleus pulposus by using the dorsal column nucleus implant, and described implant is by expandable, and bionical plastics and hydrophobic and aqueous favoring are formed, and it can be expanded in position to adapt to natural size and shape.See U.S.6 for example, 264,695.Described artificial dish can be made up of the center marrow, and described marrow forms the biocompatibility elastomer that wraps up from by multi-layer sheet, and described multi-layer sheet is formed by elastomer and fiber.See U.S.4 for example, 911,718.Described intervertebral disk prosthesis can by the capsula interna of fluid filled and mix with biology can be recrementitious firmly the skin of inert fiber is formed, but described biology recrement promotes tissue ingrowth.See, for example, U.S.4,772,287.

On the one hand, the invention provides intervertebral disk prosthesis, thus it compositions promotion cicatrization and fixing described flexibility that is installed in the bone on every side and keeps natural disc that comprises the fibre modification derivant or comprise the fibre modification derivant.On the one hand, with the described artificial dish of the fibre modification derivant compositions of fibre modification derivant (or comprise) coating to improve healing and to form the fibrous tissue that is similar to fibrous ring.On the other hand, fibrous tissue can be formed agent is attached to artificial dish is fixed in the adhesive/cement of correct position.On the other hand, with silk screen eye or grid cover (all or part of) thus described intervertebral disk prosthesis promote cicatrization and implant be anchored in the surrounding bone.

The carrier system of aforesaid many polymerization rerum naturas and non-polymeric rerum natura can be used for providing of the lasting release of fibre modification derivant from artificial dish.With become fiber composition to be attached on the intervertebral disk prosthesis or among method comprise: (a) directly will become fiber composition be attached to described device (for example, by aforesaid with or not with the spraying process or the dip coating of carrier); (b) directly will become fiber composition be attached in the described device (for example, by as mentioned above with or not with the spraying process or the dip coating of carrier); (c) by being coated with described device such as the hydrogel that can absorb into fiber composition again with material; (d) by becoming in fiber composition braiding (for example, discharging the silk chain or the other polymer line of fibre modification derivant) the auto levelizer structure; (e) by described device is inserted in sleeve pipe or the mesh, described sleeve pipe or mesh are by becoming fiber composition to form or by its coating; (f) with becoming fiber composition construction device itself, or the part of described device; Or (g) directly be covalently bound to apparatus surface by fibrous tissue being formed agent, or in the joint (micromolecule or polymer), described joint is applied or be attached to apparatus surface.For these devices, can carry out coating process by this way, described mode is the surface of the device that contact with vertebra of (a) coating, (b) device that do not contact with bone of coating surperficial or (c) be coated with and contact all or part of with the surface of the device that does not contact with bone with bone.

Except with becoming fiber composition to be coated with the artificial dish, mix with the material that is used for producing device and make fibrous tissue form agent to be attached to final prosthese intervertebral disc thereby fibrous tissue can be formed agent.

In one embodiment, (for example therapeutic agent directly can be attached in the preparation, directly the fibre modification derivant is attached in expandable, the bionical polymer, described polymer is used to produce artificial nucleus pulposus, and its original position expansion is to adapt to natural size and the shape of nucleus pulposus (intervertbral disc core)).In another embodiment, the fibre modification derivant can be attached to (for example, aforesaid micelle in the secondary carrier, liposome, Emulsion, microsphere, nanometer spheroids etc.), described carrier then is used in the structure of artificial dish or as the ingredient of artificial dish.

Should it is evident that to those skilled in the art, any above-mentioned fibre modification derivant can be used alone or in combination in the practice of the present embodiment potentially.The exemplary fibers texturizer that is used in the spinal prostheses (for example, device and filler) comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin, and CTGF, and aforesaid analog and derivant.

Randomly, described device can comprise inflammatory cytokine (for example, TGF β, PDGF in addition, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6 and growth hormone and/or bone hormone) and/or bone morphogenetic protein (BMP) is (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant).

In addition, described device can be individually or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, all-trans retinoic acid (ATRA), and analog and derivant.

(vi) be described with in these embodiments using of these reagent with dosage part below.

(vi) be used in the fibre modification derivant in the spinal disease

Because spinal prostheses and injectable thing are made with multiple configuration and size, the exact dose of using can be with the amount or the device size of injection, surface area and kind of design and change.Yet, some principle can be applied in the application of this area.Can be the function of per unit area (part of applied device) dosage with medication dose calculation, can measure the total drug dose of using, and can determine the suitable surface concentration of active medicine.No matter to the employed method of spinal prostheses, the exemplary fibers texturizer that is used alone or in combination should use under following administration is instructed with medicament administration:

Talcum is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the lip-deep steatitic accumulated dose of sending from spinal prostheses or be applied to spinal prostheses should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the steatitic accumulated dose that discharges from prosthese should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the steatitic dosage of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the spinal prostheses surface with Talcum.In one embodiment, Talcum from the surface of spinal prostheses or from compositions (for example, filler) thus in discharge and to promote fibre modification in the tissue in the period of a few hours to several months in the scope.Drug level in filler or other this material should be in above-mentioned scope, except being worth at mm ³In.For example, Talcum can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is to be used for purpose of the present invention with having active talcous analog of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the Talcum effect with half of above-mentioned parameter, use half in chemical compound of Talcum effect etc.) with the twice of above-mentioned parameter.

Silk is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep silk of sending from spinal prostheses or be applied to spinal prostheses should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the silk that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the silk of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the spinal prostheses surface with silk.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge silk with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the silk that the rate of release of medicine from spinal prostheses is used in combination the Cmin that makes 0.01nM-1000 μ M.In one embodiment, silk from the surface of spinal prostheses or from injectable compositions (for example, filler) thus in discharge and to promote fibre modification in the tissue in the period of a few hours to several months in the scope.For example, silk can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active silk of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles an effect with half of above-mentioned parameter, use half in chemical compound of silk effect etc.) with the twice of above-mentioned parameter.

Chitosan is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep chitosan of sending from spinal prostheses or be applied to spinal prostheses should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the chitosan that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the chitosan of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the spinal prostheses surface with chitosan.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge chitosan with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from spinal prostheses the chitosan of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, chitosan from the surface of spinal prostheses or from injectable compositions (for example, filler) thus in discharge and to promote fibre modification in the tissue in the period of a few hours to several months in the scope.For example, chitosan can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active chitosan of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the chitosan effect with half of above-mentioned parameter, use half in chemical compound of chitosan effect etc.) with the twice of above-mentioned parameter.

Polylysine is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep polylysine of sending from spinal prostheses or be applied to spinal prostheses should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the polylysine that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the polylysine of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the spinal prostheses surface with polylysine.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge polylysine with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from spinal prostheses the polylysine of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, polylysine from the surface of spinal prostheses or from compositions (for example, filler) thus in discharge and to promote fibre modification in the tissue in the period of a few hours to several months in the scope.For example, polylysine can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active polylysine of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the polylysine effect with half of above-mentioned parameter, use half in chemical compound of polylysine effect etc.) with the twice of above-mentioned parameter.

Fibronectin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep fibronectin of sending from spinal prostheses or be applied to spinal prostheses should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the fibronectin that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the fibronectin of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the spinal prostheses surface with fibronectin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge fibronectin with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from spinal prostheses the fibronectin of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, fibronectin from the surface of spinal prostheses or from compositions (for example, filler) thus in discharge and to promote fibre modification in the tissue in the period of a few hours to several months in the scope.For example, fibronectin can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active fibronectin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the fibronectin effect with half of above-mentioned parameter, use half in chemical compound of fibronectin effect etc.) with the twice of above-mentioned parameter.

Bleomycin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep bleomycin of sending from spinal prostheses or be applied to spinal prostheses should be no more than 100mg (scope of 0.01 μ g-100mg).The total amount of the bleomycin that discharges from prosthese in one embodiment, should be in the scope of 0.10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the bleomycin of the function of the surface area of the part of bonded device) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the spinal prostheses surface with bleomycin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge bleomycin with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the bleomycin that the rate of release of medicine from spinal prostheses is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, bleomycin from the surface of spinal prostheses or from compositions (for example, filler) thus in discharge and to promote fibre modification in the tissue in the period of a few hours to several months in the scope.For example, bleomycin can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active bleomycin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the bleomycin effect with half of above-mentioned parameter, use half in chemical compound of bleomycin effect etc.) with the twice of above-mentioned parameter.

CTGF is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep CTGF that sends from spinal prostheses or be applied to spinal prostheses should be no more than 100mg (scope of 0.01 μ g-100mg).In one embodiment, the total amount of the CTGF that discharges from prosthese should be in the scope of 0.10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the CTGF of the function of the surface area of the part of bonded device) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the spinal prostheses surface with CTGF.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge CTGF with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the CTGF that the rate of release of medicine from spinal prostheses is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, CTGF from the surface of spinal prostheses or from compositions (for example, filler) thus in discharge and to promote fibre modification in the tissue in the period of a few hours to several months in the scope.For example, CTGF can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active CTGF of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the CTGF effect with half of above-mentioned parameter, use half in chemical compound of CTGF effect etc.) with the twice of above-mentioned parameter.

As mentioned above, described device can comprise inflammatory cytokine (for example, TGF β, PDGF in addition, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) and/or bone morphogenetic protein (BMP) is (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant).

Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, with bone morphogenetic protein (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant) be used in the preparation with concentration range from 0.001 μ g/ml to about 20mg/ml.Preferably, bone morphogenetic protein discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.001 μ g is to the scope of 500mg); Preferred 1 μ g is to 250mg.When being used as the device coating, dosage is 0.001 μ g-1000 μ g/mm of per unit area ²Preferred dosage is 0.01 μ g/mm ²-200 μ g/mm ²With 10 ^-9-10 ^-4The Cmin of the bone morphogenetic protein of M maintains on the apparatus surface.

Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of inflammatory cytokine from 0.0001 μ g/ml to about 20mg/ml is used in the preparation.Preferably, inflammatory cytokine discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 100mg); Preferred 0.001 μ g is to 50mg.When being used as the device coating, dosage is 0.0001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.001 μ g/mm ²-200 μ g/mm ²With 10 ^-10-10 ^-4The Cmin of the inflammatory cytokine of g/ml maintains on the apparatus surface.

In addition, described device can be separately or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA), and analog and derivant.Used dosage is to be proved to be those concentration (seeing embodiment 16) that stimulate cellular proliferation.Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of multiplication agent from 0.1ng/ml to 25mg/ml is used in the preparation.Preferably, multiplication agent discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 200mg); Preferred 0.001 μ g is to 100mg.When being used as the device coating, dosage is 0.00001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.0001 μ g/mm ²-200 μ g/mm ²With 10 ^-11-10 ^-6The Cmin of the multiplication agent of M maintains on the apparatus surface.

Should be that it is evident that can be with aforementioned fibers degeneration derivant for those skilled in the art, or derivatives thereof and analog any under the situation that does not deviate from spirit and scope of the invention be used to produce the variation of above-mentioned composition.Also should it is evident that described reagent can be used in the compositions that has or do not have polymer support and change described carrier and not deviate from scope of the present invention.So, in brief, aspects more of the present invention are: a kind of method, it comprise will the treatment effective dose fibrous tissue form agent or comprise that the compositions that fibrous tissue forms agent introduces in the patient's who needs it the intervertebral disc space, wherein said fibrous tissue forms agent and induce the fibre modification reaction in patient's intervertebral disc space, provides useful effect to the patient thus.Randomly, subsequently standard one or more can be used to describe this aspect of the present invention: useful effect is the repairing of spinal disc; Useful effect is fibrous ankylosis; Useful effect is a bony ankylosis; Described reagent promotes regeneration; Described reagent promotes blood vessel to take place; Described reagent promotes the fibroblast migration; Described reagent promotes fibroblast proliferation; Described reagent promotes the deposition of extracellular matrix (ECM); Described reagent promotes to reinvent, i.e. ripe the and composition of fibrous tissue; Described reagent is the ductus arteriosus wall stimulant; Described fibrous tissue forms agent and is or comprises silk; Described fibrous tissue forms agent and is or comprises silkworm silk; Described fibrous tissue forms agent and is or comprises spider silk; Described fibrous tissue forms the silk that agent is or comprises reorganization; Described fibrous tissue forms agent and is or comprises raw silk; Described fibrous tissue forms the silk that agent is or comprises hydrolysis; Described fibrous tissue formation agent is or comprises with acid-treated silk; Described fibrous tissue forms the silk that agent is or comprises acidylate; Described fibrous tissue formation agent exists with the form of chain; Described fibrous tissue form agent with bunch form exist; Described fibrous tissue formation agent exists with the form of microgranule; Described fibrous tissue forms agent and is or comprises mineral particle; Described fibrous tissue forms agent and is or comprises Talcum; Described fibrous tissue forms agent and is or comprises chitosan; Described fibrous tissue forms agent and is or comprises polylysine; Described fibrous tissue forms agent and is or comprises fibronectin; Described fibrous tissue forms agent and is or comprises bleomycin; Described fibrous tissue forms agent and is or comprises CTGF; Described fibrous tissue formation agent exists with the form of line, or contacts with line, randomly, described line be biodegradable (for example., it comprises the material that is selected from by the following group of forming: polyester, polyanhydride, poly-(acid anhydride ester), poly-(ester-amide), poly-(ester-urea), poe, poly phosphate, polyphosphazine, polybutylcyanoacrylate, collagen protein, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose, cellulose esters), or described line be not biodegradable (for example, it comprises the material that is selected from by the following group of forming: polyester, polyurethane, siloxanes, polyethylene, polypropylene, polystyrene, poly-propionic ester, poly-methylpropionate, and silk), with polymer-coated described line, be used in and induce the medicament of fibre modification reaction to be coated with described line among the patient, the medicament that is used in induced osteogenesis reaction among the patient is coated with described line; Described compositions also comprises the reagent of promote osteogenesis; The reagent of promote osteogenesis is that the reagent of bone morphogenetic protein or promote osteogenesis is osteogenic growth factor (for example, transforming growth factor, platelet-derived somatomedin and fibroblast growth factor); Described compositions comprises that also (sclerosing agent for example is selected from the sclerosing agent by the following group of forming to the medicament of inducing sclerosis: ethanol, dimethyl sulfoxine, sucrose, sodium chloride, dextrose, glycerol, minocycline, tetracycline, doxycycline, Polidocanol, sodium tetradecyl sulfate, sodium morrhuate, Sotradecol, or described sclerosing agent can be a surfactant); Described compositions also comprises inflammatory cytokine (for example, being selected from the β by TGF, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, the inflammatory cytokine of the group that IL-6 and growth hormone are formed); Described compositions comprises that also the medicament that stimulates cellular proliferation (for example, is selected from by dexamethasone isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, all-trans retinoic acid (ATRA), and the cell proliferating agent of the group of analog and derivant composition); Described compositions also comprises filler; Described compositions also comprises sealant; Described compositions also comprises polymer support; Described compositions also comprises can resorbent Inorganic Non-metallic Materials; Described compositions also comprises contrast agent; Described compositions also comprises line; Described compositions exists with the form of gel; Described compositions exists with the form of paste; Described compositions exists with the form of spray; Described compositions exists with aerocolloidal form; Described compositions exists with the form of suspension; Described compositions exists with the form of Emulsion or microemulsion; Described compositions exists with the form of microsphere; Described compositions exists with the form of microgranule; Described compositions exists with the form of solid implant.

2. joint implant

The invention provides the combination of fibre modification derivant and prosthese joint implant.When being used for this paper, term " joint implant " refers to be designed to replace the implant in the joint of weakened physically or damage.The example of joint implant includes, but not limited to rectificating surgery implant, orthopedics's prosthese, modular implant, prosthese joint, modular prosthese, articular prosthesis, local prosthese, hip implant, knee implant, shoulder implant and finger toe implant.The rectificating surgery implant of other type that can be used in combination with joint implant comprises, for example, hardware, such as inside and outside fixture, pin, plate and screw.

On the one hand, rectificating surgery implant is the internal fixation implant.The internal fixation implant is implanted patient of mode (normally nonvolatil) that can rebuild with the orthopedics of invasive degree minimum and the fixing and stable medical apparatus of often indicating limb fracture and unstable fracture.

The representative example of internal fixation implant comprises marrow inner fixing device such as nail between marrow and plate and screw combination; Bar in the marrow is stablized the vertical through (transarticular) in joint pin of serious fracture of ankle, plate (as, by titanium, the plate that rustless steel etc. are made), the plate with spring of support subchondral bone, slap the dorsal plate of application, elastic plate, screw, clip, pin, nail, ridge, tinsel, subgrade shape (sublaminar) tinsel and vertebra is placed the metal prostheses of tram.

The internal fixation implant can be used in the multiple open internal fixation that resets (ORIF) program.The open internal fixation that resets is a kind of method of the bone with surgery operative repair fracture, and it typically comprises and uses in plate and screw or the marrow (IM) bar to arrange and stable fracture.For example, the IM bar can be inserted the acra long bone (as, femur or tibia) in the medullary canal at center.

On the other hand, rectificating surgery implant is the component (for example, pin, tinsel, bolt or stake) of external fixation device or the implanted part (that is, being positioned at the intravital part of patient) of external fixation device (being also referred to as " external stability implant " at this paper).Thereby external fixation device is to be used for fixing the medical apparatus that bone is allowed knitting.Be used in external fixation device in the orthopaedic surgery of multiple intrusion degree minimum and be the alternative of fixture such as the model of other type and inner fixing device.

In brief, can be by placing the bone of fracture both sides successfully to realize external stability on pin or screw.Then, at external preparation for skin clip and bar pin is fixed together, it can form external frame.

External fixer typically comprises and is placed in acra, the outside and adhesion metal silk such as limb, the support of pin etc. or framework.Described device keeps taking place up to healing in place, then is removed when healing takes place, and does not stay any foreign body at acra.

External fixer can take various ways and can have one-sided, multiplanar or mixed structure.One-sided fixture comprises bar or the fence that adheres to the pin that pierces through bone (for example, femur).The Multiplanar external fixer can comprise the part of ring or ring, and it has the fixed pin that adheres to and/or the tinsel that can be used to guarantee bone.Hybrid system can comprise the framework that both form by ring (multiplanar) and bar (one-sided).

External fixer can also be according to their function, and for example, described device can be fixed or the classifying of migration.Fixture can be used for the segmental arrangement of bone (that for example, fractures is stable rapidly) and keep in place to removing the time from time of application.On the contrary, the animal migration fixture can be used in the recovery gradually of acute acra fracture.The configuration of animal migration fixture can change in time to proofread and correct gradually.

External fixer can be used for the treatment of multiple disease.For example, external fixer can be used for fixing damage such as articular fracture.External fixation can provide rapidly or fracture is gradually recovered.Especially, external fixer can be used in cardines-articular fracture, and open fracture and having in the treatment of fractures of bone-loss comprises, for example, near the fracture in joint such as distal radius, in proximal tibia level ground and the distal tibia pilon fracture.Other of external fixer used the treatment that comprises reconstruction capability orthopedics program such as deformity, bone-loss, contracture, disconnected (loose or atrophy) treatment and limb difference in length.

The modular prosthese is the prosthese with a plurality of components (two or more), and it can be assembled to form whole biomethanics structure.Before implanting prosthetic, thereby surgeon can be adjusted the needs that the various characteristics of component adapt to each patient.For example, the modular prosthese can have and can be adjusted independently by surgeon the component of (rotatably and axially), maybe can change the length of component.The modular prosthese can be used in the various surgical procedure.Described modular prosthese can be adjustable long bone prosthese, thereby it can adjust the difference that solves in treating alternate long bone measurement in the patient.Thereby exist prosthetic joint to substitute hip, knee and ankle joint with modular component.Other representative example of modular orthopedics prosthese comprises the modular femoral shaft, modular shoulder prosthesis and modular elbow prosthese.

The long-term reason of many artificial joint faults is in implant and described implant is anchored on unclamping of taking place in time between the surrounding bone of correct position.Inadequate bone and tissue growth can cause the unsuccessful acute combination of implant or unclamp afterwards and can take place in time.In the situation of hip, for example, the patient of as many as 5% can suffer joints open in back 10 years in implantation.Symptom comprises the pain that can make people's weakness and finally causes the repetition surgical operation also may repair implant.

(i) hip implant

In the artificial femoral articulation, described hip implant replaces the front portion (that is sphere) of femur and/or (acetabular bone) (that is the mortar) in joint.Typically, because non-inflammatory degenerative arthritis (for example, osteoarthritis, post-traumatic arthritis), the inflammatory degenerative arthritis (for example, rheumatoid arthritis, infective arthritis), wound is (for example, the fracture of pelvis or hip), congenital hip dysplasia, or the irremediable damage that causes of stremma and the inductive damage of other fracture at femur and/or acetabular bone, hip joint is substituted.The hip implant typically comprises two or three component system, and it comprises femoral shaft or shin, femur shin and be suitable for acetabular bone or the sphere of prosthese acetabular cup.Femoral shaft, neck and sphere, and acetabular cup can be made up of metal (for example, titanium, titanium alloy, cobalt-chromium or chromium-molybdenum) or polymer synthetic.For the hip implant being fixed in the existing femur of host, (for example use bone cement, methyl methacrylate) surface treatment that the hip implant can be joined in the bone or use to no cement (for example, the porous coating, such as hydroxyapatite porous coating, or the sponginess coating) can fix described hip implant thus the hip implant allow that osteogenesis from femur is to be anchored to it position.

On the one hand, the hip implant can be used to the hip substituent that provides enough.For example, described hip implant can be the prosthese of the three module altogether with initial fixation that is designed, described initial fixation can comprise pin that partial linear extends being inserted in the shaft of femur, and described insertion provides rotation adjustment between shaft of femur and described pin to carry out various arrangements and size combinations.See, for example, U.S.4,938,773.Described hip implant can be by sphere, and neck and fixation kit are formed, and its assembly that has is adapted to limit the dislocation of sphere and the mode of selecting directed fixation kit is provided.See U.S.6 for example, 042,611.Described hip implant can be designed to two components that connected by the joint mutually, it is made up of cochrome, and one of them has low carbon content and another component has high-carbon content.See, for example, U.S.5,904,720.

In yet another aspect, described hip implant can be adapted to be glued onto in the position to guarantee in accurate position stability implant.For example, the hip implant can be by forming along the cement interstitial area of doing (shaft), and it allows the optimum thickness that cement covers behind the spinal canal of implanted femur.See U.S.5 for example, 314,489.

In yet another aspect, the hip implant can be a module, in described module, can adjust shape or size to be suitable for the host to component.For example, described hip implant can be by a plurality of transportable, the modular hip prosthesis that the pipe boxes of different sizes are formed, and described pipe box can be used to extend femoral shaft component or neck size, the customization thing that it becomes described implant to be suitable for concrete host.See U.S.5 for example, 507,830.

On the other hand, can design so that the damping of shocks effect to be provided in the joint the hip implant.For example, described hip implant can be made up of extension assembly, and described extension assembly extends coaxially from the sphere part, and described sphere part movably extends in the chamber that comprises the spring that carries out the damping of shocks effect.See U.S.5 for example, 389,107.The hip implant can be a modular damping of shocks effect prosthese, and it is designed to have adjustable femoral shaft, neck and sphere, and because the adjustable tension force of its unique coupling module spring mechanism.See, for example, U.S.6,336,941.

On the other hand, thus the hip implant can be formed hardness or the retentivity that provides bigger in femur by composite.For example, described hip implant can be made of (for example, by carbon, Inorganic Non-metallic Materials, metal or glass fiber are formed) a plurality of fibrous layers in substrate (for example, polymeric matrix), and wherein can to divide in other layer at each be unidirectional substantially to fiber.See, for example, U.S.5,522,904,5,163,962,5,064,439 and 4,892,552.Described hip implant can have by interior metallic core and outer plyability shell form dried, described shell has with the bonded fiber of thermoplastic resin and its far-end and is suitable for being inserted in the chamber that forms in the bone.See U.S.5 for example, 314,492.Described hip implant can be made up of expandable material, thus its absorb body fluids and the part that makes implant that enlarges in the hole of the bone of host are maintained in the bone and the part of implant in the outside of bone.See, for example, U.S.6,361,565.

On the other hand, the hip implant can only be the hip substituent of part.For example, described hip implant can be a prosthese acetabular cup assemblage, and it is made up of the supporting assembly (bearing component) of the sphere of accepting to be attached to femur and the shell component that is attached to acetabular bone.See, for example, U.S.5,049,158.In addition, other hip implant can be improved hip prosthesis, and it has and increases the fixed design features of implant in the zone with bone defective.For example, described hip implant can be long dryness hip prosthesis device and be designed to have the specificity curved distal segment, described device has the distal portions of the length of femur component, and in the time of in being implanted in spinal canal, the distal portions of described length extends on the gorge of femur (isthmus).See, for example, U.S.4,871,369.Other description about the hip implant is provided in U.S.5,755,810; 5,336,265; 5,286,260; 5,019,108; 4,986,834; 4,808,186; With 4,670, in 015.

Can make up with one or more hip implants and comprise many commercially available products according to medicine of the present invention, for example from DePuy Orthopaedics, Inc. (Warsaw, S-ROMTotal Hip System IN) and AML Total Hip System.

On the one hand, the invention provides hip prosthesis, thereby it compositions that comprises the fibre modification derivant or comprise the fibre modification derivant promotes cicatrization to provide on the bone around described device is fixed on.On the one hand, form agent with fibrous tissue or comprise that the compositions of fibrous tissue formation agent is coated with described hip prosthesis.On the other hand, fibrous tissue can be formed agent and be attached to adhesive or the cement that prosthese is placed correct position.On the other hand, described hip prosthesis cover with (all or part of) thus silk screen eye or grid promote cicatrization and be anchored on around bone in.For example, thus silk screen eye or grid can be applied to surface that implant does all or part of go up promote cicatrization and be anchored on around bone in.

The carrier system of aforesaid many polymerization rerum naturas and non-polymeric rerum natura can be used for the practice of the present embodiment.These compositionss may further include one or more fibre modification derivants to promote the formation of granulation tissue (granulation tissue).With become fiber composition to be attached on the rectificating surgery implant or among method comprise: (a) directly will become fiber composition be attached to described device (for example, by aforesaid with or not with the spraying process or the dip coating of carrier); (b) directly will become fiber composition be attached in the described device (for example, by as mentioned above with or not with the spraying process or the dip coating of carrier); (c) by being coated with described device such as the hydrogel that can absorb into fiber composition again with material; (d) be woven in the described apparatus structure by the line (or polymer itself of formation line) that will become the fiber composition coating; (e) by described device is inserted in sleeve pipe or the mesh, described sleeve pipe or mesh are by becoming fiber composition to form or by its coating; (f) with becoming fiber composition construction device itself, or the part of described device; And/or (g) directly be covalently bound to apparatus surface by fibrous tissue being formed agent, or on the joint (micromolecule or polymer), described joint is applied or be attached to apparatus surface.For these devices, can carry out coating process by this way, described mode is the surface of the device that contact with bone of (a) coating, (b) device that do not contact with bone of coating surperficial or (c) be coated with and contact all or part of with the surface of the device that does not contact with bone with bone.

Except with becoming fiber composition to be coated with the described device, mix with the material that is used for making described device and make fibrous tissue form agent to be attached to final device thereby fibrous tissue can be formed agent.

Should it is evident that to those skilled in the art, in the practice of the present embodiment, any aforementioned binding agent or fibre modification derivant can be used alone or in combination potentially.The exemplary fibers texturizer that is used for hip prosthesis comprises Pulvis Talci, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin, and CTGF, and aforesaid analog and derivant.

Because hip prosthesis is made with multiple configuration and size, the exact dose of using can be with the device size, surface area and kind of design and change.Yet, some principle can be applied in the application of this area.Can be the function of per unit area (part of applied device) dosage with medication dose calculation, can measure the total drug dose of using, and can determine the suitable surface concentration of active medicine.No matter how medicament administration arrives the employed method of hip prosthesis, the exemplary fibers texturizer that is used alone or in combination should use under following administration is instructed:

Talcum is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from hip prosthesis, send or be applied to the lip-deep steatitic accumulated dose of hip prosthesis and should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the steatitic accumulated dose that discharges from prosthese should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the steatitic dosage of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the hip prosthesis surface with Talcum.In one embodiment, thus Talcum discharges from the surface of hip prosthesis and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, Talcum can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is to be used for purpose of the present invention with having active steatitic analog of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the Talcum effect with half of above-mentioned parameter, use half in chemical compound of Talcum effect etc.) with the twice of above-mentioned parameter.

Silk is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep silk of sending from hip prosthesis or be applied to hip prosthesis should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the silk that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the silk of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the hip prosthesis surface with silk.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge silk with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the silk that the rate of release of medicine from hip prosthesis is used in combination the Cmin that makes 0.01nM-1000 μ M.In one embodiment, thus silk discharges from the surface of hip prosthesis and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, silk can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active silk of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles an effect with half of above-mentioned parameter, use half in chemical compound of silk effect etc.) with the twice of above-mentioned parameter.

Chitosan is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep chitosan of sending from hip prosthesis or be applied to hip prosthesis should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the chitosan that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the chitosan of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the hip prosthesis surface with chitosan.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge chitosan with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from hip prosthesis the chitosan of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, thus chitosan discharges from the surface of hip prosthesis and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, chitosan can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active chitosan of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the chitosan effect with half of above-mentioned parameter, use half in chemical compound of chitosan effect etc.) with the twice of above-mentioned parameter.

Polylysine is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep polylysine of sending from hip prosthesis or be applied to hip prosthesis should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the polylysine that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the polylysine of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the hip prosthesis surface with polylysine.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge polylysine with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from hip prosthesis the polylysine of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, thus polylysine discharges from the surface of hip prosthesis and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, polylysine can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active polylysine of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the polylysine effect with half of above-mentioned parameter, use half in chemical compound of polylysine effect etc.) with the twice of above-mentioned parameter.

Fibronectin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep fibronectin of sending from hip prosthesis or be applied to hip prosthesis should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the fibronectin that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the fibronectin of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the hip prosthesis surface with fibronectin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge fibronectin with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from hip prosthesis the fibronectin of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, thus fibronectin discharges from the surface of hip prosthesis and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, fibronectin can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active fibronectin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the fibronectin effect with half of above-mentioned parameter, use half in chemical compound of fibronectin effect etc.) with the twice of above-mentioned parameter.

Bleomycin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep bleomycin of sending from hip prosthesis or be applied to hip prosthesis should be no more than 100mg (scope of 0.01 μ g-100mg).The total amount of the bleomycin that discharges from prosthese in one embodiment, should be in the scope of 0.10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the bleomycin of the function of the surface area of the part of bonded device) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the hip prosthesis surface with bleomycin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge bleomycin with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the bleomycin that the rate of release of medicine from hip prosthesis is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, thus bleomycin discharges from the surface of hip prosthesis and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, bleomycin can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active bleomycin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the bleomycin effect with half of above-mentioned parameter, use half in chemical compound of bleomycin effect etc.) with the twice of above-mentioned parameter.

CTGF is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep CTGF that sends from hip prosthesis or be applied to hip prosthesis should be no more than 100mg (scope of 0.01 μ g-100mg).In one embodiment, the total amount of the CTGF that discharges from prosthese should be in the scope of 0.10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the CTGF of the function of the surface area of the part of bonded device) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the hip prosthesis surface with CTGF.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge CTGF with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the CTGF that the rate of release of medicine from hip prosthesis is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, thus CTGF discharges from the surface of hip prosthesis and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, CTGF can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active CTGF of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the CTGF effect with half of above-mentioned parameter, use half in chemical compound of CTGF effect etc.) with the twice of above-mentioned parameter.

Randomly, described device can comprise inflammatory cytokine (for example, TGF β, PDGF in addition, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) and/or bone morphogenetic protein (BMP) is (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant).

According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or required surface area cover, with bone morphogenetic protein (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant) be used in the preparation with concentration range from 0.001 μ g/ml to about 20mg/ml.Preferably, bone morphogenetic protein discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.001 μ g is to the scope of 500mg); Preferred 1 μ g is to 250mg.When being used as the device coating, dosage is 0.001 μ g-1000 μ g/mm of per unit area ²Preferred dosage is 0.01 μ g/mm ²-200 μ g/mm ²With 10 ^-9-10 ^-4The Cmin of the bone morphogenetic protein of M maintains on the apparatus surface.

According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of inflammatory cytokine from 0.0001 μ g/ml to about 20mg/ml is used in the preparation.Preferably, inflammatory cytokine discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 100mg); Preferred 0.001 μ g is to 50mg.When being used as the device coating, dosage is 0.0001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.001 μ g/mm ²-200 μ g/mm ²With 10 ^-10-10 ^-4The Cmin of the inflammatory cytokine of g/ml maintains on the apparatus surface.

In addition, described device can be separately or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA), and analog and derivant.Used dosage is to be proved to be those concentration (seeing that embodiment 16) that stimulate cellular proliferation.According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of multiplication agent from 0.1ng/ml to 25mg/ml is used in the preparation.Preferably, multiplication agent discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 200mg); Preferred 0.001 μ g is to 100mg.When being used as the device coating, dosage is 0.00001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.0001 μ g/mm ²-200 μ g/mm ²With 10 ^-11-10 ^-6The Cmin of the multiplication agent of M maintains on the apparatus surface.

Should it will be apparent to one skilled in the art that aforementioned fibers degeneration derivant, any of or derivatives thereof and analog can be used to produce the variation of above-mentioned composition under the prerequisite that does not deviate from spirit and scope of the invention.Also should it is evident that described reagent can with or be not used in the compositions and change described carrier and do not depart from scope of the present invention with polymer support.

(ii) knee joint implant

On the one hand, the invention provides the knee joint implant, it is induced fibre modification or implant is attached in the surrounding tissue.Knee joint replaces normally needs of patients of surgical operation, and described patient suffers from serious gonalgia and because of rheumatoid arthritis, the deformity that osteoarthritis or wound cause their articular cartilage damage to bring.Easing the pain and recovering in the function of joint this is the height successful method.The arthroplasty of knee program extensively is categorized as initial property or the property revised and be (unicompartmental) (part) of not distinguished or whole.Can be used to replace knee prostheses (this paper is called the knee joint implant) kneed all or part of.In total knee arthroplasty (TFA), femur (femur), the ill cartilage surface of tibia (tibia) and Patella (patella), by metal alloy (for example, titanium or based on the alloy of cobalt/chromium) and the prosthese made of senior plastics and polymer material (for example, VHD polyethylene) replace.Other structure of the great majority of knee is formed ligament such as knot and is kept perfectly.In the process of TKA, nearly three bone surfaces can be substituted: the far-end of femur (condyle), the nearly surface of tibia and patellar rear surface.Thereby design component makes metal be connected in plastics always, and it provides level and smooth migration and causes minimum wearing and tearing.

Knee implant typically has three components (that is, femur, tibia and patella component).Thereby described metal femur component the terminal bent around of femur and have septal fossula when knee bends when stretching, described patella can move up and down with respect to bone smoothly.Usually, new surface of end that bulk is used to give bone.If femur only has a condyle to be damaged, littler piece can be used for (the knee substituent of not distinguished) and give this part of described bone with new surface.Some designs (for example, back Stability Design) have inner post, and described inner post has annular device (cam), thus its work when the knee bends with corresponding tibia component, help prevent femur too far away to front slide on tibia.The tibia component is a flat metal platform with polyethylene pads.Described pad can be the part (fixed) or the separator (migration) of platform, and described separator has plane surface (PCL-keeps) or raises, the surface of inclination (PCL-replaces).The patella component is poly dome-shaped, and it duplicates the patellar shape that is anchored on the flat metal plate.In case knee prostheses is implanted and arrangement, by adhesive, use the non-adhesive method, or by the Mixed Stationary method, the knee joint substituent is fixing in place.

Multiple knee prostheses has been described.For example, U.S. Patent number 6,443,991 knee prostheses have been described in; 6,402,786; 6,068,658; 6,558,427; 6,554,866; 6,447,549; 6,419,707; 6,143,034; 6,120,546; With 6,074, in 424.Be suitable for making up and comprise many commercially available products with knee joint implant according to one or more fibre modification derivants of the present invention.These comprise, for example, and from NEXGEN LEGACY Knee Posterior Stabilized (LPS) and the NEXGEN LEGACY LPS femur component (Femoral Component) of Zimmer.Other example that is suitable for sending the knee joint implant of fibre modification derivant comprises Stryker Howmedica OsteonicsDURACON Total Knee System, SCORPIO Knee System and SCORPIOCruciate Retaining Single Axis Knee; The implant that can be purchased from DePuy Orthopaedics is such as LCS Total Knee System, P.F.C.Sigma RP Platform Knee System, KeaneUni-Compartmental Knee System, P.F.C.Sigma Uni-Compartmental KneeSystem, AMK Total Knee System, P.F.C.Sigma Knee System (Cruciate-Retaining), P.F.C.Sigma Knee System (Cruciate-Substituting), Coordinate Revision Knee System, P.F.C.Sigma Knee System TC3 Revision implant and S-ROM Noiles Rotating Hinge; From Smith ﹠amp; The knee joint implant of NephewOrthopaedics such as GENESID I and GENESIS II Total KneeSystems.Other manufacturer initial and the improvement knee implant who is suitable for use among the present invention comprises Biomet, Inc. (Warsaw, IN), Sulzer Orthopedics, Inc. (Austin, TX), WrightMedical Technologies, Exactech, Inc., (Henderson NV), is called Zimmer to Encore Orthopedics Corporation now, Inc., StelKast Company (McMurray, Implex PA), Hayes Medical, Inc. (El Dorado Hills, CA) and Link Orthopedics (PineBrook, NJ).

On the one hand, thus the knee prostheses that the invention provides the compositions that comprises the fibre modification derivant or comprise the fibre modification derivant promotes cicatrization and device is fixed on around bone in.On the one hand, described knee prostheses is coated with the compositions that a kind of fibrous tissue forms agent or comprises described fibrous tissue formation agent.On the other hand, described fibrous tissue can be formed agent mixes in the adhesive or cement that described prosthese maintenance is motionless.On the other hand, described knee prostheses covering (whole or in part) is gone in the bone on every side to promote cicatrization and grappling with silk screen eye or grid.For example, the silk screen eye or the network coverage can be gone in the bone on every side with promotion cicatrization and grappling to all or part of surface of implant stem.

The carrier system of aforesaid many polymerization rerum naturas and non-polymeric rerum natura can be used for the practice of the present embodiment.These compositionss may further include one or more fibre modification derivants to promote the formation of granulation tissue.With become fiber composition to be attached on the rectificating surgery implant or among method comprise: (a) directly will become fiber composition be attached to described device (for example, by aforesaid with or not with the spraying process or the dip coating of carrier); (b) directly will become fiber composition be attached in the described device (for example, by as mentioned above with or not with the spraying process or the dip coating of carrier); (c) by being coated with described device such as the hydrogel that can absorb into fiber composition again with material; (d) be woven in the described apparatus structure by the line (or polymer itself of formation line) that will become the fiber composition coating; (e) by described device is inserted in sleeve pipe or the mesh, described sleeve pipe or mesh are by becoming fiber composition to form or by its coating; (f) with becoming fiber composition construction device itself, or the part of described device; Or (g) directly be covalently bound to apparatus surface by fibrous tissue being formed agent, or on the joint (micromolecule or polymer), described joint is applied or be attached to apparatus surface.For these devices, can carry out coating process by this way, described mode is the surface of the device that contact with bone of (a) coating, (b) device that do not contact with bone of coating surperficial or (c) be coated with and contact all or part of with the surface of the device that does not contact with bone with bone.

Except with becoming fiber composition to be coated with the described device, mix with the material that is used for making described device and make fibrous tissue form agent to be attached to final device thereby fibrous tissue can be formed agent.

Should it is evident that to those skilled in the art, in the practice of the present embodiment, any binding agent or fibre modification derivant can be used alone or in combination potentially.The exemplary fibers texturizer that is used for knee prostheses comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin, and CTGF, and aforesaid analog and derivant.

Because knee prostheses is made with multiple configuration and size, the exact dose of using can be with the device size, surface area and kind of design and change.Yet, some principle can be applied in the application of this area.Can be the function of per unit area (part of applied device) dosage with medication dose calculation, can measure the total drug dose of using, and can determine the suitable surface concentration of active medicine.No matter how medicament administration arrives the employed method of knee prostheses, the exemplary fibers texturizer that is used alone or in combination should use under following administration is instructed:

Talcum is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from knee prostheses, send or be applied to the lip-deep steatitic accumulated dose of knee prostheses and should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the steatitic total amount that discharges from prosthese should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the steatitic dosage of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the knee prostheses surface with Talcum.In one embodiment, thus Talcum discharges from the surface of knee prostheses and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, Talcum can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is to be used for purpose of the present invention with having active steatitic analog of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the Talcum effect with half of above-mentioned parameter, use half in chemical compound of Talcum effect etc.) with the twice of above-mentioned parameter.

Silk is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep silk of sending from knee prostheses or be applied to knee prostheses should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the silk that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the silk of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the knee prostheses surface with silk.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge silk with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the silk that the rate of release of medicine from knee prostheses is used in combination the Cmin that makes 0.01nM-1000 μ M.In one embodiment, thus silk discharges from the surface of knee prostheses and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, silk can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active silk of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles an effect with half of above-mentioned parameter, use half in chemical compound of silk effect etc.) with the twice of above-mentioned parameter.

Chitosan is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep chitosan of sending from knee prostheses or be applied to knee prostheses should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the chitosan that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the chitosan of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the knee prostheses surface with chitosan.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge chitosan with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from knee prostheses the chitosan of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, chitosan from knee prostheses (for example filler) thus the surface discharge and to promote fibre modification the tissue in the period of a few hours to several months in the scope.For example, chitosan can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active chitosan of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the chitosan effect with half of above-mentioned parameter, use half in chemical compound of chitosan effect etc.) with the twice of above-mentioned parameter.

Polylysine is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep polylysine of sending from knee prostheses or be applied to knee prostheses should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the polylysine that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the polylysine of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the knee prostheses surface with polylysine.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge polylysine with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from knee prostheses the polylysine of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, thus polylysine discharges from the surface of knee prostheses and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, polylysine can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active polylysine of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the polylysine effect with half of above-mentioned parameter, use half in chemical compound of polylysine effect etc.) with the twice of above-mentioned parameter.

Fibronectin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep fibronectin of sending from knee prostheses or be applied to knee prostheses should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the fibronectin that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the fibronectin of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the knee prostheses surface with fibronectin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge fibronectin with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from knee prostheses the fibronectin of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, thus fibronectin discharges from the surface of knee prostheses and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, fibronectin can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active fibronectin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the fibronectin effect with half of above-mentioned parameter, use half in chemical compound of fibronectin effect etc.) with the twice of above-mentioned parameter.

Bleomycin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep bleomycin of sending from knee prostheses or be applied to knee prostheses should be no more than 100mg (scope of 0.01 μ g-100mg).The total amount of the bleomycin that discharges from prosthese in one embodiment, should be in the scope of 0.10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the bleomycin of the function of the surface area of the part of bonded device) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the knee prostheses surface with bleomycin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge bleomycin with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the bleomycin that the rate of release of medicine from knee prostheses is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, thus bleomycin discharges from the surface of knee prostheses and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, bleomycin can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active bleomycin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the bleomycin effect with half of above-mentioned parameter, use half in chemical compound of bleomycin effect etc.) with the twice of above-mentioned parameter.

CTGF is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep CTGF that sends from knee prostheses or be applied to knee prostheses should be no more than 100mg (scope of 0.01 μ g-100mg).In one embodiment, the total amount of the CTGF that discharges from prosthese should be in the scope of 0.10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the CTGF of the function of the surface area of the part of bonded device) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the knee prostheses surface with CTGF.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge CTGF with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the CTGF that the rate of release of medicine from knee prostheses is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, thus CTGF discharges from the surface of knee prostheses and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, CTGF can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active CTGF of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the CTGF effect with half of above-mentioned parameter, use half in chemical compound of CTGF effect etc.) with the twice of above-mentioned parameter.

Randomly, described device can comprise inflammatory cytokine (for example, TGF β, PDGF in addition, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) and/or bone morphogenetic protein (BMP) is (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant).

According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or required surface area cover, with bone morphogenetic protein (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant) be used in the preparation with concentration range from 0.001 μ g/ml to about 20mg/ml.Preferably, bone morphogenetic protein discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.001 μ g is to the scope of 500mg); Preferred 1 μ g is to 250mg.When being used as the device coating, dosage is 0.001 μ g-1000 μ g/mm of per unit area ²Preferred dosage is 0.01 μ g/mm ²-200 μ g/mm ²With 10 ^-9-10 ^-4The Cmin of the bone morphogenetic protein of M maintains on the apparatus surface.

According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of inflammatory cytokine from 0.0001 μ g/ml to about 20mg/ml is used in the preparation.Preferably, inflammatory cytokine discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 100mg); Preferred 0.001 μ g is to 50mg.When being used as the device coating, dosage is 0.0001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.001 μ g/mm ²-200 μ g/mm ²With 10 ^-10-10 ^-4The Cmin of the inflammatory cytokine of g/ml maintains on the apparatus surface.

In addition, described device can be separately or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA), and analog and derivant.Used dosage is to be proved to be those concentration (seeing that for example, embodiment 16) that stimulate cellular proliferation.According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of multiplication agent from 0.1ng/ml to 25mg/ml is used in the preparation.Preferably, multiplication agent discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 200mg); Preferred 0.001 μ g is to 100mg.When being used as the device coating, dosage is 0.00001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.0001 μ g/mm ²-200 μ g/mm ²With 10 ^-11-10 ^-6The Cmin of the multiplication agent of M maintains on the apparatus surface.

Should it will be apparent to one skilled in the art that aforementioned fibers degeneration derivant, any of or derivatives thereof and analog can be used to produce the variation of above-mentioned composition under the prerequisite that does not deviate from spirit and scope of the invention.Also should it is evident that described reagent can with or be not used in the compositions and change described carrier and do not depart from scope of the present invention with polymer support.

(iii) take on implant

Typically, need the function of shoulder joint reconstruction, described disease such as fracture, osteoarthritis, rheumatoid arthritis, avascular necrosis and tumor growth (benign or virulent) to ease the pain and to recover to lose owing to medical conditions.Relate to the hemiarthroplasty (part is takeed on implant) of only implanting the humerus component, typically carry out for the patient who suffers from shoulder fracture and avascular necrosis.All shoulder alternative (humerus and glenoid component are all implanted) is more common in the patient who suffers from osteoarthritis and rheumatoid arthritis.The joint that is associated with tumor resection is replaced quite rare, account for accept shoulder substitute patient with operation less than one of percentage.In the cancer patient, it is essential that the excision of bone may make that the part or all of replacement in joint becomes.

Described multiple shoulder prosthesis (see, for example, U.S. Patent number 6,494,913; 6,193,758; 6,168,628; 6,102,953; 6,045,582; 5,961,555; 5,593,448; 5,549,682; With 5,108,440).Be suitable for making up one or more shoulder implants and comprise multiple commercially available product according to fibre modification derivant of the present invention.These comprise that the implant of being produced by DePuy Orthopaedics (for example, GLOBAL TX Total Shoulder System, GLOBAL Shoulder EccentricHead, GLOBAL Total Shoulder System), Biomet (for example, Bio-Modular, Bi-Angular/Bi-Polar, Proximal Humeral Replacement and IntegratedShoulder System), Stryker Howmedica Osteonics is (for example, SOLAR ShoulderBipolar Heads, Humeral Heads, Humeral Components, and GlenoidComponents), Sulzer (for example, Anatomical Shoulder and Select Shoulder), Zimmer (B igliani/Flatow Shoulder) and Smith ﹠amp; The shoulder implant that Nephew Orthopaedics (for example, COFIELD 2 Total Shoulder System, NEER II Total Shoulder System and Modular Shoulder System) produces.

On the one hand, the invention provides shoulder prosthesis, it compositions that comprises the fibre modification derivant or comprise the fibre modification derivant is to promote in cicatrization and the described device bone around being fixed into.On the one hand, described shoulder prosthesis is coated with the compositions that a kind of fibrous tissue forms agent or comprises described fibrous tissue formation agent.On the other hand, described fibrous tissue can be formed agent mix described prosthese is remained in the adhesive or cement of appropriate location.On the other hand, described shoulder prosthesis covering (whole or in part) is gone in the bone on every side to promote cicatrization and grappling with silk screen eye or grid.For example, the silk screen eye or the network coverage can be gone in the bone on every side with promotion cicatrization and grappling to all or part of surface of implant stem.

The carrier system of aforesaid many polymerization rerum naturas and non-polymeric rerum natura can be used for the practice of the present embodiment.These compositionss may further include one or more fibre modification derivants to promote the formation of granulation tissue.With become fiber composition to be attached on the rectificating surgery implant or among method comprise: (a) directly will become fiber composition be attached to described device (for example, by aforesaid with or not with the spraying process or the dip coating of carrier); (b) directly will become fiber composition be attached in the described device (for example, by as mentioned above with or not with the spraying process or the dip coating of carrier); (c) by being coated with described device such as the hydrogel that can absorb into fiber composition again with material; (d) be woven in the described apparatus structure by the line (or polymer itself of formation line) that will become the fiber composition coating; (e) by described device is inserted in sleeve pipe or the mesh, described sleeve pipe or mesh are by becoming fiber composition to form or by its coating; (f) with becoming fiber composition construction device itself, or the part of described device; Or (g) directly be covalently bound to apparatus surface by fibrous tissue being formed agent, or on the joint (micromolecule or polymer), described joint is applied or be attached to apparatus surface.For these devices, can carry out coating process by this way, described mode is the surface of the device that contact with bone of (a) coating, (b) device that do not contact with bone of coating surperficial or (c) be coated with and contact all or part of with the surface of the device that does not contact with bone with bone.

Except with becoming fiber composition to be coated with the described device, mix with the material that is used for making described device and make fibrous tissue form agent to be attached to final device thereby fibrous tissue can be formed agent.

Should it is evident that to those skilled in the art, in the practice of the present embodiment, any binding agent or fibre modification derivant can be used alone or in combination potentially.The exemplary fibers texturizer that is used for shoulder prosthesis comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin, and CTGF, and aforesaid analog and derivant.

Because shoulder prosthesis is made with multiple configuration and size, the exact dose of using can be with the device size, surface area and kind of design and change.Yet, some principle can be applied in the application of this area.Can be the function of per unit area (part of applied device) dosage with medication dose calculation, can measure the total drug dose of using, and can determine the suitable surface concentration of active medicine.No matter how medicament administration arrives the employed method of shoulder prosthesis, the exemplary fibers texturizer that is used alone or in combination should use under following administration is instructed:

Talcum is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from shoulder prosthesis, send or be applied to the lip-deep steatitic accumulated dose of shoulder prosthesis and should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the steatitic accumulated dose that discharges from prosthese should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the steatitic dosage of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the shoulder prosthesis surface with Talcum.In one embodiment, thus Talcum discharges from the surface of shoulder prosthesis and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, Talcum can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is to be used for purpose of the present invention with having active steatitic analog of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the Talcum effect with half of above-mentioned parameter, use half in chemical compound of Talcum effect etc.) with the twice of above-mentioned parameter.

Silk is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep silk of sending from shoulder prosthesis or be applied to shoulder prosthesis should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the silk that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the silk of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the shoulder prosthesis surface with silk.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge silk with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the silk that the rate of release of medicine from shoulder prosthesis is used in combination the Cmin that makes 0.01nM-1000 μ M.In one embodiment, thus silk discharges from the surface of shoulder prosthesis and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, silk can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active silk of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles an effect with half of above-mentioned parameter, use half in chemical compound of silk effect etc.) with the twice of above-mentioned parameter.

Chitosan is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep chitosan of sending from shoulder prosthesis or be applied to shoulder prosthesis should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the chitosan that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the chitosan of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the shoulder prosthesis surface with chitosan.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge chitosan with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the chitosan that the rate of release of medicine from shoulder prosthesis is used in combination the Cmin that makes 0.01nM-1000 μ M.In one embodiment, thus chitosan discharges from the surface of shoulder prosthesis and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, chitosan can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active chitosan of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the chitosan effect with half of above-mentioned parameter, use half in chemical compound of chitosan effect etc.) with the twice of above-mentioned parameter.

Polylysine is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep polylysine of sending from shoulder prosthesis or be applied to shoulder prosthesis should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the polylysine that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the polylysine of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the shoulder prosthesis surface with polylysine.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge polylysine with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from shoulder prosthesis the polylysine of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, thus polylysine discharges from the surface of shoulder prosthesis and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, polylysine can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active polylysine of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the polylysine effect with half of above-mentioned parameter, use half in chemical compound of polylysine effect etc.) with the twice of above-mentioned parameter.

Fibronectin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep fibronectin of sending from shoulder prosthesis or be applied to shoulder prosthesis should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the fibronectin that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the fibronectin of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the shoulder prosthesis surface with fibronectin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge fibronectin with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the fibronectin that the rate of release of medicine from shoulder prosthesis is used in combination the Cmin that makes 0.01nM-1000 μ M.In one embodiment, thus fibronectin discharges from the surface of shoulder prosthesis and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, fibronectin can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active fibronectin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the fibronectin effect with half of above-mentioned parameter, use half in chemical compound of fibronectin effect etc.) with the twice of above-mentioned parameter.

Bleomycin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep bleomycin of sending from shoulder prosthesis or be applied to shoulder prosthesis should be no more than 100mg (scope of 0.01 μ g-100mg).The total amount of the bleomycin that discharges from prosthese in one embodiment, should be in the scope of 0.10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the bleomycin of the function of the surface area of the part of bonded device) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the shoulder prosthesis surface with bleomycin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge bleomycin with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the bleomycin that the rate of release of medicine from shoulder prosthesis is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, thus bleomycin discharges from the surface of shoulder prosthesis and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, bleomycin can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active bleomycin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the bleomycin effect with half of above-mentioned parameter, use half in chemical compound of bleomycin effect etc.) with the twice of above-mentioned parameter.

CTGF is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep CTGF that sends from shoulder prosthesis or be applied to shoulder prosthesis should be no more than 100mg (scope of 0.01 μ g-100mg).In one embodiment, the total amount of the CTGF that discharges from prosthese should be in the scope of 0.10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the CTGF of the function of the surface area of the part of bonded device) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the shoulder prosthesis surface with CTGF.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge CTGF with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the CTGF that the rate of release of medicine from shoulder prosthesis is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, thus CTGF discharges from the surface of shoulder prosthesis and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, CTGF can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active CTGF of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the CTGF effect with half of above-mentioned parameter, use half in chemical compound of CTGF effect etc.) with the twice of above-mentioned parameter.

Randomly, described device can comprise inflammatory cytokine (for example, TGF β, PDGF in addition, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) and/or bone morphogenetic protein (BMP) is (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant).

According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the required persistent period of using, the type at medical apparatus interface and volumes of formulation and or required surface area cover, with bone morphogenetic protein (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant) be used in the preparation with concentration range from 0.001 μ g/ml to about 20mg/ml.Preferably, bone morphogenetic protein discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.001 μ g is to the scope of 500mg); Preferred 1 μ g is to 250mg.When being used as the device coating, dosage is 0.001 μ g-1000 μ g/mm of per unit area ²Preferred dosage is 0.01 μ g/mm ²-200 μ g/mm ²With 10 ^-9-10 ^-4The Cmin of the bone morphogenetic protein of M maintains on the apparatus surface.

According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of inflammatory cytokine from 0.0001 μ g/ml to about 20mg/ml is used in the preparation.Preferably, inflammatory cytokine discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 100mg); Preferred 0.001 μ g is to 50mg.When being used as the device coating, dosage is 0.0001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.001 μ g/mm ²-200 μ g/mm ²With 10 ^-10-10 ^-4The Cmin of the inflammatory cytokine of g/ml maintains on the apparatus surface.

In addition, described device can be separately or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA), and analog and derivant.Used dosage is to be proved to be those concentration (seeing that for example, embodiment 16) that stimulate cellular proliferation.According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of multiplication agent from 0.1ng/ml to 25mg/ml is used in the preparation.Preferably, multiplication agent discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 200mg); Preferred 0.001 μ g is to 100mg.When being used as the device coating, dosage is 0.00001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.0001 μ g/mm ²-200 μ g/mm ²With 10 ^-11-10 ^-6The Cmin of the multiplication agent of M maintains on the apparatus surface.

Should it will be apparent to one skilled in the art that aforementioned fibers degeneration derivant, any of or derivatives thereof and analog can be used to produce the variation of above-mentioned composition under the prerequisite that does not deviate from spirit and scope of the invention.Also should it is evident that described reagent can with or be not used in the compositions and change described carrier and do not depart from scope of the present invention with polymer support.

(iv) the fibre modification derivant penetrates in the artificial joint tissue on every side

Perhaps, before the implanting prosthetic joint, among or afterwards, can handle artificial joint with the fibre modification derivant and be placed on wherein tissue cavity's (normally bone cavity wherein inserts doing of artificial joint).This can be undertaken by several modes, described mode comprises: (a) fibrous tissue is formed agent and locally apply in the anatomy gap, (what be particularly useful in this embodiment is the application of polymer support artificial joint can be placed described gap, described polymer support forms agent with fibrous tissue and discharges-fluid in the time range of a few hours to several weeks, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, solid implant and can will discharge other formulation delivered that fibrous tissue forms agent to zone that described prosthetic joint can be inserted into); (b) targeted delivery is to the microgranule silk of implantation site and/or silk chain (for example, straight line, side chain, and/or curl); (c) with the sprayable preparation that comprises collagen protein such as COSTASIS or by 4-arm mercaptan PEG (10K), 4-arm NHS PEG (10K), with methylated collagen protein such as the above-mentioned material of making, separately or load and be applied to implantation site (or described implant/apparatus surface) together with the fibre modification derivant; (d) with the sprayable preparation that comprises PEG such as COSEAL, FOCALSEAL, SPRAYGEL or DURASEAL are separately or load and be applied to implantation site (or described implant/apparatus surface) together with the fibre modification derivant; (e) will comprise preparation such as the FLOSEAL or the TISSEAL of fibrinogen, separately or load and be applied to implantation site (or described implant/apparatus surface) together with the fibre modification derivant; (f) comprise hyaluronic preparation such as RESTYLANE, HYLAFORM, PERLANE, SYNVISC, SEPRAFILM or SEPRACOAT, it loads to be applied to the fibre modification derivant of implantation site (or implant/apparatus surface); (g) be used for polymer gel such as REPEL or the FLOWGEL that surgical operation is implanted, it loads to be applied to the fibre modification derivant of implantation site (or implant/apparatus surface); (h) be used for prosthese and tissue maintenance orthopedics's cement in place, it loads to be applied to the fibre modification derivant of implantation site (or described implant/apparatus surface), such as OSTEOBOND, LVC, SIMPLEX P, PALACOS, and ENDURANCE; (i) will comprise the surgical operation adhesive of cyanoacrylate such as DERMABOND, INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND, TISSUMENDII, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT or as above-mentioned, separately or load and be applied to implantation site (or described implant/apparatus surface) together with the fibre modification derivant; (j) comprise the implant (or synthetic property bone material such as calcium sulfate, VITOSS and CORTOSS) of hydroxyapatite, it loads to be applied to the fibre modification derivant of implantation site (or described implant/apparatus surface); (k) loading is with the tissue filler of other biocompatibility of fibre modification derivant, such as by BioCure, those that 3M Company and Neomend makes, it loads to be applied to the fibre modification derivant of implantation site (or described implant/apparatus surface); (I) polysaccharide gel is such as the gel of ADCON series; (m) will be separately or load film with fibre modification derivant, bone morphogenetic protein and/or somatomedin, sponge or mesh such as INTERCEED or VICRYL mesh and GELFOAM are expelled to around intraarticular or the joint; And/or (n) form Polyethylene Glycol (for example, 4-arm four-amino PEG) [10k] from aminofunctional) and the functionalized PEG (for example, tetramethylolmethane gathers (ethylene glycol) ether four-succinimido glutarate) of 4-arm NHS (10K)) hydrogel.This hydrogel can also comprise collagen protein, methylated collagen protein and/or gelatin.This hydrogel can also comprise above-mentioned fibre modification derivant (for example, silk powder or silk thread), (m) film, sponge or mesh are such as INTERCEED, VICRYL mesh, and GELFOAM, it loads to be applied to the fibre modification derivant of implantation site (or implant/apparatus surface).

Tackling in those skilled in the art is to it is evident that potentially, above-mentioned any fibre modification derivant can be used alone or in combination in the practice of the present embodiment.The exemplary fibers texturizer that is used for infiltrating the tissue around the articular prosthesis comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF and above-mentioned analog and derivant.

Because articular prosthesis is made with multiple configuration and size, the exact dose that is administered in the tissue around the implant can be with the device size, surface area and kind of design and change.Yet, some principle can be applied in the application of this area.Can be the function of per unit area (part of implanted device) dosage with medication dose calculation, can measure the total drug dose of using, and can determine the suitable surface concentration of active medicine.No matter the method for medicament administration is how, the exemplary fibers texturizer that is used alone or in combination should use under following administration is instructed:

Talcum as exemplary fibers degeneration derivant, no matter it is to use polymer support to use, or is used without polymer support, and the steatitic accumulated dose of being sent be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the steatitic total amount that discharges from Periprosthetic should be in the scope of 10 μ g-50mg.The dosage of the per unit area of the device steatitic dosage of function of the surface area of the implanted part of device (that is, as) should be at 0.05 μ g-10 μ g/mm ²Scope in.In one embodiment, thus Talcum is released the fibre modification that promotes in the tissue in the period of a few hours to several months scope.For example, Talcum can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is to be used for purpose of the present invention with having active steatitic analog of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the Talcum effect with half of above-mentioned parameter, use half in chemical compound of Talcum effect etc.) with the twice of above-mentioned parameter.

Silk as exemplary fibers degeneration derivant, no matter it is to use polymer support to use, or is used without polymer support, and the accumulated dose that is delivered to the silk in the tissue of Periprosthetic should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, be released to Periprosthetic the silk total amount should be in the scope of 10 μ g-50mg.The dosage of the per unit area of the device dosage of the silk of the function of the surface area of the part of implanted device (that is, as) should be at 0.05 μ g-10 μ g/mm ²Scope in.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge silk with different speed, thereby above-mentioned administration parameter should be delivered in the described tissue with the silk that release rate of drugs is used in combination the Cmin that makes 0.01nM-1000 μ M.In one embodiment, thus silk is released in the tissue of Periprosthetic and promotes fibre modification in the tissue in the period of a few hours to several months in the scope.For example, silk can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active silk of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles an effect with half of above-mentioned parameter, use half in chemical compound of silk effect etc.) with the twice of above-mentioned parameter.

Chitosan is used as exemplary fibers degeneration derivant, no matter it is to use polymer support to use, or use without polymer support, the accumulated dose of the chitosan from the tissue that is delivered to Periprosthetic should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, being released to the total amount of the chitosan of Periprosthetic should be in the scope of 10 μ g-50mg.The dosage of the per unit area of the device dosage of the chitosan of the function of the surface area of the part of implanted device (that is, as) should be at 0.05 μ g-10 μ g/mm ²Scope in.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge chitosan with different speed, thereby above-mentioned administration parameter should be delivered in the described tissue with the chitosan that release rate of drugs is used in combination the Cmin that makes 0.01nM-1000 μ M.In one embodiment, thus the tissue that chitosan is delivered to Periprosthetic promotes fibre modification in the tissue in the scope in the period of a few hours to several months.For example, chitosan can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active chitosan of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the chitosan effect with half of above-mentioned parameter, use half in chemical compound of chitosan effect etc.) with the twice of above-mentioned parameter.

Polylysine is used as exemplary fibers degeneration derivant, no matter it is to use polymer support to use, or use without polymer support, the accumulated dose that is delivered to the polylysine in the tissue of Periprosthetic should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the total amount of d/d polylysine should be in the scope of 10 μ g-50mg.The dosage of the per unit area of the device dosage of the polylysine of the function of the surface area of the part of implanted device (that is, as) should be at 0.05 μ g-10 μ g/mm ²In the scope.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge polylysine with different speed, thereby above-mentioned administration parameter should be delivered in the described tissue with the polylysine that release rate of drugs is used in combination the Cmin that makes 0.01nM-1000 μ M.In one embodiment, thus polylysine is released in the zone of Periprosthetic and promotes fibre modification in the tissue in the period of a few hours to several months in the scope.For example, polylysine can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active polylysine of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the polylysine effect with half of above-mentioned parameter, use half in chemical compound of polylysine effect etc.) with the twice of above-mentioned parameter.

Fibronectin is used as exemplary fibers degeneration derivant, no matter it is to use polymer support to use, or use without polymer support, the accumulated dose that is delivered to the fibronectin in the tissue of Periprosthetic should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the total amount of d/d fibronectin should be in the scope of 10 μ g-50mg.The dosage of the per unit area of the device dosage of the fibronectin of the function of the surface area of the part of implanted device (that is, as) should be at 0.05 μ g-10 μ g/mm ²Scope in.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge fibronectin with different speed, thereby above-mentioned administration parameter should be delivered in the tissue of Periprosthetic with the fibronectin that release rate of drugs is used in combination the Cmin that makes 0.01nM-1000 μ M.In one embodiment, thus fibronectin is discharged in the artificial joint contiguously and is promoted fibre modification in the tissue in the period of a few hours to several months in the scope.For example, fibronectin can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active fibronectin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the fibronectin effect with half of above-mentioned parameter, use half in chemical compound of fibronectin effect etc.) with the twice of above-mentioned parameter.

Bleomycin is used as exemplary fibers degeneration derivant, no matter it is to use polymer support to use, or use without polymer support, the accumulated dose that is delivered to the bleomycin in the tissue of Periprosthetic should be no more than 100mg (scope of 0.01 μ g-100mg).In one embodiment, the total amount of d/d bleomycin should be in the scope of 0.10 μ g-50mg.The dosage of the per unit area of the device dosage of the bleomycin of the function of the surface area of the part of implanted device (that is, as) should be at 0.005 μ g-10 μ g/mm ²Scope in.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge bleomycin with different speed, thereby above-mentioned administration parameter should be delivered to the bleomycin that release rate of drugs is used in combination the Cmin that makes 0.001nM-1000 μ M in the tissue around the articular prosthesis.In one embodiment, thus bleomycin is released in Periprosthetic promotes fibre modification in the tissue in the period of a few hours to several months scope.For example, bleomycin can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active bleomycin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the bleomycin effect with half of above-mentioned parameter, use half in chemical compound of bleomycin effect etc.) with the twice of above-mentioned parameter.

CTGF is used as exemplary fibers degeneration derivant, no matter it is to use polymer support to use, or use without polymer support, the accumulated dose that is delivered to the CTGF in the tissue of Periprosthetic should be no more than 100mg (scope of 0.01 μ g-100mg).In one embodiment, the total amount of d/d CTGF should be in the scope of 0.10 μ g-50mg.The dosage of the per unit area of device (that is, as the CTGF of the function of the surface area of the part of implanted device dosage) should be at 0.005 μ g-10 μ g/mm ²Scope in.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge CTGF with different speed, thereby above-mentioned administration parameter should be delivered to the CTGF that release rate of drugs is used in combination the Cmin that makes 0.001nM-1000 μ M in the tissue around the artificial joint.In one embodiment, thus CTGF is released the fibre modification that promotes in the tissue in the period of a few hours to several months scope.For example, CTGF can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active CTGF of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the CTGF effect with half of above-mentioned parameter, use half in chemical compound of CTGF effect etc.) with the twice of above-mentioned parameter.

Randomly, described device can comprise inflammatory cytokine (for example, TGF β, PDGF in addition, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) and/or bone morphogenetic protein (BMP) is (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant).

Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, with bone morphogenetic protein (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant) be used in the preparation with concentration range from 0.001 μ g/ml to about 20mg/ml.Preferably, bone morphogenetic protein discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.001 μ g is to the scope of 500mg); Preferred 1 μ g is to 250mg.When being used as the device coating, dosage is 0.001 μ g-1000 μ g/mm of per unit area ²Preferred dosage is 0.01 μ g/mm ²-200 μ g/mm ²With 10 ^-9-10 ^-4The Cmin of the bone morphogenetic protein of M maintains on the apparatus surface.

Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of inflammatory cytokine from 0.0001 μ g/ml to about 20mg/ml is used in the preparation.Preferably, inflammatory cytokine discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 100mg); Preferred 0.001 μ g is to 50mg.When being used as the device coating, dosage is 0.0001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.001 μ g/mm ²-200 μ g/mm ²With 10 ^-10-10 ^-4The Cmin of the inflammatory cytokine of g/ml maintains on the apparatus surface.

In addition, described device can be separately or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA), and analog and derivant.Used dosage is to be proved to be those concentration (seeing that for example embodiment 16) that stimulate cellular proliferation.Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of multiplication agent from 0.1ng/ml to 25mg/ml is used in the preparation.Preferably, multiplication agent discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 200mg); Preferred 0.001 μ g is to 100mg.When being used as the device coating, dosage is 0.00001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.0001 μ g/mm ²-200 μ g/mm ²With 10 ^-11-10 ^-6The Cmin of the multiplication agent of M maintains on the apparatus surface.

Should be that it is evident that can be with aforementioned fibers degeneration derivant for those skilled in the art, any of or derivatives thereof and analog be used to produce the variation of above-mentioned composition under the situation that does not deviate from spirit and scope of the invention.Also should it is evident that described reagent can be used in the compositions that has or do not have polymer support and change described carrier and not deviate from scope of the present invention.

3. tooth device

On the one hand, the invention provides tooth device and implant, it comprises fibre modification or adheres to derivant to help out in that implant is attached in the surrounding tissue.In using, uses tooth multiple device.Representative example comprises dental implant and guiding osteanagenesis device.

On the one hand, a kind of important concrete dental implant is little titanium implant (fixture), and it serves as the root substituent of the natural teeth of disappearance.Described dental implant is placed in the bone of maxillary or lower jaw and as the deadman that replaces tooth and plays a role.They can be used to support the substituent of single missing tooth or be used for the individual group of function completely, and described individuality has lost a lot of or whole teeth.Dental implant can be implanted in the bone (in the bone) or on bone (subperiosteal).Implant for into bones is modal implant type of service.Have various types of implant for into bones, it can comprise with the screw in the surgical operation implantation jawbone, cylindric or lobate implant.Every kind of implant is supported one or more artificial tooths.Usually, with the implant of the type as having the bridge work (bridge) or patient alternative of artificial tooth movably.The subperiosteum implant is placed on the top, Hubei Province, and wherein metal frame trestle (post) is outstanding to support described prosthese on whole gingiva.The implant of these types is used for wearing the patient of conventional artificial tooth and has the patient of ossiculum height.

Described many dental implants that are suitable for making up with the fibre modification derivant and (seen that for example U.S. Patent number 6,627,321; 6,582,228; 6,572,373; 6,527,553; With 6,506,051).

On the one hand, fibrous tissue can be formed agent and be attached to adhesive or the cement that device is placed correct position.On the other hand, cover tooth device (all or part of) with silk screen eye or grid thus promote cicatrization and be anchored on around bone in.For example, thus silk screen eye or grid can be covered that implant does the surface all or part of go up promote cicatrization and be anchored on around bone in.

On the other hand, the device that is used to send the fibre modification derivant can be that guide tissue regeneration (guided tissue regeneration) (GTR) installs, such as the GTR film.The GTR film can be by can absorbing again of making of biological or abiotic derived material or can not resorbent film.The GTR film can be used in combination or be used for the treatment of bone-loss with dental implant.The GTR film can be made by multiple material, comprises collagen protein (for example, porcine collagen, type i and II) for example, PTFE, polylactic acid, lactide and co-glycolide polymers and ePTFE).The GTR film can be purchased from following: W.L.Gore ﹠amp; Associates (Newark, DE) (for example, GORE-TEX and GORE-RESOLUT reproducibility material), Guidor, Atrix Laboratories, Inc. (Fort Collins, CO), GeistlichBiomaterials, Inc. (for example, BIO-GIDE), LifeCore Biomedical, Inc. (Chaska, MN), Ethicon Inc. (for example, VICRYL), is called Kensey Nash Corporation (Exton now, PA) THM Biomedical, with Suzler Calcitek, and Inc. (Carlsbad, CA).

On the other hand, will be suitable for making up dental apparatus with the fibre modification derivant be used to guide osteanagenesis (GBR) thus strengthen inadequate osseous tissue and guide regrowth.The GBR device comprises, what for example be used to fill up the bone defective can resorbent bone substituent.These devices can be by biomaterial (the deutero-material of bone that for example, demineralizes and cattle) and synthetic property material such as crystalline hydroxy apatite and calcium sulfate composition.Many dentale substituents can be purchased, comprise following products: OSTEOGRAF/N, OSTEOGRAF/LD, OSTEOGRAF/D, and PERMARIDGE (all from Ceramad), bioactivity glass, such as PERIOGLAS (U.S.Biomaterials), OSTEOGEN (Impladent, Inc.), VITOSS and CORTOSS.

On the other hand, the invention provides the dental implant that comprises the fibre modification derivant, be used in the treatment of common periodontal.In brief, periodontal is the diseases associated with inflammation of the supporting structure of tooth, and the supporting structure of described tooth comprises ligament, cementum, periosteum, alveolar bone and tooth is anchored on the gingiva that closes on of correct position.Described disease starts from the hemorrhage of gingiva, but can make progress loosening for tooth, and gingiva retreats, the abscess of gingiva and interdental bag and cause downright bad ulcerative gingivitis.In the progress stage, can need method such as gingivectomy, the correction of gingivoplasty and tooth bone structure is to treat this disease.Conventional therapy comprises the open-flap debridement of periodontal pocket, and it removes ill periodontal matter, periodontal ligament and the alveolar bone that is damaged by periodontal infection.Unfortunately, epithelial tissue can sometimes be moved to defect mending that surgical operation the produces correct cementum of healing, in ligament and the bone.

Developed dental implant, made great efforts the control agglutination and optimize tissue regeneration.Implant commonly used comprises permanent implant, such as e-PTFE film (for example from W.L.Gore GORE-TEX).Implant commonly used comprises for example can be available from Sulzer Medica, and (it is by the collagen film of forming derived from the compressed type i collagen albumen substrate of cattle Ah Maurice Schilles tendon for Houston, BIOMEND TX) for Inc..With collagen film (with sheet, 15mm x 20mm for example; 20mm x 30mm; Provide with 30mm x 40mm) be cut into suitable size and shape, carry out hydration and as barrier be placed on eclipsed gingival tissues and the periodontal defective that is eliminated between; Described barrier can be stitched in place, but this is always unessential.Film faced that root of the tooth comfortable (snugly) is placed and hide on around the alveolar bone (on defect area, extending 3mm at least) thus keep the regeneration gap effectively.The first closure of the mucoperiosteum flap on collagen film is important, because described film can cause too early degraded with contacting of oral cavity.Described barrier stops the epithelial tissue of faster growth to enter described zone and makes the periodontal ligament and the osteocyte of growth more slowly be positioned at described zone again and influence suitable healing.Described collagen film is can be biological resorbent, is kept to reach 6-7 week, and is fully absorbed by host's enzyme (collagenase) in 8 weeks.

Yet if it thoroughly absorbed before healing fully, it is relevant that the limited durability of collagen protein implant can become clinical problem-this special and big tissue defects.In the effort that addresses this problem, the manufacturer has attempted producing by crosslinked (usually by collagen protein is contacted with aldehyde) that increase collagen protein has the collagen protein implant of improving durability.Use this method, (Sulzer Medica Inc.) can be used as barrier and bring into play function in longer period product such as BIOMEND EXTEND, thereby did not absorb described collagen protein in the period that is organized in about 18 weeks around making.Another kind of collagen protein dental implant product, OSSIX (Colbar R﹠amp; D Ltd. Israel) uses metabolite to come crosslinked with collagen albumen and the structural intergrity that prolongs substrate reaches 6 months period of as many as.

Except the commercially available product of above-mentioned treatment periodontal, the implant based on collagen protein of other type can be used in the practice of the present invention based on collagen protein.The representative example of these implants comprises and is used in the multiple dentistry method those, comprise: COLLATAPE (Sulzer Medica, Inc.), it is based on the implant of collagen protein, be used to repair less oral cavity wound, closed transplanted sites is also repaired the Schneiderian film; COLLACOTE (Sulzer Medica, Inc.), the wound dressing that it is based on collagen protein is used for the palate donor site and is used in the mucosa flap; And COLLAPLUG (Sulzer Medica, Inc.), it is based on the proteic implant of solid collagen, is used in the bigger tissue defects of repairing such as extracing in site or the biopsy site.

On the one hand, the invention provides dental apparatus, thereby the compositions that described dental apparatus comprises the fibre modification derivant or comprises the fibre modification derivant promotes the fibre modification in the periodontal pocket.On the one hand, the dental apparatus or the material that are used to fill or keep periodontal pocket form agent by fibrous tissue, or comprise the compositions that fibrous tissue forms agent and form, or comprise it.

The carrier system of above-mentioned many polymerization rerum naturas and non-polymeric rerum natura can be used for the practice of the present embodiment.These compositionss may further include one or more fibre modification derivants to promote the formation of fibrous tissue around dental implant.To become fiber composition to be attached on the dental implant (such as (endosteal) in the periosteum or perioosteal titanium implant) or among method comprise: (a) directly will become fiber composition be attached on the described tooth hardware (for example, by aforesaid with or not with the spraying process or the dip coating of carrier); (b) directly will become fiber composition be attached in the described tooth hardware (for example, by aforesaid with or not with the spraying process or the dip coating of carrier); (c) by being coated with described tooth hardware with material such as the hydrogel that can absorb into fiber composition again; (d) by inducing the line (or fibre modification induced polymer itself of formation line) of compositions coating to be woven in the described apparatus structure with fibre modification; (e) by described device is inserted in sleeve pipe or the mesh, described sleeve pipe or mesh are by becoming fiber composition to form or by its coating; (f) with the compositions construction device itself that comprises fibrous tissue formation agent, or the part of device; Or (g) directly be covalently bound to apparatus surface by fibrous tissue being formed agent, or on the joint (micromolecule or polymer), described joint is applied or be attached to apparatus surface.For the dentistry hardware unit, can carry out coating process by this way, described mode is the surface of the device that contact with bone of (a) coating, (b) device that do not contact with bone of coating surperficial or (c) be coated with and contact all or part of with the surface of the device that does not contact with bone with bone.Except with becoming fiber composition to be coated with the described device, mix with the material that is used for manufacturing installation and make fibrous tissue form agent to be attached to final device thereby fibrous tissue can be formed agent.

For the treatment of periodontal, the polymer gel, paste, injectable thing, solution, microgranule and the solid implant that are placed in the periodontal pocket are the preferred forms of local delivery fibre modification derivant.All uses that all comprises biomaterial, described biomaterial covers the fibre modification derivant in the periodontal pocket (as mentioned above) of surgical operation generation.Can carry out the practice of the present embodiment in the following manner, comprise: (a) fibrous tissue is formed agent and locally apply to that (what be particularly useful in this embodiment is the application of polymer support on the periodontal pocket, described polymer support forms agent with fibrous tissue and discharges-fluid in the time range of a few hours to several weeks, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, solid implant and release fibrous tissue form agent and can be delivered to other preparation in described zone by special delivery catheter or other applicator); (b) microgranule silk and/or silk chain (for example, straight line, side chain, and/or curl) are placed periodontal pocket; (c) with the sprayable preparation that comprises collagen protein such as COSTASIS or by 4-arm mercaptan PEG (10K), 4-arm NHS PEG (10K), with methylated collagen protein such as the above-mentioned material of making, separately or load and be applied in the periodontal pocket together with the fibre modification derivant; (d) with the sprayable preparation that comprises PEG such as COSEAL, FOCALSEAL, SPRAYGEL or DURASEAL, separately or load and be applied in the periodontal pocket together with the fibre modification derivant; (e) will comprise preparation such as the FLOSEAL or the TISSEAL of fibrinogen, separately or load and be applied in the periodontal pocket together with the fibre modification derivant; (f) comprise hyaluronic preparation such as RESTYLANE, HYLAFORM, PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT, it loads to be applied to the fibre modification derivant in the periodontal pocket; (g) be used for polymer gel such as REPEL or the FLOWGEL that surgical operation is implanted, it loads with the fibre modification derivant, is administered in the periodontal pocket; (h) orthopedics's " cement ", such as OSTEOBOND, LVC, SIMPLEX P, PALACOS, ENDURANCE and CORTOSS, it loads with the fibre modification derivant, is applied in the periodontal pocket; (i) will comprise the surgical operation adhesive of cyanoacrylate such as DERMABOND, INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND, TISSUMEND II, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT or as above-mentioned, load and to be applied in the periodontal pocket together with the fibre modification derivant; (j) comprise hydroxyapatite, calcium sulfate, or the surgical implants of VITOSS, it loads with the fibre modification derivant, is administered in the periodontal pocket; (k) tissue filler of other biocompatibility, such as by BioCure, those that 3M Company andNeomend makes, its loading is administered in the periodontal pocket with the fibre modification derivant together; (1) polysaccharide gel is such as the gel of ADCON series, and it loads to be applied to the fibre modification derivant in the periodontal pocket; (m) loading is with the film of fibre modification derivant, and sponge or mesh are such as INTERCEED, and VICRYL mesh, and GELFOAM are administered in the periodontal pocket; And/or (n) form Polyethylene Glycol (for example, 4-arm four-amino PEG) [10k] from aminofunctional) and the functionalized PEG (for example, tetramethylolmethane gathers (ethylene glycol) ether four-succinimido glutarate) [10K] of 4-arm NHS) hydrogel.This hydrogel can also comprise collagen protein, methylated collagen protein and/or gelatin.This hydrogel can also comprise above-mentioned fibre modification derivant (for example, silk powder or silk thread).

In many above-mentioned embodiments, add radiopaque material (for example, tantalum, barium, other metal or radiography material) thus make injected material can by radiography or by MRI carry out by visual also be useful.Described contrast agent can be water miscible or the undissolvable radiopaque material of water.

Tackling in those skilled in the art is to it is evident that potentially, above-mentioned any binding agent or fibre modification derivant can be used alone or in combination in the practice of the present embodiment.The exemplary fibers texturizer that is used in the tooth prosthese comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF and above-mentioned analog and derivant.

Randomly, described device can comprise inflammatory cytokine (for example, TGF β, PDGF in addition, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) and/or bone morphogenetic protein (BMP) is (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant).

Because the tooth prosthese is made with multiple configuration and size, the exact dose of using can be with the device size, surface area and kind of design and change.Yet, some principle can be applied in the application of this area.Can be the function of per unit area (part of applied device) dosage with medication dose calculation, can measure the total drug dose of using, and can determine the suitable surface concentration of active medicine.No matter medicament administration in tooth prosthese or the periodontal implant employed method how, the exemplary fibers texturizer that is used alone or in combination should use under following administration is instructed:

Talcum is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the lip-deep steatitic accumulated dose of sending from the tooth prosthese or be applied to the tooth prosthese should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the steatitic accumulated dose that discharges from prosthese should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the steatitic dosage of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the tooth prosthetic surface with Talcum.In one embodiment, thus Talcum discharges from the surface of tooth prosthese and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, Talcum can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is to be used for purpose of the present invention with having active steatitic analog of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the Talcum effect with half of above-mentioned parameter, use half in chemical compound of Talcum effect etc.) with the twice of above-mentioned parameter.

Silk is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep silk of sending from the tooth prosthese or be applied to the tooth prosthese should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the silk that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the silk of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the tooth prosthetic surface with silk.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge silk with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the silk that the rate of release of medicine from the tooth prosthese is used in combination the Cmin that makes 0.01nM-1000 μ M.In one embodiment, thus silk discharges from the surface of tooth prosthese and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, silk can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active silk of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles an effect with half of above-mentioned parameter, use half in chemical compound of silk effect etc.) with the twice of above-mentioned parameter.

Chitosan is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep chitosan of sending from the tooth prosthese or be applied to the tooth prosthese should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the chitosan that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the chitosan of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the tooth prosthetic surface with chitosan.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge chitosan with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the chitosan that the rate of release of medicine from the tooth prosthese is used in combination the Cmin that makes 0.01nM-1000 μ M.In one embodiment, thus chitosan discharges from the surface of tooth prosthese and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, chitosan can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active chitosan of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the chitosan effect with half of above-mentioned parameter, use half in chemical compound of chitosan effect etc.) with the twice of above-mentioned parameter.

Polylysine is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the total amount of the lip-deep polylysine of sending from the tooth prosthese or be applied to the tooth prosthese should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the polylysine that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the polylysine of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the tooth prosthetic surface with polylysine.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge polylysine with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from the tooth prosthese polylysine of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, thus polylysine discharges from the surface of tooth prosthese and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, polylysine can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active polylysine of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the polylysine effect with half of above-mentioned parameter, use half in chemical compound of polylysine effect etc.) with the twice of above-mentioned parameter.

Fibronectin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep fibronectin of sending from the tooth prosthese or be applied to the tooth prosthese should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the fibronectin that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the fibronectin of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the tooth prosthetic surface with Talcum.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge fibronectin with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the fibronectin that the rate of release of medicine from the tooth prosthese is used in combination the Cmin that makes 0.01nM-1000 μ M.In one embodiment, thus fibronectin discharges from the surface of tooth prosthese and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, fibronectin can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active fibronectin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the fibronectin effect with half of above-mentioned parameter, use half in chemical compound of fibronectin effect etc.) with the twice of above-mentioned parameter.

Bleomycin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep bleomycin of sending from the tooth prosthese or be applied to the tooth prosthese should be no more than 100mg (scope of 0.01 μ g-100mg).The total amount of the bleomycin that discharges from prosthese in one embodiment, should be in the scope of 0.10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the bleomycin of the function of the surface area of the part of bonded device) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the tooth prosthetic surface with bleomycin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge bleomycin with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the bleomycin that the rate of release of medicine from the tooth prosthese is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, thus bleomycin discharges from the surface of tooth prosthese and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, bleomycin can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active bleomycin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the bleomycin effect with half of above-mentioned parameter, use half in chemical compound of bleomycin effect etc.) with the twice of above-mentioned parameter.

CTGF is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep CTGF that sends from the tooth prosthese or be applied to the tooth prosthese should be no more than 100mg (scope of 0.01 μ g-100mg).In one embodiment, the total amount of the CTGF that discharges from prosthese should be in the scope of 0.10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the CTGF of the function of the surface area of the part of bonded device) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the tooth prosthetic surface with CTGF.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge CTGF with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the CTGF that the rate of release of medicine from the tooth prosthese is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, thus CTGF discharges from the surface of tooth prosthese and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, CTGF can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active CTGF of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the CTGF effect with half of above-mentioned parameter, use half in chemical compound of CTGF effect etc.) with the twice of above-mentioned parameter.

If exist, depend on concrete clinical practice, preparation type is (for example, gel, liquid, solid, semi-solid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, with bone morphogenetic protein (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant) be used in the preparation with concentration range from 0.001 μ g/ml to about 20mg/ml.Preferably, bone morphogenetic protein discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.001 μ g is to the scope of 500mg); Preferred 1 μ g is to 250mg.When being used as the device coating, dosage is 0.001 μ g-1000 μ g/mm of per unit area ²Preferred dosage is 0.01 μ g/mm ²-200 μ g/mm ²With 10 ^-9-10 ^-4The Cmin of the bone morphogenetic protein of M maintains on the apparatus surface.

If exist, depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semi-solid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of inflammatory cytokine from 0.0001 μ g/ml to about 20mg/ml is used in the preparation.Preferably, inflammatory cytokine discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 100mg); Preferred 0.001 μ g is to 50mg.When being used as the device coating, dosage is 0.0001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.001 μ g/mm ²-200 μ g/mm ²With 10 ^-10-10 ^-4The Cmin of the inflammatory cytokine of g/ml maintains on the apparatus surface.

In addition, described device can be separately or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA), and analog and derivant.Used dosage is to be proved to be those concentration (seeing that for example, embodiment 16) that stimulate cellular proliferation.Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of multiplication agent from 0.0.1ng/ml to 25mg/ml is used in the preparation.Preferably, multiplication agent discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 200mg); Preferred 0.001 μ g is to 100mg.When being used as the device coating, dosage is 0.00001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.0001 μ g/mm ²-200 μ g/mm ²With 10 ^-11-10 ^-6The Cmin of the multiplication agent of M maintains on the apparatus surface.

Should be that it is evident that can be with aforementioned fibers degeneration derivant for those skilled in the art, any of or derivatives thereof and analog be used to produce the variation of above-mentioned composition under the situation that does not deviate from spirit and scope of the invention.Also should it is evident that described reagent can be used in the compositions that has or do not have polymer support and change described carrier and not deviate from scope of the present invention.

4. rectificating surgery implant

On the one hand, the invention provides rectificating surgery implant, thereby it comprises the fibre modification derivant or comprises the compositions promotion cicatrization of fibre modification derivant and device is fixed in bone or tissue on every side.

(i) the orthopedics's hardware that is coated with the fibre modification derivant

On the one hand, described rectificating surgery implant is appliedly to form agent or comprise orthopedics's " hardware " device that fibrous tissue forms the compositions of agent with fibrous tissue.The representative example of orthopedics's hardware unit comprises inside and outside fixture, hold-down screw (degradable or nondegradable), interfere screw (degradable or nondegradable), rotor screw, plate, tinsel (for example, the K-tinsel), pin and the nail that is used in the fracture repairing, reconstruction capability method and joint fusion method are (for example, ankle merges, cervical vertebra and lumbar spinal fusion).Also provide compositions to be used for apparatus for coating, described device is used in the senior repairing of fusion and fracture.Use rectificating surgery implant such as, for example with fibrous tissue form the agent coating, with comprise fibrous tissue form agent the compositions coating or by discharging (especially for polymeric, biodegradable orthopedics hardware) hold-down screw that polymer that fibrous tissue forms agent is formed, pin, plate, nail, tinsel and plate promote implant to be anchored to better in the bone on every side.Perhaps, or in addition, fibrous tissue can be formed agent is attached to implant is remained in the adhesive or cement of correct position.On the other hand, orthopedics hardware is covered with (all or part of) thus silk screen eye or grid promote cicatrization and be anchored to around bone in.For example, thus silk screen eye or grid can be applied to implant do all or part of promotion cicatrization on surface and be anchored to around bone.

On the other hand, rectificating surgery implant is the collagen protein implant, and it is as the substituent from body or allogenic bone graft.Developed many collagen protein implants that are used in the orthopaedic surgery, it is as the substituent from body or allogenic bone graft.Collagen protein is the basic organic component of bone and can makes up with mineral preparation, autologous bone marrow, and bone graft, and/or somatomedin (such as BMPs) is to be used as bone substituent or skeleton repair products.Typically use and (for example include, but not limited to the total joint lieu of surgery, artificial hip, knee joint etc.), the spinal fusion surgical operation, long bone fracture, thus autograft is strengthened in the repairing in traumatic bone defective, space or crack and in the bone graft collection point as bone filler.Example based on the commercially available bone graft of collagen protein comprises the Pharmaceuticals by Angiotech, COLLAGRAFT Paste and COLLAGRAFT Strips that Inc makes.COLLAGRAFT is following combination: the mixture of highly purified I type Corii Bovis seu Bubali fibril collagen protein and 65% hydroxyapatite and 35% tricalcium phosphate.This material is more absorbed once more by bone near people's bone and in agglutination and replaces.The representative example of bone graft is described in U.S. Patent number 6,083,522 and 6,280,474 and PCT publication number WO98/52498 in.

The carrier system of above-mentioned many polymerization rerum naturas and non-polymeric rerum natura can be used for the practice of the present embodiment.These compositionss may further include one or more fibre modification derivants with the formation that promotes granulation tissue (part below (iii) in further describe).With become fiber composition to be attached on the rectificating surgery implant or among method comprise: (a) directly will become fiber composition be attached to described device (for example, by aforesaid with or not with the spraying process or the dip coating of carrier); (b) directly will become fiber composition be attached in the described device (for example, by as mentioned above with or not with the spraying process or the dip coating of carrier); (c) by being coated with described device such as the hydrogel that can absorb into fiber composition again with material; (d) be woven in the described device by the line (or fibrous tissue forms the polymer form formation line of agent itself) that will become the fiber composition coating; (e) by described device is inserted in sleeve pipe or the mesh, described sleeve pipe or mesh are by becoming fiber composition to form or by its coating; (f) with becoming fiber composition construction device itself, or the part of described device (effective especially for biodegradable orthopedics hardware and collagen protein implant); Or (g) directly be covalently bound to apparatus surface by fibrous tissue being formed agent, or on the joint (micromolecule or polymer), described joint is applied or be attached to apparatus surface.For these devices, can carry out coating process by this way, described mode is the surface of the device that contact with bone of (a) coating, (b) device that do not contact with bone of coating surperficial or (c) be coated with and contact all or part of with the surface of the device that does not contact with bone with bone.

Should it is evident that to those skilled in the art, potentially, can any binding agent or fibre modification derivant is independent, or combination is used in the practice of above-mentioned the present embodiment.The exemplary fibers texturizer that is used in the coating orthopedics hardware comprises, Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin, and/or CTGF and above-mentioned analog and derivant.Correct use with dosage and front about artificial hip, the part 2 (i) of knee joint and shoulder prosthesis, 2 (ii) with 2 identical described in (iii).

(ii) invade the warm art in joint of degree minimum

On the other hand, the invention provides injectable compositions with promotion cicatrization and fixing (immobilization) joint, and do not need open surgery.In some clinical scenarios, fixing joint needs, and described joint has been badly damaged or has caused the reason of chronic pain.For example, the compositions that comprises binding agent or fibre modification derivant can be expelled to and have in arthritis or the impaired joint with fixing (that is the immobilization) that promote cicatrization and joint (interphalangeal joint particularly, instep-sole of the foot joint, metacarpal joint, ankle joint, knee joint, near-end shin-diseased joint, hip joint, sacroiliac joint, acromioclavicular joint, sternoclavicular joint and the face joint in cervical spinal column, breast spinal column and lumbar spine).In the method, insert a needle in the articular cavity, lead is put in the joint space, with double channel catheter (for the many hydrogels that describe below such as by 4-arm mercaptan PEG (10K), the material of 4-arm NHS PEG (10K) and methylated collagen protein such as above-mentioned preparation, COSEAL, COSTASIS, FLOSEAL, TISSEAL, VITOSS) or single lumen catheter (for material such as cyanoacrylate, CORTOSS, bone cement, hydroxyapatite, calcium phosphate, calcium sulfate, hyaluronic acid, protein, carbohydrate, sclerosing agent etc.) on lead, put in the joint space, remove lead, and will comprise fibre modification derivant, bone morphogenetic protein by conduit, and/or osteogenic growth factor (such as, transforming growth factor, platelet-derived somatomedin, fibroblast growth factor) compositions be expelled in the joint and be filled up to the joint space.Before injection of joint merges compositions, or among, reagent such as collagenase, chymopapain or other tissue degradation enzyme are used for the remaining cartilage of chemical degradation.Passage in time, fibre modification derivant, bone morphogenetic protein, and/or osteogenic growth factor can promote the fibrous ankylosis in processed joint, follow by bony ankylosis, cause moving, the minimizing (or thoroughly forfeiture) of stability boundary, and/or pain reduces.

When carrying out the direct injection in joint, technology can be used for increasing the development that places joint space pin (or conduit), described technology comprises, but be not limited to, use the pin that is coated with by ECHO-COAT, thereby the injection air can position by ultrasound wave, or interpolation contrast agent (barium, tantalum, technitium, gadolinium etc.) to carry out location by x-ray or MRI.

A method of using in the arthroscope in joint is estimated, forms agent with fibrous tissue and/or the skeletonization agent is sent under direct observation., by the side of arthroscope, will comprise the fibre modification derivant here, bone morphogenetic protein, and/or the compositions of osteogenic growth factor is expelled in the joint space is preferably after remaining articular cartilage is removed by mechanicalness or chemical.In some cases, thus the fibre modification derivant can also directly be delivered to the efficient that increases this method in the tissue in open joint fusion surgical operation.

Injectable material can also be made up of the Injectable polymer system in the arthrodesis that is used in intrusion degree minimum.In addition, thus described polymer system can provide the lasting release of fibre modification derivant, bone morphogenetic protein and/or osteogenic growth factor to increase effect and reduce the needs that the repetition intraarticular of activating agent is used.What be used for the object of the invention is suitable for sending the fibre modification derivant, bone morphogenetic protein, and/or the injection mass of the somatomedin of promote osteogenesis can be made up of nondegradable or degradable material.The non-degradable material that is fit to can comprise crosslinked compositions, described crosslinked compositions comprises PVA, PVP, polyacrylamide, methyl methacrylate (MMA) and methyl methacrylate-styrene (MMA-styrene), when mixing, form polymethyl methacrylate (PMMA) or bone cement (for example, SIMPLEX P, ZIMMER REGULAR and ZIMMER LOW VISCOSITY CEMENT, PALACOS, CMW-1 and CMW-2, ENDURANCE), synthetic cancellous bone infilling (for example, CORTOSS), pHEMA, poly-(vinyl PEG), poly-(styrene sulfonate), poly-(acrylic acid), poly-(methacrylic acid), and the polymer of other known formation hydrogel.Other compositions comprises the admixture and the copolymer of the reagent of listing above.Suitable degradable substance include, but not limited to by bata-tricalcium phosphate form can resorbent Inorganic Non-metallic Materials (for example VITOSS and PROOSTEON 500R), hydroxyapatite or Ca ₁₀(PO ₄) ₆OH (for example, BIOOSS and OSTEOGRAF), calcium carbonate or CaCO ₃, calcium sulfate (for example, OSTEOSET and ALLOMATRIX), calcium phosphate (for example, CALCIBON or NORIAN SRS), the crosslinked material of PEG, gelatin, collagen protein, bone allograft is (for example, ALLOGRO, ORTHOBLAST, OPTEFORM, GRAFTON), mescenchymal stem cell, hyaluronic acid, derivatives of hyaluronic acids, polysaccharide, carbohydrate, protein (for example, albumin, casein, lactalbumin, phytoprotein or fish protein etc.), from the body bone, the bone matrix that demineralizes, cellulose derivative (for example, HPC), chitosan, chitosan derivative, polyester-polyalkylene oxide block copolymer (for example, PLGA-PEG-PLGA or MePEG-PLGA) and other can be by excretory low-molecular weight polymers.Interested especially a kind of material is by 4-arm mercaptan PEG (10K), and 4-arm NHS PEG (10K) and methylated collagen protein are such as above-mentioned preparation.In one embodiment, injectable material also comprises can induce fibre modification and ankylopoietic bioactivator in processed joint.Preferred bioactivator comprises the fibre modification derivant, bone morphogenetic protein, and somatomedin (transforming growth factor, platelet-derived d somatomedin, fibroblast growth factor), their dosage and release dynamics all describe in detail below part (iii) in.

Except the fibre modification derivant, outside bone morphogenetic protein and the somatomedin, or alternatively, injectable substance can be used for sclerosing agent is delivered to the joint space.Sclerosing agent comprises chemical compound such as ethanol, DMSO, surfactant, sucrose, NaCl, dextrose, glycerol, minocycline, tetracycline, doxycycline, Polidocanol, sodium tetradecyl sulfate, sodium morrhuate, Sotradecol and other.Hydrogel also can comprise reagent such as glycerol, glycerol, and PEG200, triethyl citrate and glycerol triacetate are as plasticizer.

Above-mentioned injectable material also can further be modified to be formed or to be comprised polymer line by polymer line.Polymer line has the ability of inducing the fibroplasia reaction from surrounding tissue.These polymer lines can be degradable or nondegradable.Degradable line can be by degradable polyester, polyanhydride, poly-(acid anhydride ester), poly-(ester-amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, cyanoacrylate polymer, collagen protein, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose, cellulose esters, its admixture and copolymer, and other known degradable polymer is formed.Operable non-degradable polymer include, but not limited to polyester (for example, PET), polyurethane, siloxanes, PE, PP, PS, PAA, PMA, the silk, its admixture, copolymer and other known polymer.Used line can be made up of or the admixture of different components is formed single compositions.Described polymer line itself can further be modified by the polymer coating that interpolation is applied to line.Be used to be coated with that the polymer of described line can describe at line itself to top that those are similar.Described polymer coating can also comprise the bioactivator with the fibroplasia of inducing or osteogenic response ability.Operable reagent be further described in following part (iii) in.

Above-mentioned injectable substance can be used for the delivery of particles material, described particulate matter has induces ankylopoietic ability in the joint.These granules are degradable or nondegradable and similar to top description at line.In addition, the particulate matter useful for putting into practice of the present embodiment comprises Talcum, starch, glass, silicate, Silicon stone, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic property mineral (for example, VITOSS and CORTOSS), PMMA, silver nitrate, Inorganic Non-metallic Materials granule and other inorganic particle of inducing the fibroplasia reaction to carry out mineralising subsequently known in the art.The granule that is used in the present embodiment can be all same combinations or the admixture of different components.As mentioned above, can also be with these granules as the coating that is applied on the aforesaid polymer chain.

Thereby can also make up injectable material makes it by polymer line and granulometric composition.The line that uses and granule are to above-mentioned those are similar and can be the compositions of uniform composition or fusion.In fact, particulate any combination of the line of different components and different components can be used in the present embodiment.As described below, can be with hydrogel, polymer line and granule all are used to send one or more bioactivators.

A kind of concrete compositions comprises poly-(ethylene glycol) compositions by methylated collagen protein-crosslinked such as above-mentioned, the bar of preparation, and it added pulverous granule and/or mineral particle in the compositions before solidifying.In case use, described bar can absorb water, the filling joint space also is attached on the bone of any articular cartilage or exposure.This expansion can stop described bar migration, and pulverous and/or inorganic silk (mineral silk) of while can start makes ankylopoietic reaction.When described granule begins degraded, described material can support starting of described granule and the osseous tissue of strengthening inwardly to grow.Bone morphogenetic protein and/or somatomedin (front and back is described) also are used in and are included in this compositions.In order further to increase the initial speed of this fibroplasia reaction, can add sclerosing agent such as surfactant (SDS), ethamolin (ester) or DMSO.In addition, can also add or replace the 4-arm mercaptan PEG of all (or part) with the amino PEG of 4-arm.Described amino PEG can provide the gel that can need the longer time degraded and can provide some positive charges to the other porous material that attractability is arranged.

Second kind of specific embodiment is made up of injectable implant, and described implant is made up of the polymerized form (that is, fibrous tissue forms the recurring unit that agent condenses together) that silk fiber or fibrous tissue form agent itself.Bone morphogenetic protein and/or somatomedin (front and back is described) also are useful for the interpolation of said composition.

Except hydrogel, bone cement and comprising outside the material of above-mentioned calcium phosphate, exist some other be suitable for use in Injectable composition in the joint fusion method of invasive degree minimum.All comprising is used in biomaterial in the joint space, follows or do not follow the fibre modification derivant, bone morphogenetic protein, and/or the interpolation of suitable somatomedin.Compositions subsequently can be passed through special delivery catheter, endoscope (arthroscope typically passes through sideport), pin or other applicator, drainage tube or entry port that operation is settled, or other transdermal access to plant is delivered in the joint, comprise and use (a) fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the preparation of solid implant and other release bioactive agent; (b) independent, or load with additional fibers degeneration derivant, bone morphogenetic protein, and/or the microgranule silk of somatomedin and/or silk chain (linearity, side chain, and/or curl) to be expelled to for orientation also be useful in the joint; (c) be injected into that injectable in the joint space comprises preparation such as the COSTASIS of collagen protein or by 4-arm mercaptan PEG (10K), the material of 4-arm NHS PEG (10K) and methylated collagen protein such as above-mentioned preparation, it is independent or loads with the fibre modification derivant, bone morphogenetic protein, and/or somatomedin; (d) preparation that is injected into the injectable PEG of comprising in the joint space is such as COSEAL, FOCALSEAL, and SPRAYGEL or DURASEAL, it is independent or loads with fibre modification derivant, bone morphogenetic protein, and/or somatomedin; (e) be injected into the preparation that comprises fibrinogen such as FLOSEAL or TISSEAL in the joint space, it is independent or loads with fibre modification derivant, bone morphogenetic protein, and/or somatomedin; (f) be injected into and comprise hyaluronic preparation such as RESTYLANE, HYLAFORM, PERLANE in the joint space, SYNVISC, SEPRAFILM, SEPRACOAT, it is independent or loads with fibre modification derivant, bone morphogenetic protein, and/or somatomedin; (g) be injected into polymer gel such as the REPEL or the FLOWGEL that implant at surgical operation in the joint space, it is independent or loads with the fibre modification derivant bone morphogenetic protein, and/or somatomedin; (h) be injected into orthopedics's " cement " in the joint space such as OSTEOBOND, cement LVC, SIMPLEX P, PALACOS, CORTOSS and ENDURANCE, described " cement " are independent or load with the fibre modification derivant, bone morphogenetic protein, and/or somatomedin; (i) be injected into the surgical operation binding agent that comprises cyanoacrylate in the joint space such as DERMABOND, INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND, TISSUMEND II, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUIDPROTECTANT or as mentioned above, it is independent, or load with the fibre modification derivant bone morphogenetic protein, and/or somatomedin; (j) be injected into the hydroxyapatite that comprises in the joint space, calcium phosphate (such as VITOSS), or the surgical implants of calcium sulfate, it is independent or loads with the fibre modification derivant bone morphogenetic protein, and/or somatomedin; (k) be injected into other biocompatible tissue filler in the joint space, such as by BioCure, those that 3MCompany and Neomend make, it is independent or loads with the fibre modification derivant bone morphogenetic protein, and/or somatomedin; (1) be injected into the gel of polysaccharide gel such as the ADCON series in the joint space, it is independent or loads with the fibre modification derivant bone morphogenetic protein, and/or somatomedin; (m) be injected into film in the joint space, sponge, or mesh is such as INTERCEED, VICRYL mesh, and GELFOAM, and it is independent or loads with the fibre modification derivant bone morphogenetic protein, and/or somatomedin; And/or (N) form the hydrogel of Polyethylene Glycol from amino-functional (for example, 4-arm tetramino PEG[10k] and the functionalized PEG of 4-arm NHS) (for example, tetramethylolmethane gathers (ethylene glycol) ether four-succinimido glutarate [10K]).This hydrogel also can comprise collagen protein, methylated collagen protein and/or gelatin.This hydrogel also can comprise above-mentioned fibre modification derivant (for example, silk powder or silk thread).In many these embodiments, add radiopaque material (for example, tantalum, barium, other metal or developing materials) thus make that injected material can by radiography or to develop by MRI also be useful.

Tackling in those skilled in the art is to it is evident that potentially, aforesaid any binding agent or fibre modification derivant can be used alone or in combination in the practice of the present embodiment.Being used in exemplary fibrous tissue in the joint fusion method of intrusion degree minimum forms agent and comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF, bone morphogenetic protein, and/or osteogenic growth factor is (such as transforming growth factor, platelet-derived somatomedin, fibroblast growth factor), and above-mentioned analog and derivant.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF in addition, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or bone morphogenetic protein (BMP) is (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant).

In addition, described device can be separately or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, all-trans retinoic acid (ATRA), and analog and derivant.

Can will further describe in correct administration and the dosage part (c) below.

The fibrous tissue that (iii) is used for the arthrodesis of intrusion degree minimum forms agent

Be used in that exemplary fibrous tissue in the arthrodesis of intrusion degree minimum forms agent and the skeletonization agent comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin, CTGF, bone morphogenetic protein, and/or osteogenic growth factor (such as transforming growth factor, platelet-derived somatomedin, and above-mentioned analog and derivant fibroblast growth factor).In some clinical conditions, may need duplicate injection activating agent described below.

The exact dose of using can change with the concrete joint of being treated.Yet, some principle can be applied in the application of this area.Can be the function of per unit volume (injected amount) dosage with medication dose calculation, can measure the total drug dose of using, and can determine the suitable surface concentration of active medicine.No matter how medicament administration arrives the employed method in affected joint, the exemplary fibers texturizer, the bone morphogenetic protein that are used alone or in combination, and/or osteogenic growth factor is (such as transforming growth factor, platelet-derived somatomedin, fibroblast growth factor) should under instructing, following administration use:

Talcum is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming the injectable thing, or use without polymer support, the steatitic accumulated dose that is applied in any single injection in the joint should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the steatitic total amount that is applied should be in the scope of 10 μ g-50mg.The dosage of injected per unit volume should be at 0.05 μ g-10 μ g/mm ³In the scope.In one embodiment, thus Talcum discharges the ankylosis that promote in the joint in the period of a few hours to several months scope from the injectable thing.For example, Talcum can discharge the period that reaches 2-12 week scope with valid density.What consider that discussion provided herein it should be obvious that is to be used for purpose of the present invention with having active steatitic analog of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the Talcum effect with half of above-mentioned parameter, use half in chemical compound of Talcum effect etc.) with the twice of above-mentioned parameter.

Silk is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming the injectable thing, or use without polymer support, the accumulated dose that is delivered to the silk in the joint in any single injection should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, be applied to the joint the silk total amount should be in the scope of 10 μ g-50mg.The dosage of injected per unit volume should be at 0.05 μ g-10 μ g/mm ³In the scope.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge silk with different speed, thereby the silk that above-mentioned administration parameter should be used in combination the Cmin that makes 0.01nM-1000 μ M with the rate of release of medicine from carrier is continued to be delivered to described tissue in treatment period of needs.In one embodiment, thus silk is released in the joint and promotes ankylosis in the period of a few hours to several months in the scope.For example, silk can discharge the period that reaches all scopes in 2 week-12 with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active silk of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles an effect with half of above-mentioned parameter, use half in chemical compound of silk effect etc.) with the twice of above-mentioned parameter.

Chitosan is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming the injectable thing, or use without polymer support, the accumulated dose that is delivered to the chitosan in the joint should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, being applied in any single injection should be in the scope of 10 μ g-50mg to the total amount of the chitosan in joint.The dosage of injected per unit volume should be at 0.05 μ g-10 μ g/mm ³In the scope.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge chitosan with different speed, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from carrier and makes the chitosan of 0.01nM-1000 μ M Cmin be continued to be delivered in the described joint tissue.In one embodiment, thus chitosan is released in the joint and promotes ankylosis in the period of a few hours to several months in the scope.For example, chitosan can discharge the period that reaches 2-12 week scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active chitosan of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the chitosan effect with half of above-mentioned parameter, use half in chemical compound of chitosan effect etc.) with the twice of above-mentioned parameter.

Polylysine is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming the injectable thing, or use without polymer support, the accumulated dose that is delivered to the polylysine in the joint in single injection should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, being delivered to the total amount of the polylysine in joint should be in the scope of 10 μ g-50mg.The dosage of injected per unit volume should be at 0.05 μ g-10 μ g/mm ³In the scope.In another embodiment, polylysine should be with 0.05-10 μ g/mm ³Dosage be expelled in the joint.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge polylysine with different speed, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from carrier and makes the polylysine of 0.01nM-1000 μ M Cmin be continued to be delivered to described joint tissue.In one embodiment, thus polylysine is applied to described joint promotes ankylosis in the period of a few hours to several months in the scope.For example, polylysine can discharge the period that reaches 2-12 week scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active polylysine of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the polylysine effect with half of above-mentioned parameter, use half in chemical compound of polylysine effect etc.) with the twice of above-mentioned parameter.

Fibronectin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming the injectable thing, or use without polymer support, the accumulated dose that is delivered to the fibronectin in the joint in single injection should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, being injected into the total amount of the fibronectin in the joint should be in the scope of 10 μ g-50mg.The dosage of the per unit volume of injection should be at 0.05 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.05-10 μ g/mm ³Dosage by injection mass is used Talcum.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge fibronectin with different speed, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from carrier and makes the fibronectin of 0.01nM-1000 μ M Cmin be continued to be delivered in the described tissue.In one embodiment, thus fibronectin is released in the joint and promotes ankylosis in the period of a few hours to several months in the scope.For example, fibronectin can discharge the period that reaches all scopes in 2 week-12 with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active fibronectin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the fibronectin effect with half of above-mentioned parameter, use half in chemical compound of fibronectin effect etc.) with the twice of above-mentioned parameter.

Bleomycin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming the injectable thing, or use without polymer support, the accumulated dose that is applied to the bleomycin in the joint in single injection should be no more than 100mg (scope of 0.01 μ g-100mg).In one embodiment, being injected into the total amount of the bleomycin in the joint should be in the scope of 0.10 μ g-50mg.The dosage of injected per unit volume should be at 0.005 μ g-10 μ g/mm ³Scope in.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge bleomycin with different speed, thereby above-mentioned administration parameter should be continued to be delivered in the described joint with the bleomycin that the rate of release of medicine from carrier is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, thus bleomycin discharges the ankylosis that promote in the joint in the period of a few hours to several months scope from injection.For example, bleomycin can discharge the period that reaches all scopes in 2 week-12 with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active bleomycin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the bleomycin effect with half of above-mentioned parameter, use half in chemical compound of bleomycin effect etc.) with the twice of above-mentioned parameter.

CTGF is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming the injectable thing, or use without polymer support, the accumulated dose that is applied to the CTGF in the joint in single injection should be no more than 100mg (scope of 0.01 μ g-100mg).In one embodiment, being injected into the total amount of the CTGF in joint should be in the scope of 0.10 μ g-50mg.The dosage of the per unit volume of injection should be at 0.005 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.005-10 μ g/mm ³Dosage CTGF is injected.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge CTGF with different speed, thereby above-mentioned administration parameter should be continued to be delivered in the described joint with the CTGF that the rate of release of medicine from carrier is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, thus CTGF discharges the ankylosis that promote in the joint in the period of a few hours to several months scope from the injectable thing.For example, CTGF can discharge the period that reaches all scopes in 2 week-12 with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active CTGF of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the CTGF effect with half of above-mentioned parameter, use half in chemical compound of CTGF effect etc.) with the twice of above-mentioned parameter.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF in addition, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or bone morphogenetic protein (BMP) is (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant).

Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of inflammatory cytokine from 0.0001 μ g/ml to about 20mg/ml is used in the preparation.Preferably, inflammatory cytokine discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 100mg); Preferred 0.001 μ g is to 50mg.When being used as the device coating, dosage is 0.0001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.001 μ g/mm ²-200 μ g/mm ²With 10 ^-10-10 ^-4The Cmin of the inflammatory cytokine of g/ml maintains on the apparatus surface.

Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, with bone morphogenetic protein (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant) be used in the preparation with concentration range from 0.001 μ g/ml to about 20mg/ml.Preferably, bone morphogenetic protein discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.001 μ g is to the scope of 500mg); Preferred 1 μ g is to 250mg.When being used as the device coating, dosage is 0.001 μ g-1000 μ g/mm of per unit area ²Preferred dosage is 0.01 μ g/mm ²-200 μ g/mm ²With 10 ^-9-10 ^-4The Cmin of the bone morphogenetic protein of M maintains on the apparatus surface.

In addition, described device can be separately or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA), and analog and derivant.Used dosage is to be proved to be those concentration (embodiment 16) that stimulate cellular proliferation.Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of multiplication agent from 0.01ng/mL to 25mg/ml is used in the preparation.Preferably, multiplication agent discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 200mg); Preferred 0.001 μ g is to 100mg.When being used as the device coating, dosage is 0.00001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.0001 μ g/mm ²-200 μ g/mm ²With 10 ^-11-10 ^-6The Cmin of the multiplication agent of M maintains on the apparatus surface.

Should be that it is evident that can be with aforementioned fibers degeneration derivant for those skilled in the art, bone morphogenetic protein, or osteogenic growth factor or derivatives thereof and analog is any under the situation that does not deviate from spirit and scope of the invention, is used to produce the variation of above-mentioned composition.Also should it is evident that described reagent can be used in the compositions that has or do not have polymer support and change described carrier and not deviate from scope of the present invention.

5. women and male sterilization device

In the masculinity and femininity health care, needs are persistent, highly reliable, the method for the prevention pregnancy of intrusion degree minimum.Although Unterbindung des Eileiter (tubal ligation) and vasectomy mortality very low (about 1%), recently make described method invasive littler aspect obtained progress.This is particularly suitable in Unterbindung des Eileiter, in described Unterbindung des Eileiter, no matter is open or the surgical method of endoscope needs " clamping " fallopian tube.Designed the implant of upgrading and placed inaccessible described fallopian tube (or the deferent duct among the male), the inner chamber of described implant sealing reproductive tract with non-surgery operation by implant.Unfortunately, because reproductive tract exist fallopian tube (or deferent duct) can lead to and recover the probability of fertility in time more not physical break (and two ends are as being closed by folder in surgical operation).The invention provides the compositions that comprises the fibre modification derivant, thereby implant and device promote near the cicatrization of the wall of the reproductive tract implant or device.The result forms permanent scar tissue between the wall of fallopian tube (or deferent duct), its thorough inaccessible chamber stops gamete to move by described pipeline, and reduces the mortality (conceived and measured as preventing an accident) of described method.

(i) permanent female contraception device

(a) fallopian tube implant

Thereby it is known and can obtain many technology and device and come ligation or inaccessible fallopian tube to make ovum can not reach uterus and fertilization and implantation can not to take place.As mentioned above, for many years, with the surgical operation ligation and/or clamp " golden standard " that fallopian tube is thought permanent contraception among the women.Described many anchor clamps and clips that can be used for this purpose, for example comprised: at U.S. Patent number 4,489, the conduit anchor clamps of describing in 725; At U.S. Patent number 3,704, that describes in 704 and 3,777,737 has a lobe sterillization device; With at U.S. Patent number 3,918, the of short duration sterillization device of describing in 431.Thereby these devices are suitable for being coated with effectiveness that further increases them and the mortality that reduces them with the fibre modification derivant.Unfortunately, these methods have tangible inferior position, promptly need place in open or endoscope type surgical procedures.

Yet the preferred embodiments of the invention comprise that described device and implant are designed to not need surgical operation and are placed in the fallopian tube with the sending and the combination of many devices and implant of fibre modification derivant.Although it is variable in design, all being placed (that is, is inserted into vagina with described device or implant, passes through the uterus with all tending to transvaginal, and be placed in oviducal inner chamber), therefore eliminated the needs that enter fallopian tube outer (in the abdomen/pelvis) surface with surgical operation by abdominal part.As a result, these implants (surface, chamber) inaccessible fallopian tube and can in the patient of conscious mind, carrying out internally in the mode very identical with the department of obstetrics and gynecology medical inspection.The example that is suitable for sending the fallopian tube implant of the fibre modification derivant that increases tubal occlusion comprises: implantable, intratubal female sterilization device is (such as in U.S. Patent number 6,245,090; 6,068,626; With 3,675, those that describe in 639); Occlusive tinsel or coil fallopian tube implant (such as at U.S. Patent number 5,601, those that describe in 600); Transcatheter occlusive implant (such as at U.S. Patent number 6,245, those that describe in 090); With fallopian tube stent (for example at U.S. Patent number 5,474, those that describe in 089).In addition, contraception uterus implant, (IUDs) also can be suitable for use in the present embodiment such as intrauterine device.

The concrete female sterilization device (fallopian tube implant) that is suitable for sending according to one or more fibre modification derivants of the present invention comprises some commercially available products.For example, the ESSURE device is the stent (soft little-insert) with the catheter delivery of fiber filled, and it is designed to inaccessible fallopian tube, and (San Carlos is CA) and at U.S. Patent number: 6,176,240 for Conceptus, Inc.; 6,526,979; 5,601,600; With 5,746, describe to some extent in 769.From Ovion (Redwood City, ECLIPSE CA) be with polyester fiber fill from-expansion the nitinol stent, its by the conduit transvaginal be delivered in the fallopian tube.Other contraception fallopian tube implant comprises the porous plastic fiber, and (CA) and from OrganonCorporation (West Orange, single rod-shaped implant NJ) is such as IMPLANON for Adiana, Redwood.

No matter concrete design how, aforesaid contraception implant goes for and will induce the reagent of fibre modification or adhesion to be discharged in the fallopian tube.The result can be that the cicatrization around implant increases, the filling and/or the obturation of more complete (and lasting) of fallopian tube lumen, and reduce women or male germ cell can be by inaccessible and the probability that contacts with each other-reduce the thus probability of unexpected intrauterine pregnancy or fallopian tube pregnancy.The fallopian tube implant can be adapted to have the fibre modification derivant that is attached in their structures, is suitable for having the face coat of fibre modification derivant and/or is suitable for discharging the fibre modification derivant.This can finish by the following mode, comprise: (a) by required fibre modification derivant or the compositions that comprises the fibre modification derivant directly being invested fallopian tube implant/device (for example, by coming that with medicine and/or medicine-carrier (polymerism or non-polymerization)-compositions implant is sprayed whole (or part) generation film/coating at the interior and/or outer surface of described device; By described implant or device being immersed medicine and/or medicine-carrier (polymerism or non-polymerization) thereby-solution is coated with whole (or parts) of described device/implant; Or by with therapeutic agent covalently or non-covalently (, use binding agent, heat treatment, electrostatic adherence, ion adheres to, hydrophobic interaction or hydrogen bond) such as mechanical attachment by knotting be attached to described fallopian tube device/implant surface; (b) by being coated with fallopian tube device/implant with material such as hydrogel, described hydrogel can absorb required fibre modification derivant or compositions again; (c) by " line " being woven in described fallopian tube implant/device, described line is made up of the fibre modification derivant or by its coating, (for example, by fibre modification derivant (for example, silk, collagen protein, EVA, PLA, polyurethane, polymeric pharmaceutical composition) polymer chain formed or use the polymer-coated line of forming or discharge it by the fibre modification derivant); (d) by using the sleeve pipe that comprises the fibre modification derivant, lid (cover) or mesh cover described fallopian tube device/implant all or part of (promptly, by fibre modification derivant-polymer such as silk, collagen protein, EVA, PLA, polyurethane-or discharge the overcover that the polymer composition of fibre modification derivant is formed); (e) with the fibre modification derivant make up described fallopian tube implant/device all or part of (for example, with polymer such as silk, collagen protein, EVA, PLA, the polymer composition of polyurethane or fibre modification derivant makes up it)-for IMPLANON bar or Adiana porous fiber, it can be effective especially; (f) for fallopian tube stent device (such as ESSURE or ECLIPSE), described center " filling " material can be made up of the fibre modification derivant, or (for example (for example by the fibre modification derivant with its coating, silk, collagen protein, EVA, PLA, polyurethane, polymeric pharmaceutical composition) polymer fiber of forming or use the polymer-coated described fiber of forming or discharge it by the fibre modification derivant); (g) or, flood described fallopian tube implant/device with required fibre modification derivant or compositions; (h) scratch on described device or implant surface all or part of (that is, producing ridge or impression) thereby produce stimulates and finally causes fibre modification; (i) described device or implant is all or part of by inducing fibrotic metal alloy (for example, copper) to form; (j) from the degradable that discharges one or more fibre modification derivants or nondegradable polymer make up described device or implant itself all or part of-it can be for the IMPLANON bar, Adiana porous fiber or the center filler in ESSURE or ECLIPSE device are effective especially; And/or (k) use the multiple medicines thing release medical apparatus system of specialization (to be described in for example U.S. Patent number 6,562,065; Application No. 2003/0199970 and 2003/0167085; With in WO 03/015664 and WO 02/32347) send the fibre modification derivant alone or in combination.

Tackling in those skilled in the art is to it is evident that potentially, any binding agent or fibre modification derivant can be used alone or in combination in the practice of aforesaid the present embodiment.The exemplary fibrous tissue formation agent that is used in fallopian tube implant and the device comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF, and above-mentioned analog and derivant.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF in addition, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or bone morphogenetic protein (BMP) is (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant).

In addition, described device can be separately or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, all-trans retinoic acid (ATRA), and analog and derivant.

Can will further describe in correct administration and the dosage part (c) below.

(b) injectable fallopian tube implant

Another preferred embodiment of the present invention comprises with the biomaterial combination sends the fibre modification derivant, thereby described biomaterial is designed to be expelled to " obstruction " or inaccessible described pipeline in the fallopian tube.Many different biomaterials are adapted to pass through transvaginal route of administration and are expelled in the fallopian tube (promptly, delivery apparatus is inserted in the vagina, pass through the uterus, place oviducal inner chamber, and the biomaterial injection that will comprise the fibre modification derivant is in oviducal chamber), therefore eliminated the needs that enter fallopian tube outer (in the abdominal part/pelvis) surface with surgical operation by abdominal part.As a result, these implants (surface, chamber) inaccessible described fallopian tube and can be internally in the patient of conscious mind, to carry out with the quite similar mode of department of obstetrics and gynecology medical inspection.Described biomaterial can inaccessible described oviducal chamber, thereby simultaneously described fibre modification derivant promotes the formation permanent occlusion described chamber of scar tissue between tubal wall, stop gamete by pipeline motion and reduce the mortality (pregnancy is measured as preventing an accident) of described method.

Injectable material can be made up of the hydrogel that is used in the female sexual sterilization of mammal.Described hydrogel can be made up of nondegradable or degradable material.The non-degradable material can comprise crosslinked compositions, and described crosslinked compositions comprises PVA, PVP, polyacrylamide, pHEMA, poly-(vinyl PEG), poly-(styrene sulfonate), poly-(acrylic acid), poly-(methacrylic acid), and the polymer of other known formation hydrogel.Other compositions comprises the admixture and the copolymer of the reagent of listing above.Degradable material comprises, but be not limited to the crosslinked material of PEG, gelatin, collagen protein, hyaluronic acid, derivatives of hyaluronic acids, polysaccharide, carbohydrate, protein (for example, albumin, casein, lactalbumin, phytoprotein and fish protein), cellulose derivative is (for example, HPC), chitosan, chitosan derivative, polyester-polyalkylene oxide block copolymer (for example, PLGA-PEG-PLGA and MePEG-PLGA) and other can be by excretory low-molecular weight polymers.A kind of interested especially material preparation is from 4-arm mercaptan PEG (10K), and 4-arm NHSPEG (10K) and methylated collagen protein are such as above-mentioned.In preferred embodiments, described hydrogel also comprises can induce fibrotic bioactivator in fallopian tube.Preferably, bioactive fibre modification derivant, the release dynamics of their dosage and they all is described in the following part (c).

Except the fibre modification derivant, or alternatively, described hydrogel can be used for sclerosing agent is delivered to fallopian tube.Sclerosing agent comprises chemical compound such as ethanol, DMSO, surfactant, sucrose, NaCl, dextrose, glycerol, minocycline, tetracycline, doxycycline, Polidocanol, sodium tetradecyl sulfate, sodium morrhuate, Sotradecol and other.Described hydrogel can also comprise reagent such as glycerol, glycerol, and PEG200, triethyl citrate and triacetin are as plasticizer.

Thereby can also modify the line that makes its line form or comprise polymer to above-mentioned hydrogel by polymer.Polymer line has the ability of inducing the fibroplasia reaction in fallopian tube from surrounding tissue.These polymer lines can be degradable or nondegradable.Degradable line can be by degradable polyester, polyanhydride, poly-(acid anhydride ester), poly-(ester-amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, cyanoacrylate polymer, collagen protein, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose, cellulose esters, its admixture and copolymer, and other known degradable polymer is formed.Operable non-degradable polymer include, but not limited to polyester (for example, PET), polyurethane, siloxanes, PE, PP, PS, PAA, PMA, the silk, its admixture, copolymer and other known polymer.Used line can be made up of the admixture of single compositions or different components.Can come polymer line itself is further modified by the polymer coating that interpolation is applied on the described line.Be used to be coated with described line polymer can on to regard to described line itself described similar.Described polymer coating can also comprise bioactivator, and it has the ability of inducing the fibroplasia reaction.Operable reagent further is described in the following part (c).

Above-mentioned hydrogel can be used for the delivery of particles material, it has the ability of inducing the fibroplasia reaction in fallopian tube.These granules can be degradable or nondegradable and state at line drawing to above-mentioned those are similar.Except those, the particulate matter useful for putting into practice of the present embodiment comprises Talcum, starch, glass, silicate, Silicon stone, silver nitrate, Inorganic Non-metallic Materials granule and other inorganic particle of inducing the fibroplasia reaction known in the art.The granule that is used in the present embodiment can be all same combinations or the admixture of different components.As mentioned above, can also be with these granules as the coating that is applied on the polymer chain.

As conspicuous, make it by polymer line and granulometric composition thereby can also make up hydrogel.The line that uses and granule are to above-mentioned those are similar and can be the compositions of uniform composition or fusion.In fact, particulate any combination of the line of different components and different components can be used in the present embodiment.As described below, can be with hydrogel, polymer line and granule all are used to send one or more bioactivators.

In another embodiment, described hydrogel can be formed for implanting oviducal multiple shape and size.For example, described hydrogel can form the rod of required size or further be cut into appropriate length subsequently.Described hydrogel can be made another kind of shape and then be further processed the rod that forms suitable size.Described bar can be columned or they can have taper or hourglass shape.Can also make hydrogel form rectangle by suitable reagent being added in the mould and following solidification composition.The cork borer types of devices of suitable size can be used to produce bar.If these bars need further be cut into appropriate length, the thickness of initial hydrogel can be determined.Then, can these bars be dewatered by lyophilization or by air-dry.Cryodesiccated bar can have more foaming structures and air-dry bar can have more solid properties.Before solidification stages, described granule and/or bioactivator can be attached in the hydrogel.Described granule can roll extrusion be applied to the surface or by immersing, spraying or smearing is applied to the surface with described granule by described bar is carried out in granule.Described granule can with the coated polymeric combined administration of solubilized or degraded.This coated polymeric can be a gelatin, hydroxypropyl cellulose, MePEG-PLA, MePEG-polyester, polyester-PEG-polyester, or analog.

Described polymer line can be added into before solidification stages or they can be added into after hydrogel solidifies.Described polymer line can add before or after the drying stage of bar.Described line can be wrapped in the external surface peripheral of described bar.Pin can be used for vertical, level, diagonal way or its combination described line being passed through bar.Thereby can settle described line to make them form the ring on outstanding described bar surface.

A kind of concrete compositions comprises poly-(ethylene glycol) compositions by methylated collagen protein-crosslinked such as above-mentioned, the bar of preparation, and it added pulverous granule in the compositions before solidifying.In case use, described bar can absorb water and inaccessible thus fallopian tube.This expansion can stop described bar migration, and simultaneously pulverous silk can start the fibroplasia reaction.When poly-(ethylene glycol) of methylated collagen protein-crosslinked when compositions begins to degrade, described material can be supported inwardly to be grown by starting of described silk granule and the fibrous tissue strengthened.In order further to increase the initial speed of this fibroplasia reaction, can add sclerosing agent such as surfactant (SDS), ethamolin (ester) or DMSO.In addition, can also add or replace the 4-arm mercaptan PEG of all (or part) with the amino PEG of 4-arm.Described amino PEG can provide the gel that can need the longer time degraded and can provide some positive charges to the other porous material that attractability is arranged.

Second specific embodiments is made up of implant, and the polymerized form (that is, fibrous tissue forms the recurring unit that agent condenses together) of agent itself is made of or is formed from fibrous tissue to described implant silk fiber.

Except hydrogel, outside above-mentioned relevant implant, exist some to put into practice alternate manner of the present invention.All comprising is used in biomaterial in the oviducal chamber, follows or do not follow the interpolation of fibre modification derivant.The practice of this embodiment can be undertaken by some modes, described mode comprises: (a) fibrous tissue is formed agent and locally apply to that (what be particularly useful in this embodiment is the application of polymer support on the surface, oviducal chamber, described carrier forms agent with fibrous tissue and discharges-fluid in the time range of a few hours to several weeks, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, solid implant and release fibrous tissue form other preparation of agent, can be delivered in the fallopian tube by delivery catheter or other applicator of specialization); (b) independent or load that also to be expelled in the fallopian tube in orientation with the microgranule silk of additional fibers degeneration derivant and/or silk chain (straight line, side chain, and/or curl) be useful; (c) with the sprayable preparation that comprises collagen protein such as COSTASIS or by 4-arm mercaptan PEG (10K), 4-arm NHS PEG (10K), with methylated collagen protein such as the above-mentioned material of making, separately or load and be applied to oviducal chamber with the fibre modification derivant; (d) with the sprayable preparation that comprises PEG such as COSEAL, FOCALSEAL, SPRAYGEL or DURASEAL are separately or load and be applied to oviducal chamber with the fibre modification derivant; (e) will comprise preparation such as the FLOSEAL or the TISSEAL of fibrinogen, separately or load and be applied to oviducal chamber with the fibre modification derivant; (f) comprise hyaluronic preparation such as RESTYLANE, HYLAFORM, PERLANE, SYNVISC, SEPRAFILM or SEPRACOAT, it loads with the fibre modification derivant, is administered in the fallopian tube lumen; (g) be used for polymer gel such as REPEL or the FLOWGEL that surgical operation is implanted, it is independent or loads with the fibre modification derivant, is administered in the fallopian tube lumen; (h) orthopedics's " cement ", such as OSTEOBOND, LVC, SIMPLEXP, PALACOS, CORTOSS and ENDURANCE, it is independent or loads with the fibre modification derivant, is applied in the surface, oviducal chamber; (i) will comprise the surgical operation binding agent of cyanoacrylate such as DERMABOND, INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND, TISSUMEND II, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT or as above-mentioned, separately or load and be applied to oviducal chamber with the fibre modification derivant; (j) comprise hydroxyapatite, calcium phosphate (for example, VITOSS), or the surgical implants of calcium sulfate, it is independent or loads with the fibre modification derivant, is administered in the fallopian tube lumen; (k) with the tissue filler of other biocompatibility, such as by BioCure, those that 3M Company and Neomend make, independent or load and be administered in the oviducal chamber with the fibre modification derivant; (I) polysaccharide gel is such as the gel of ADCON series, and it loads with the fibre modification derivant, is administered in the oviducal chamber; (m) film, sponge or mesh be such as INTERCEED, VICRYL mesh, and GELFOAM, its be independent loading with the fibre modification derivant, be administered in the fallopian tube lumen; And/or (n) form Polyethylene Glycol (for example, 4-arm four-amino PEG) [10k] from aminofunctional) and the functionalized PEG (for example, tetramethylolmethane gathers (ethylene glycol) ether four-succinimido glutarate) of 4-arm NHS (10K)) hydrogel.This hydrogel can also comprise collagen protein, methylated collagen protein and/or gelatin.This hydrogel can also comprise above-mentioned fibre modification derivant (for example, silk powder or silk thread).

In many above-mentioned embodiments, add radiopaque material (for example, tantalum, technetium, gadolinium, barium, other metal or developing materials) thus make injected material can by radiography or visual by MRI also be useful.Described contrast agent can be water miscible or the undissolvable radiopaque material of water.Perhaps, described gel or applied implant can comprise bubble (for example, thus ECHO-COAT) maybe can inject air in the described pipe and to increase by ultransonic visual.

Tackling in those skilled in the art is to it is evident that potentially, above-mentioned any binding agent or fibre modification derivant can be used alone or in combination in the practice of aforesaid the present embodiment.The exemplary fibers texturizer that is used in fallopian tube implant and the device comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF and above-mentioned analog and derivant.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) in addition.

In addition, described device can be separately or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, all-trans retinoic acid (ATRA), and analog and derivant.

Can will further describe in correct administration and the dosage part (c) below.

(c) fibrous tissue that is used for the fallopian tube implant forms agent

Because the fallopian tube implant is made with multiple configuration and size, the exact dose of using can be with the device size, surface area and kind of design and change.Yet, some principle can be applied in the application of this area.Can be the function of per unit area (part of applied device) dosage with medication dose calculation, can measure the total drug dose of using, and can determine the suitable surface concentration of active medicine.No matter to the method for sterillization device how medicament administration, the exemplary fibers texturizer that is used alone or in combination should use under following administration is instructed:

Talcum is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, be attached in the injectable thing, or use without polymer support, the steatitic accumulated dose of sending from the sterillization device or be applied on the sterillization apparatus surface should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the steatitic accumulated dose that discharges from prosthese should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the steatitic dosage of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the sterillization apparatus surface with Talcum.In one embodiment, thus Talcum discharges from the surface of sterillization device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, Talcum can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is to be used for purpose of the present invention with having active steatitic analog of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the Talcum effect with half of above-mentioned parameter, use half in chemical compound of Talcum effect etc.) with the twice of above-mentioned parameter.

Silk is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, be attached in the injectable thing, or use without polymer support, the accumulated dose of the lip-deep silk of sending from the sterillization device or be applied to the sterillization device should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the silk that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the silk of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the sterillization apparatus surface with silk.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge silk with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the silk that the rate of release of medicine from the sterillization device is used in combination the Cmin that makes 0.01nM-1000 μ M.In one embodiment, thus silk discharges from the surface of sterillization device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, silk can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active silk of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles an effect with half of above-mentioned parameter, use half in chemical compound of silk effect etc.) with the twice of above-mentioned parameter.

Chitosan is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, be attached in the injectable thing, or use without polymer support, the accumulated dose of the lip-deep chitosan of sending from the sterillization device or be applied to the sterillization device should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the chitosan that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the chitosan of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the sterillization apparatus surface with chitosan.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge chitosan with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from the sterillization device chitosan of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, thus chitosan discharges from the surface of sterillization device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, chitosan can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active chitosan of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the chitosan effect with half of above-mentioned parameter, use half in chemical compound of chitosan effect etc.) with the twice of above-mentioned parameter.

Polylysine is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, be attached in the injectable thing, or use without polymer support, the accumulated dose of the lip-deep polylysine of sending from the sterillization device or be applied to the sterillization device should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the polylysine that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the polylysine of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the sterillization apparatus surface with polylysine.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge polylysine with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from the sterillization device polylysine of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, thus polylysine discharges from the surface of sterillization device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, polylysine can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active polylysine of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the polylysine effect with half of above-mentioned parameter, use half in chemical compound of polylysine effect etc.) with the twice of above-mentioned parameter.

Fibronectin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, be attached in the injectable thing, or use without polymer support, the accumulated dose of the lip-deep fibronectin of sending from the sterillization device or be applied to the sterillization device should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the fibronectin that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the fibronectin of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the sterillization apparatus surface with fibronectin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge fibronectin with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from the sterillization device fibronectin of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, thus fibronectin discharges from the surface of sterillization device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, fibronectin can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active fibronectin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the fibronectin effect with half of above-mentioned parameter, use half in chemical compound of fibronectin effect etc.) with the twice of above-mentioned parameter.

Bleomycin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, be attached in the injectable thing, or use without polymer support, the accumulated dose of the lip-deep bleomycin of sending from the sterillization device or be applied to the sterillization device should be no more than 100mg (scope of 0.01 μ g-100mg).The total amount of the bleomycin that discharges from prosthese in one embodiment, should be in the scope of 0.10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the bleomycin of the function of the surface area of the part of bonded device) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the sterillization apparatus surface with bleomycin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge bleomycin with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the bleomycin that the rate of release of medicine from the sterillization device is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, thus bleomycin discharges from the surface of sterillization device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, bleomycin can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active bleomycin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the bleomycin effect with half of above-mentioned parameter, use half in chemical compound of bleomycin effect etc.) with the twice of above-mentioned parameter.

CTGF is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, be attached in the injectable thing, or use without polymer support, the accumulated dose of the lip-deep CTGF that sends from the sterillization device or be applied to the sterillization device should be no more than 100mg (scope of 0.01 μ g-100mg).In one embodiment, the total amount of the CTGF that discharges from prosthese should be in the scope of 0.10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the CTGF of the function of the surface area of the part of bonded device) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the sterillization apparatus surface with CTGF.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge CTGF with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the CTGF that the rate of release of medicine from the sterillization device is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, thus CTGF discharges from the surface of sterillization device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, CTGF can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active CTGF of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the CTGF effect with half of above-mentioned parameter, use half in chemical compound of CTGF effect etc.) with the twice of above-mentioned parameter.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) in addition.According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of inflammatory cytokine from 0.0001 μ g/ml to about 20mg/ml is used in the preparation.Preferably, inflammatory cytokine discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 100mg); Preferred 0.001 μ g is to 50mg.When being used as the device coating, dosage is 0.0001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.001 μ g/mm ²-200 μ g/mm ²With 10 ^-10-10 ^-4The Cmin of the inflammatory cytokine of g/ml maintains on the apparatus surface.

In addition, described device can be separately or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA), and analog and derivant.Used dosage is to be proved to be those concentration (embodiment 16) that stimulate cellular proliferation.According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of multiplication agent from 0.01ng/ml to 25mg/ml is used in the preparation.Preferably, multiplication agent discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 200mg); Preferred 0.001 μ g is to 100mg.When being used as the device coating, dosage is 0.00001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.0001 μ g/mm ²-200 μ g/mm ²With 10 ^-11-10 ^-6The Cmin of the multiplication agent of M maintains on the apparatus surface.

Should it will be apparent to one skilled in the art that aforementioned fibers degeneration derivant, any of or derivatives thereof and analog can be used to produce the variation of above-mentioned composition under the prerequisite that does not deviate from spirit and scope of the invention.Also should it is evident that described reagent can with or be not used in the compositions and change described carrier and do not depart from scope of the present invention with polymer support.

The (ii) permanent contraception device of male

For male's permanent contraception, vasectomy is the commonly used of control fertility, high-efficiency method.Vasectomy method commonly used is included in the deferent duct sidenote and penetrates local anesthetic, open scrotum with the fixed point dissecting forecps, deferent duct is pulled out by puncture, and it is inaccessible or (for example cut off deferent duct, use wherein with suture at one end or two ends with the ligation technology of duct ligation, use transplantable clip, or by cutting off and/or burn described conduit).

(a) deferent duct implant

Disclose some and be used for the device of male contraception, be included in U.S. Patent number 3,704,704 and 3, being used for of describing in 777,737 inserted the deferential lobe sterillization device that has with surgical operation, at U.S. Patent number 4,682, the reversible male sterilization device of describing in 592 and at U.S. Patent number 3,589,355 and 4,200,088,3,648,683, with 3,589, device in vasectomy of describing in 355 and the conduit.Commercially available vasectomy clip comprises the MeditechInternational by Advanced, Inc. (Flushing, NY) those of Sheng Chaning and from VMBC, LLC (Roseville, VASCLIP MN).In the present invention, the fibre modification derivant vasectomy suture, clip or transplantable device (such as above-mentioned those) on or among combination can promote deferential fibre modification, produce obturation more completely, and increase the success rate of described method.

For clip, suture, with other transplanted device, exist obtainable certain methods to be used for the one-tenth fiber composition is attached on the deferent duct implant or among, comprise: (a) directly will become fiber composition (for example to be attached to described device, by aforesaid with or not with the spray method or the immersion method of carrier); (b) directly will become fiber composition be attached in the described device (for example, by aforesaid with or not with the spray method or the immersion method of carrier); (c) by being coated with described device such as the hydrogel that can absorb into fiber composition again with material; (d) by being woven into (or fibre modification reagent-polymer composition itself forms line) in the described apparatus structure with the line of fibre modification derivant coating; (e) by described device is inserted sleeve pipe or mesh, described sleeve pipe or mesh are made up of the one-tenth fiber composition, or are coated with it; (f) use into fiber composition construction device itself (or part of described device); Or (g) form agent by fibrous tissue and directly be covalently bound to described apparatus surface or joint (micromolecule or polymer), described joint is applied or be attached to apparatus surface.

Except with becoming fiber composition to be coated with the described device, can mix with the material that is used for preparation facilities and make fibrous tissue form the final structure that agent is attached to device itself thereby described fibrous tissue forms agent.

In another embodiment, also comprise the film of fibre modification derivant or mesh can be wrapped in deferent duct or deferential be cut part around.The success rate that this can promote the deferential fibre modification that is cut and can increase described method.In another embodiment, described fibre modification derivant can be incorporated in the gel combination of original position formation.Using clip, using the suture ligation, or behind the cutting deferent duct, original position can be formed compositions be applied to treatment site (for example, deferential incision tip) thus promote fibre modification and increase the success rate of described method.

Tackling in those skilled in the art is to it is evident that potentially, any binding agent or fibre modification derivant can be used alone or in combination in the practice of aforesaid the present embodiment.The exemplary fibrous tissue formation agent that is used in deferent duct implant and the device comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF, and above-mentioned analog and derivant.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) in addition.

In addition, described device can comprise the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, all-trans retinoic acid (ATRA), and analog and derivant.

Can will further describe in correct administration and the dosage part (c) below.

(b) injectable deferent duct implant

A particularly preferred embodiment of the present invention comprises and biomaterial combination dermal delivery fibre modification derivant, thereby described biomaterial is designed to be expelled to " obstruction " or inaccessible male genetic road in the deferent duct.By palpation (in both sides) deferent duct is positioned, insert a needle into tube chamber, guide wire is advanced in the deferential chamber, with double channel catheter (for many hydrogels that describe below such as by 4-arm mercaptan PEG (10K), the material of 4-arm NHS PEG (10K) and methylated collagen protein such as above-mentioned preparation, COSEAL, COSTASIS, FLOSEAL, TISSEAL or single lumen catheter are (for material such as cyanoacrylate, hyaluronic acid, protein, carbohydrate, sclerosing agent etc.) on tinsel, be advanced in the deferential chamber, guide wire is removed, and be expelled in the deferent duct up to described chamber by thoroughly inaccessible by the compositions that conduit will comprise the fibre modification derivant.Can be used for making the technology of pin (or conduit) development that places deferent duct to comprise, but be not limited to, the pin of quilt is wrapped in use with ECHO-COAT, or the injection air is positioning by ultrasonic, or interpolation contrast agent (for example, barium, tantalum, technitium, gadolinium) thus carry out location by x-ray or MRI.Injectable implant is (surface, chamber) inaccessible deferent duct and can carry out the needed time of described method by single (left side and right) pin puncture implantation-minimizing in the patient of conscious mind internally, invasive (not needing surgical operation to cut) and the danger of infecting.Described biomaterial is inaccessible described tube chamber on health, and the fibre modification derivant promotes the formation of scar tissue between deferential adjacent wall simultaneously, causes the permanent occlusion in described chamber.This has stoped spermatid to pass through moving of male genetic road, and can reduce the mortality (measuring as preventing unplanned pregnancy) of described method.

Injectable material can be made up of the hydrogel that is used in the male sterillization of mammal.Described hydrogel can be made up of nondegradable or degradable material.The non-degradable material can comprise crosslinked compositions, and described crosslinked compositions comprises PVA, PVP, polyacrylamide, pHEMA, poly-(vinyl PEG), poly-(styrene sulfonate), poly-(acrylic acid), poly-(methacrylic acid), and the polymer of other known formation hydrogel.Other compositions comprises the admixture and the copolymer of the reagent of listing above.Degradable material comprises, but be not limited to the crosslinked material of PEG, gelatin, collagen protein, hyaluronic acid, derivatives of hyaluronic acids, polysaccharide, carbohydrate, protein (for example, albumin, casein, lactalbumin, phytoprotein and fish protein), cellulose derivative is (for example, HPC), chitosan, chitosan derivative, polyester-polyalkylene oxide block copolymer (for example, PLGA-PEG-PLGA and MePEG-PLGA etc.) and other can be by excretory low-molecular weight polymers.A kind of interested especially material preparation is from 4-arm mercaptan PEG (10K), and 4-arm NHS PEG (10K) and methylated collagen protein are such as above-mentioned.Described hydrogel can also comprise can induce fibrotic bioactivator in deferent duct.Preferred bioactive fibre modification derivant, the release dynamics of their dosage and they are all described in detail in below the part (c).

Except the fibre modification derivant, or alternatively, described hydrogel can be used for sclerosing agent is delivered to deferent duct.Sclerosing agent comprises chemical compound such as ethanol, DMSO, surfactant, sucrose, NaCl, dextrose, glycerol, minocycline, tetracycline, doxycycline, Polidocanol, sodium tetradecyl sulfate, sodium morrhuate, Sotradecol and other.Described hydrogel can also comprise reagent such as glycerol, glycerol, and PEG200, triethyl citrate and triacetin are as plasticizer.

Thereby can also modify the line that makes its line form or comprise polymer to above-mentioned hydrogel by polymer.Polymer line has the ability of inducing the fibroplasia reaction in deferent duct from surrounding tissue.These polymer lines can be degradable or nondegradable.Degradable line can be by degradable polyester, polyanhydride, poly-(acid anhydride ester), poly-(ester-amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, cyanoacrylate polymer, collagen protein, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose, cellulose esters, its admixture and copolymer, and other known degradable polymer is formed.Operable non-degradable polymer include, but not limited to polyester (for example, PET), polyurethane, siloxanes, PE, PP, PS, PAA, PMA, the silk, its admixture, copolymer and other known polymer.Used line can be made up of the admixture of single compositions or different components.Can come polymer line itself is further modified by the polymer coating that interpolation is applied on the described line.Be used to be coated with described line polymer can on to regard to described line itself described similar.Described polymer coating can also comprise bioactivator, and it has the ability of inducing the fibroplasia reaction.Operable reagent further is described in the following part (c).

Above-mentioned hydrogel can be used for the delivery of particles material, it has the ability of inducing the fibroplasia reaction in deferent duct.These granules can be degradable or nondegradable and state at line drawing to above-mentioned those are similar.Except those, the particulate matter useful for putting into practice of the present embodiment comprises Talcum, starch, glass, silicate, Silicon stone, silver nitrate, Inorganic Non-metallic Materials granule and other inorganic particle of inducing the fibroplasia reaction known in the art.The granule that is used in the present embodiment can be all same combinations or the admixture of different components.As mentioned above, can also be with these granules as the coating that is applied on the polymer chain.

Thereby can also make up hydrogel makes it the two is formed by polymer line and granule.The line that uses and granule are to above-mentioned those are similar and can be the compositions of uniform composition or fusion.In fact, particulate any combination of the line of different components and different components can be used in the present embodiment.As described below, can be with hydrogel, polymer line and granule all are used to send one or more bioactivators.

A kind of concrete compositions comprises poly-(ethylene glycol) compositions by methylated collagen protein-crosslinked such as above-mentioned, the bar of preparation, and it had before solidifying, and was added into pulverous granule in the compositions.In case use, described bar can absorb water and inaccessible thus deferent duct.This expansion can stop described bar migration, and simultaneously pulverous silk can start the fibroplasia reaction.When poly-(ethylene glycol) of methylated collagen protein-crosslinked when material begins to degrade, described material can be supported inwardly to be grown by starting of described silk granule and the fibrous tissue strengthened.In order further to increase the initial speed of this fibroplasia reaction, can add sclerosing agent such as surfactant (SDS), ethamolin (ester) or DMSO.In addition, can also add or replace the 4-arm mercaptan PEG of all (or part) with the amino PEG of 4-arm.Described amino PEG can provide the gel that can need the longer time degraded and can provide some positive charges to the other porous material that attractability is arranged.

Another embodiment is made up of injectable implant, and the polymerized form (that is, fibrous tissue forms the recurring unit that agent condenses together) of agent itself is made of or is formed from fibrous tissue to described implant silk fiber.

Except above-mentioned hydrogel, outside relevant implant, exist some to put into practice the alternate manner of the present embodiment.All comprising is used in biomaterial in the deferential chamber, follows or do not follow the interpolation of fibre modification derivant.The practice of this embodiment can be undertaken by some modes, described mode comprises: (a) fibrous tissue is formed agent and be administered to that (what be particularly useful in this embodiment is the application of polymer support on the surface, deferential chamber, described carrier forms agent with fibrous tissue and discharges-fluid in the time range of a few hours to several weeks, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, solid implant and can discharge other preparation that fibrous tissue forms agent, delivery catheter or other applicator by specialization are delivered in the deferent duct); (b) independent, or load that also to be expelled in the deferent duct in orientation with the microgranule silk of additional fibers degeneration derivant and/or silk chain (straight line, side chain, and/or curl) be useful; (c) comprise preparation such as the COSTASIS of collagen protein or by 4-arm mercaptan PEG (10K) with injectable, 4-arm NHSPEG (10K), with methylated collagen protein such as the above-mentioned material of making, separately or load and be injected in the deferential chamber with the fibre modification derivant; (d) with the injectable preparation that comprises PEG such as COSEAL, FOCALSEAL, SPRAYGEL or DURASEAL are separately or load and be injected in deferential chamber with the fibre modification derivant; (e) will comprise preparation such as the FLOSEAL or the TISSEAL of fibrinogen, separately or load and be injected in deferential chamber with the fibre modification derivant; (f) comprise hyaluronic preparation such as RESTYLANE, HYLAFORM, PERLANE, SYNVISC, SEPRAFILM or SEPRACOAT, it is expelled in the vas deferens lumen separately or load with the fibre modification derivant; (g) be used for polymer gel such as REPEL or the FLOWGEL that surgical operation is implanted, it is independent or loads to be injected into the fibre modification derivant of vas deferens lumen; (h) orthopedics's " cement ", such as OSTEOBOND, LVC, SIMPLEX P, PALACOS, CORTOSS and ENDURANCE, it is independent or loads with the fibre modification derivant, is expelled in the surface, deferential chamber; (i) will comprise the surgical operation binding agent of cyanoacrylate such as DERMABOND, INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND, TISSUMEND II, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUIDPROTECTANT or as above-mentioned, separately or load and be injected in the deferential chamber with the fibre modification derivant; (j) comprise the surgical implants of hydroxyapatite such as VITOSS (Orthovita) or calcium sulfate, it is independent or loads with the fibre modification derivant, is expelled in the vas deferens lumen; (k) with the tissue filler of other biocompatibility, such as by BioCure, those that 3M Company and Neomend make, independent or load and be expelled in the deferential chamber with the fibre modification derivant; (1) polysaccharide gel is such as the gel of ADCON series, and it is independent or loads with the fibre modification derivant, is expelled in the deferential chamber; (m) film, sponge or mesh be such as INTERCEED, VICRYL mesh, and GELFOAM, its be independent loading with the fibre modification derivant, be expelled in the vas deferens lumen; And/or (n) form Polyethylene Glycol (for example, 4-arm four-amino PEG) [10k] from aminofunctional) and the functionalized PEG (for example, tetramethylolmethane gathers (ethylene glycol) ether four-succinimido glutarate) of 4-arm NHS (10K)) hydrogel.This hydrogel can also comprise collagen protein, methylated collagen protein and/or gelatin.This hydrogel can also comprise above-mentioned fibre modification derivant (for example, silk powder or silk thread).

In many above-mentioned embodiments, add radiopaque material (such as tantalum, technetium, other metal or developing materials) thus make injected material can by radiography or visual by MRI also be useful.Described contrast agent can be water miscible or the undissolvable radiopaque material of water.

Tackling in those skilled in the art is to it is evident that potentially, above-mentioned any binding agent or fibre modification derivant can be used alone or in combination in the practice of aforesaid the present embodiment.The exemplary fibers texturizer that is used in deferent duct implant and the device comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF and above-mentioned analog and derivant.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) in addition.

In addition, described device can comprise the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, all-trans retinoic acid (ATRA), and analog and derivant.

Can will further describe in correct administration and the dosage part (c) below.

(c) fibrous tissue that is used for the deferent duct implant forms agent

Because deferent duct implantable and injectable thing are made with multiple configuration and size, the exact dose of using can be with the device size, surface area and kind of design and change.Yet, some principle can be applied in the application of this area.Can be the function of per unit area (part of applied device) dosage with medication dose calculation, can measure the total drug dose of using, and can determine the suitable surface concentration of active medicine.No matter to the method for sterillization device how medicament administration, the exemplary fibers texturizer that is used alone or in combination should use under following administration is instructed:

Talcum is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, be attached in the injectable thing, or use without polymer support, the steatitic accumulated dose of sending from the sterillization device or be applied on the sterillization apparatus surface should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the steatitic accumulated dose that discharges from prosthese should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the steatitic dosage of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the sterillization apparatus surface with Talcum.In one embodiment, thus Talcum discharges from the surface of sterillization device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, Talcum can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is to be used for purpose of the present invention with having active steatitic analog of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the Talcum effect with half of above-mentioned parameter, use half in chemical compound of Talcum effect etc.) with the twice of above-mentioned parameter.

Silk is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, be attached in the injectable thing, or use without polymer support, the accumulated dose of the lip-deep silk of sending from the sterillization device or be applied to the sterillization device should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the silk that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the silk of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the sterillization apparatus surface with silk.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge silk with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the silk that the rate of release of medicine from the sterillization device is used in combination the Cmin that makes 0.01nM-1000 μ M.In one embodiment, thus silk discharges from the surface of sterillization device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, silk can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active silk of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles an effect with half of above-mentioned parameter, use half in chemical compound of silk effect etc.) with the twice of above-mentioned parameter.

Chitosan is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, be attached in the injectable thing, or use without polymer support, the accumulated dose of the lip-deep chitosan of sending from the sterillization device or be applied to the sterillization device should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the chitosan that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the chitosan of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the sterillization apparatus surface with chitosan.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge chitosan with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from the sterillization device chitosan of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, thus chitosan discharges from the surface of sterillization device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, chitosan can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active chitosan of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the chitosan effect with half of above-mentioned parameter, use half in chemical compound of chitosan effect etc.) with the twice of above-mentioned parameter.

Polylysine is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, be attached in the injectable thing, or use without polymer support, the accumulated dose of the lip-deep polylysine of sending from the sterillization device or be applied to the sterillization device should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the polylysine that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the polylysine of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the sterillization apparatus surface with polylysine.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge polylysine with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from the sterillization device polylysine of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, thus polylysine discharges from the surface of sterillization device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, polylysine can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active polylysine of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the polylysine effect with half of above-mentioned parameter, use half in chemical compound of polylysine effect etc.) with the twice of above-mentioned parameter.

Fibronectin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, be attached in the injectable thing, or use without polymer support, the accumulated dose of the lip-deep fibronectin of sending from the sterillization device or be applied to the sterillization device should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the fibronectin that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the fibronectin of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the sterillization apparatus surface with fibronectin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge fibronectin with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from the sterillization device fibronectin of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, thus fibronectin discharges from the surface of sterillization device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, fibronectin can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active fibronectin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the fibronectin effect with half of above-mentioned parameter, use half in chemical compound of fibronectin effect etc.) with the twice of above-mentioned parameter.

Bleomycin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, be attached in the injectable thing, or use without polymer support, the accumulated dose of the lip-deep bleomycin of sending from the sterillization device or be applied to the sterillization device should be no more than 100mg (scope of 0.01 μ g-100mg).The total amount of the bleomycin that discharges from prosthese in one embodiment, should be in the scope of 0.10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the bleomycin of the function of the surface area of the part of bonded device) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the sterillization apparatus surface with bleomycin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge bleomycin with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the bleomycin that the rate of release of medicine from the sterillization device is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, thus bleomycin discharges from the surface of sterillization device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, bleomycin can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active bleomycin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the bleomycin effect with half of above-mentioned parameter, use half in chemical compound of bleomycin effect etc.) with the twice of above-mentioned parameter.

CTGF is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, be attached in the injectable thing, or use without polymer support, the accumulated dose of the lip-deep CTGF that sends from the sterillization device or be applied to the sterillization device should be no more than 100mg (scope of 0.01 μ g-100mg).In one embodiment, the total amount of the CTGF that discharges from prosthese should be in the scope of 0.10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the CTGF of the function of the surface area of the part of bonded device) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the sterillization apparatus surface with CTGF.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge CTGF with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the CTGF that the rate of release of medicine from the sterillization device is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, thus CTGF discharges from the surface of sterillization device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, CTGF can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active CTGF of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the CTGF effect with half of above-mentioned parameter, use half in chemical compound of CTGF effect etc.) with the twice of above-mentioned parameter.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) in addition.According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of inflammatory cytokine from 0.0001 μ g/ml to about 20mg/ml is used in the preparation.Preferably, inflammatory cytokine discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 100mg); Preferred 0.001 μ g is to 50mg.When being used as the device coating, dosage is 0.0001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.001 μ g/mm ²-200 μ g/mm ²With 10 ^-10-10 ^-4The Cmin of the inflammatory cytokine of g/ml maintains on the apparatus surface.

In addition, described device can be separately or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA), and analog and derivant.Used dosage is to be proved to be those concentration (embodiment 16) that stimulate cellular proliferation.According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of multiplication agent from 0.01ng/ml to 25mg/ml is used in the preparation.Preferably, multiplication agent discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 200mg); Preferred 0.001 μ g is to 100mg.When being used as the device coating, dosage is 0.00001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.0001 μ g/mm ²-200 μ g/mm ²With 10 ^-11-10 ^-6The Cmin of the multiplication agent of M maintains on the apparatus surface.

Should it will be apparent to one skilled in the art that aforementioned fibers degeneration derivant, any of or derivatives thereof and analog can be used to produce the variation of above-mentioned composition under the prerequisite that does not deviate from spirit and scope of the invention.Also should it is evident that described reagent can with or be not used in the compositions and change described carrier and do not depart from scope of the present invention with polymer support.

6. urinary incontinence

The invention provides the compositions and the device that are used in the treatment urinary incontinence.Urinary incontinence, or the unconscious outflow of urine are common medical conditions, and it has influence in the time of in life some of the man of 20% woman and 1-2%.The most common form of incontinence is stress incontinence (stress incontinence), or the unconscious seepage of urinating when response causes increasing the activity (such as sneeze, cough, or hyperkinesia) of intra-abdominal pressure.This betides the pressure that surpasses urethra when intravesical pressure (intravesical pressure), forces when forcing urine to flow out into urethra from bladder under flesh (bladder muscle) the contraction situation in shortage.Think that some diseases causes stress incontinence, described disease comprises: (1) neck of bladder and interior sphincter of urethra descend and abdominal part; (2) owing to wound, surgical operation, sphincter of urethra decline in the body that childbirth or malignant tumor cause.Correct measure mainly concentrates on urethra and the neck of bladder that is close in the intraperitoneal support by surgical operation or non-surgery operation mode.Second method comprises uses the urethra filler, and described urethra filler is designed to increase urethra pressure and reduces stress incontinence.

No matter their composition is how, the seepage that the urethra filler is designed to provide the physical support of urethra and stops urine.Unfortunately, for Most patients, alleviating of symptom often only is temporary transient and must repeats described method.Biodegradable injectable substance (such as collagen protein, hyaluronic acid and following other) is absorbed and has lost their structural intergrity-must replace described material by duplicate injection in time by health.Nondegradable material (such as acrylic acid, hydroxyapatite, polymeric beads and following other) is not rebuild the normal configuration anatomy or the biomechanics of tissue around urethra.Add the fibre modification derivant in solving these problems in the urethra filler some.The fibre modification derivant promotes the formation at the fibrous tissue (comprising collagen protein) of periurethral health itself.This causes the formation of the lasting connective tissue that can support, and described connective tissue is supported described urethra in the mode of closer simulating normal pelvis anatomy and biomechanics.The result be continue longer, the treatment that better sx is provided and needs still less to intervene again.

(i) comprise the injectable urine filler that fibrous tissue forms agent

Can make up with one or more filleies that is used for the treatment of urinary incontinence and comprise the commercially available product that is used for the treatment of stress incontinence according to fibre modification derivant of the present invention.CONTIGEN (can pass through C.R.Bard, what Billerica, MA obtained is dispersed in the collagen protein of the purification Corii Bovis seu Bubali glutaraldehyde cross-linking in the phosphoric acid buffer physiological solt solution with 35mg/ml) is widely used urethra filler.Other the injectable product based on collagen protein can also be comprised from non-cattle that those of people or recombinant sources are with in this embodiment.Other representative example that can be used for the treatment of the commercially available filler of urinary incontinence comprises that the gel of hydroxyapatite loading is (from BioForm Medical; Inc.; San Mateo; the COAPATITE of CA); micronized alloderm acellular matrix is (from LifeCell Corporation; Branchburg; the CYMETRA of NJ); the hyaluronic acid of non-animal stabilisation (from NASHA and the DEFLUX of Q-Med); high temperature pyrolysis carbon coating microballon in comprising the hydrogel of beta glucan is (from Carbon Medical Technologies; Inc.St.Paul; MN and Boston ScientificCorporation; Natick; the DURASPHERE of MA); collagen protein fibril (the Organogenesis of through engineering approaches; Inc.; Canton; MA); hylan polymer (from the HYLAGELURO of Genzyme); from Uroplasty; Inc. (Minneapolis; MN) MACROPLASTIQUE (polydimethylsiloxane in the hydrogel carrier); microsphere (for example; the acrylic acid pearl; such as can be from Biosphere Medical, Inc.Marlborough, those that MA obtains); urethra filler (the Protein Polymer Technologies that comprises silk and elastin laminin; San Diego CA), uses biocompatible polymer (from American Medical Systems; Minnetonka; the UROVIVE of MN) crosslinked silicon microsphere of Tian Chonging and URYX filler and from Microtherapeutics, Inc., San Clemente; CA and Genyx Medical; Inc., AlisoViejo, the Embolyx of CA.Other manufacturer who is suitable for use in the carrier in the filled compositions comprises C.R.Bard, Inc. (Murray Hill, NJ), Collagenesis, Inc. (Acton, MA), AmericanMedical Systems, Mentor, Uromed Corporation (Norwood, MA), BostonScientific Corporation, Johnson ﹠amp; Johnson (Ethicon, Inc.), Cook Group, Inc. (Bloomington, IN), W.L.Gore ﹠amp; Associates, and SURx, and Inc. (Pleasonton, CA).

Using of the filler of load fibers degeneration-reagent can typically be undertaken by transurethral injection.If the carrier of fibre modification derivant comprises collagen protein, described patient should finish twice skin test (carrying out with 2 weekly intervals) thereby check allergy before using.If these tests are negative, the collagen injections agent that comprises the fibre modification derivant so can be administered to the patient.Use comprises implantation material (fibre modification derivant and urethra filler) refrigerated, disposable of 2.5ml, and the syringe of prestrain, described syringe have meticulous graduated pin (telescopic per urethra entry needle is stablized in having of 23 specifications).Described patient is placed the lithotomy position and 2% lignocaine of 10ml is inserted urethra to anaesthetize.In the women, manifest neck of bladder by cystoscopy.By cystoscopic dispensing end, in 4 o'clock direction, with acute angle, the 1-1.5cm distally at neck of bladder inserts a needle under mucous membrane of urinary bladder.Then, described pin is positioned at the just following of neck of bladder mucosa with the cystoscope propelling that is parallel to the urethra major axis up to it.Described fibre modification derivant and urethra filler are slowly injected in this site.Then 8 o'clock direction repeat described program.Can be with methylene blue, thereby or other non-toxicity coloring agent add implant and in the development of described injection, help out.

Perhaps, the periurethral injection that is loaded into the fibroid degeneration derivant in the urethra filler can also be used for the treatment of incontinence.Use comprises implantation material (fibre modification derivant and urethra filler) refrigerated, disposable of 2.5ml, and the syringe of prestrain, described syringe have meticulous graduated pin (urethra week entry needle).Described patient is placed the lithotomy position, 2% lignocaine of 10ml is inserted in the urethra to anaesthetize and to manifest neck of bladder (for the male, can also manifest urethra by cystoscopy method on the pubis) with the cystoscope method.With described pin transvaginal or insertion and urethra next-door neighbour on the pubis and in the zone on urethra next door.When it arrives appropriate location near neck of bladder when (as by cystoscopy and above-mentioned finding), slowly be expelled to this site with what be loaded into fibre modification derivant in the urethra filler.Can be with methylene blue, thereby or other non-toxicity coloring agent add implant its assosting effect in the manifesting of described injection.

Tackling in those skilled in the art is to it is evident that potentially, above-mentioned any binding agent or fibre modification derivant (alone or in combination) can be used in practice of the present invention with any injectable urethra filler.The exemplary fibers texturizer that is used in combination with injectable urethra filler comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF and above-mentioned analog and derivant.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or its analog or derivant in addition.

In addition, described device can be separately or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, all-trans retinoic acid (ATRA), and analog and derivant.

Correct administration and dosage part below can be further described in (iii).

The urine sling that (ii) comprises the fibre modification derivant

In one aspect of the method, can treat the decline of stress incontinence and urethra muscle with pubovaginal sling method.Thereby this operation can produce enough pressurizations on urethra helps described patient to regain bladder control.The sling of treatment urinary incontinence is described in, and for example U.S. Patent number 6,641, and 524; 6,592,610; 6,387,040; 6,328,686; 6,306,079; 6,221,005; 6,110,101; 6,056,687; 6,042,536; With 6,042,534 and Application No. 2003/0199732A1; 2003/0149440A1; 2002/0183588A1; 2002/0058959A1; In 2002/0022841A1.

Can make up with one or more slings for the treatment of in the urinary incontinence that is used in, comprise many commercially available products according to fibre modification derivant of the present invention.For example, can use SUSPENDTUTOPLAST (from the Processed Fascia Lata sling of Mentor) and REPLIFORMTissue Regeneration Matrix (from Boston Scientific Corporation (Natick, people allograft collagen fiber MA)).Product such as FORTAGEN surgical operation mesh and GRAFTPATCH are (from Organogenesis Inc., Canton, MA), and SURGISIS (Cook Biotech, Inc., West Lafayette IN) is made up of multilayer tablet, and described multilayer tablet mainly is made up of the type i collagen protein of strengthening soft tissue in the operation mending course (normally pig or cattle).Indicate to comprise stomach wall and chest wall defect, the muscle lobe is strengthened, rectum and vaginocele, and the repairing of tissue flap donor site, fistulation is strengthened, the reconstruction of pelvic floor, hernia is repaired, and suture is strengthened and the reconstruction purpose.The surgical operation sling, such as FORTAFLEX surgical operation sling (Organogenesis, Inc.) and SURGISIS Sling also mainly form and be used in the open Urology Surgery operation method by type i collagen albumen (normally pig or cattle).Indication comprises supports that (urethra, vagina, rectum and colon) repaired in prolapsus, proctoptosis, bladder hernia, enterocele, mastoplexy, the reconstruction of pelvic floor, bladder support, sacrocolposuspension and other reconstruction capability program in urethra week.Other representative example of sling used in this invention comprises from Ethicon, Inc. (Somerville, NJ) Tension-FreeVaginal Tape (TVT), SPARC Female Sling System (from " vagina type " product of American MedicalSystems), AMS Silicone-Coated Mesh Sling (AmericanMedical Systems), BIOSLING (InjecTx/ProSurg), VERITAS Collagen MatrixUrological Sling (Synovis Life Technologies, Inc., St.Paul, MN), the sling that PTFE makes, such as Gore-Tex MYCROMESH from Gore, and the STRATESIS Urethral Sling that makes by acellular pig intestinal mucosa (Cook, Inc.), sling by allograph fascia making, such as ALLOSLING (Alliant Medical) and the sling made by people allograft fascia, such as FASLATA Allograft Tissue (C.R.Bard).Sling can prepare from, for example polypropylene mesh (C.R.Bard) and MERSILENE polyester fiber mesh (Ethicon, Inc.).

The drug delivery system of above-mentioned many polymer and non-polymer can be used to send fibre modification derivant from urinary tract sling and implant.With become fiber composition to be attached on the urinary incontinence device or among method comprise: (a) directly will become fiber composition be attached to the urinary incontinence implant (for example, by aforesaid with or not with the spray method or the immersion method of carrier); (b) directly will become fiber composition be attached in the described device (for example, by aforesaid with or not with the spray method or the immersion method of carrier); (c) by being coated with described device such as the hydrogel that can absorb into fiber composition again with material; (d) by being woven in the described apparatus structure with the line that becomes the fiber composition coating (or polymer itself forms line); (e) by described device is inserted sleeve pipe or mesh, described sleeve pipe or mesh are made up of the one-tenth fiber composition, or are coated with it; (f) use part into fiber composition construction device itself or described device; Or (g) form agent by fibrous tissue and directly be covalently bound to described apparatus surface or joint (micromolecule or polymer), described joint is applied or be attached to apparatus surface.For these devices, can carry out coating process with such method, described method is as the outer surface of device as described in a) coating, the b) inner surface of the described device of coating, or c) the outer and inner surface of apparatus for coating all or part of.

Except with becoming fiber composition to be coated with the described device, mix and with the material that is used for preparation facilities fibrous tissue is formed agent and be attached to resulting device thereby fibrous tissue can be formed agent.

In one embodiment, thereby the fibre modification derivant directly can be attached in the preparation and produce suspension or solution (for example, silk powder, bleomycin) or its and (for example can be incorporated in the secondary carrier, micelle, liposome, microsphere, microgranule, the nanometer spheroid, microparticulate, Emulsion and/or microemulsion), described secondary carrier then is incorporated in the filled compositions.In another embodiment, the fibre modification derivant can be incorporated into statically or covalently original position forms in one or more component of polymer of compositions.

In another embodiment, the fibre modification derivant can be attached in the filler in the process of the described reagent of preparation.For example, can when preparation is used as the microsphere of filler, the silk powder be added as reagent.

Tackling in those skilled in the art is to it is evident that potentially, above-mentioned any binding agent or fibre modification derivant can be used alone or in combination in the practice of the present embodiment.The exemplary fibers texturizer that is used in urinary incontinence device and the compositions comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF and above-mentioned analog and derivant.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or its analog or derivant in addition.

In addition, described device can comprise the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, all-trans retinoic acid (ATRA), and analog and derivant.

The fibrous tissue that (iii) is used for the urinary incontinence implant forms agent

Because urinary incontinence device is made (comprising injectable filler and sling) with multiple configuration and size, the exact dose of using can be with implant or device size, surface area and kind of design and change.Yet, some principle can be applied in the application of this area.Can be the function of per unit area (part of applied device) dosage with medication dose calculation, can measure the total drug dose of using, and can determine the suitable surface concentration of active medicine.No matter to the method for urinary incontinence implant or device how medicament administration, the exemplary fibers texturizer that is used alone or in combination should use under following administration is instructed:

Talcum is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from urinary incontinence device, send or be applied to the lip-deep steatitic accumulated dose of urinary incontinence device and should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the steatitic total amount that discharges from prosthese should be in the scope of 10 μ g-50mg.The dosage of the injectable of the per unit volume urine filler steatitic dosage of the function of the volume of injected urine filler (that is, as) should be at 0.05 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to urine sling incontinence device surface with Talcum.In one embodiment, Talcum is from the urinary incontinence filler, thereby implant or device discharge the fibre modification in promoting to organize in the scope period of a few hours to several months.For example, Talcum can discharge the period that reaches 1-9 month scope with valid density.What consider that discussion provided herein it should be obvious that is to be used for purpose of the present invention with having active steatitic analog of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the Talcum effect with half of above-mentioned parameter, use half in chemical compound of Talcum effect etc.) with the twice of above-mentioned parameter.

Silk is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep silk of sending from urinary incontinence device or be applied to urinary incontinence device should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the silk that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the injectable of the per unit volume urine filler dosage of the silk of the function of the volume of injected urine filler (that is, as) should be at 0.05 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to urine sling incontinence device surface with silk.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge silk with different speed with concrete medical apparatus, above-mentioned administration parameter should with medicine from the urinary incontinence filler, be delivered in the described tissue thereby the rate of release in implant or the device is used in combination the silk of the Cmin that makes 0.01nM-1000 μ M.In one embodiment, silk is from the urinary incontinence filler, thereby implant or device discharge the fibre modification in promoting to organize in the scope period of a few hours to several months.For example, silk can discharge the period that reaches 1-9 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active silk of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles an effect with half of above-mentioned parameter, use half in chemical compound of silk effect etc.) with the twice of above-mentioned parameter.

Chitosan is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep chitosan of sending from urinary incontinence device or be applied to urinary incontinence device should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the chitosan that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit volume of the injectable urine filler dosage of the chitosan of the function of the volume of injected urine filler (that is, as) should be at 0.05 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to urine sling incontinence device surface with chitosan.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge chitosan with different speed with concrete medical apparatus, above-mentioned administration parameter should with medicine from the urinary incontinence filler, thereby the rate of release in implant or the device is used in combination the chitosan of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, chitosan is from the urinary incontinence filler, thereby implant or device discharge the fibre modification in promoting to organize in the scope period of a few hours to several months.For example, chitosan can discharge the period that reaches 1-9 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active chitosan of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the chitosan effect with half of above-mentioned parameter, use half in chemical compound of chitosan effect etc.) with the twice of above-mentioned parameter.

Polylysine is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep polylysine of sending from urinary incontinence device or be applied to urinary incontinence device should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the polylysine that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the injectable of the per unit volume urine filler dosage of the polylysine of the function of the volume of injected urine filler (that is, as) should be at 0.05 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to urine sling incontinence device surface with polylysine.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge polylysine with different speed with concrete medical apparatus, above-mentioned administration parameter should can be from the urinary incontinence filler with medicine, thereby the rate of release in implant or the device is used in combination the polylysine of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, polylysine is from the urinary incontinence filler, thus the fibre modification of release in promoting to organize in the scope period of a few hours to several months in implant or the device.For example, polylysine can discharge the period that reaches 1-9 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active polylysine of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the polylysine effect with half of above-mentioned parameter, use half in chemical compound of polylysine effect etc.) with the twice of above-mentioned parameter.

Fibronectin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep fibronectin of sending from urinary incontinence device or be applied to urinary incontinence device should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the fibronectin that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the injectable of the per unit volume urine filler dosage of the fibronectin of the function of the volume of injected urine filler (that is, as) should be at 0.05 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to urine sling incontinence device surface with Talcum.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge fibronectin with different speed with concrete medical apparatus, above-mentioned administration parameter should can be from the urinary incontinence filler with medicine, thereby the rate of release in implant or the device is used in combination the fibronectin of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, fibronectin is from the urinary incontinence filler, thus the fibre modification of release in promoting to organize in the scope period of a few hours to several months in implant or the device.For example, fibronectin can discharge the period that reaches 1-9 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active fibronectin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the fibronectin effect with half of above-mentioned parameter, use half in chemical compound of fibronectin effect etc.) with the twice of above-mentioned parameter.

Bleomycin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep bleomycin of sending from urinary incontinence device or be applied to urinary incontinence device should be no more than 100mg (scope of 0.01 μ g-100mg).The total amount of the bleomycin that discharges from prosthese in one embodiment, should be in the scope of 0.10 μ g-50mg.The dosage of the injectable of the per unit volume urine filler dosage of the bleomycin of the function of the volume of injected urine filler (that is, as) should be at 0.005 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to urine sling incontinence device surface with bleomycin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge bleomycin with different speed with concrete medical apparatus, above-mentioned administration parameter should can be delivered in the described tissue thereby the rate of release in implant or the device is used in combination the bleomycin of the Cmin that makes 0.001nM-1000 μ M from the urinary incontinence filler with medicine.In one embodiment, bleomycin is from the urinary incontinence filler, thus the fibre modification of release in promoting to organize in the scope period of a few hours to several months in implant or the device.For example, bleomycin can discharge the period that reaches 1-9 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active bleomycin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the bleomycin effect with half of above-mentioned parameter, use half in chemical compound of bleomycin effect etc.) with the twice of above-mentioned parameter.

CTGF is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep CTGF that sends from urinary incontinence device or be applied to urinary incontinence device should be no more than 100mg (scope of 0.01 μ g-100mg).In one embodiment, the total amount of the CTGF that discharges from prosthese should be in the scope of 0.10 μ g-50mg.The dosage of the injectable of per unit volume urine filler (that is, as the CTGF of the function of the volume of injected urine filler dosage) should be at 0.005 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to urine sling incontinence device surface with CTGF.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge CTGF with different speed with concrete medical apparatus, above-mentioned administration parameter should can be delivered in the described tissue thereby the rate of release in implant or the device is used in combination the CTGF of the Cmin that makes 0.001nM-1000 μ M from the urinary incontinence filler with medicine.In one embodiment, CTGF is from the urinary incontinence filler, thus the fibre modification of release in promoting to organize in the scope period of a few hours to several months in implant or the device.For example, CTGF can discharge the period that reaches 1-9 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active CTGF of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the CTGF effect with half of above-mentioned parameter, use half in chemical compound of CTGF effect etc.) with the twice of above-mentioned parameter.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6 and growth hormone or its analog or derivant) in addition.According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of inflammatory cytokine from 0.0001 μ g/ml to about 20mg/ml is used in the preparation.Preferably, inflammatory cytokine discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 100mg); Preferred 0.001 μ g is to 50mg.When being used as the device coating, dosage is 0.0001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.001 μ g/mm ²-200 μ g/mm ²With 10 ^-10-10 ^-4The Cmin of the inflammatory cytokine of g/ml maintains on the apparatus surface.

In addition, described device can comprise the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA), and analog and derivant.Used dosage is to be proved to be those concentration (embodiment 16) that stimulate cellular proliferation.According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of multiplication agent from 0.1ng/ml to 25mg/ml is used in the preparation.Preferably, multiplication agent discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 200mg); Preferred 0.001 μ g is to 100mg.When being used as the device coating, dosage is 0.00001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.0001 μ g/mm ²-200 μ g/mm ²With 10 ^-11-10 ^-6The Cmin of the multiplication agent of M maintains on the apparatus surface.

Should it will be apparent to one skilled in the art that aforementioned fibers degeneration derivant, any of or derivatives thereof and analog can be used to produce the variation of above-mentioned composition under the prerequisite that does not deviate from spirit and scope of the invention.Also should it is evident that described reagent can with or be not used in the compositions and change described carrier and do not depart from scope of the present invention with polymer support.

7. the venous occlusion material that comprises the fibre modification agent

Developed multiple device and injectable implant and be used for being expelled to vein, described injection is used for the cosmetics purpose.Typically, pin or conduit are advanced to the vein (mainly being the vein of " Aranea (spider) " vein or varicose) of defectiveness (unwanted) thus and in blood vessel, described vein stammerer is closed the injection of sclerosing agent.Unfortunately, can obtain reagent at present and often not produce permanent fibre modification (real chamber property cicatrization, wherein blood vessel wall is permanent each other sticks to each other and the inaccessible described blood vessel of described fibrous tissue), caused leading to again, rebuliding the probability (that is the failure of described method) that vein flows and vein is reappeared.Satisfy such purpose in the material that is injected in the vein thereby the invention describes the fibre modification derivant added to, described purpose is to produce permanent occlusive cicatrix in lumen of vessels, and it causes defective venous to degenerate and absorb.The occlusive fibre modification if vein flows and by permanent prevention, health absorbs and do not have the blood vessel of function and remove described vein makes the chance of recurrence few or do not have.

The commercially available sclerosing agent that exists some to be used for the treatment of Aranea vein and cirso-, described sclerosing agent can make up with one or more according to fibre modification derivant of the present invention.For example, (Collegeville, PA), (Madison NJ) sells SOTRADECOL to WyethPharmaceuticals, and it is the sodium tetradecyl sulfate injection in the department of Wyeth.Other sclerosing agent of other the obtainable spider of being used for the treatment of vein and cirso-(and can be suitable for sending the fibre modification derivant) comprises sodium morrhuate, ethamolin (ester) comprises alcoholic acid compositions, DMSO, surfactant, sucrose, NaCl, dextrose, glycerol, minocycline, tetracycline, doxycycline, Polidocanol, sodium tetradecyl sulfate, sodium morrhuate, Sotradecol and other.Other example that is suitable for the compositions of cosmetic injectable (for example comprises silk, the microgranule silk), the polymer gel of forming by the blood vessel filler of fibre modification derivant and load fibers degeneration derivant (such as from those of Polymerix Corporation).

Developed multiple product based on polymer and be used for intravascular injection, described injection is used for the purpose (being described in detail in about the part 12 of following arterial thrombosis (ii)) of arterial thrombosis.Many in these blood vessel interpolymer systems are suitable for treating Aranea vein and cirso-and more effective by adding the fibre modification derivant.The example that is suitable for the product of conjugate fiber degeneration derivant, for example comprise TRUFILL normal-butyl cyanoacrylate (n-BCA) Liquid Embolic System (can be from Cordis, the department of Johnson and Johnson obtains, Miami, FL); ONYX LiquidEmbolic System (Micro Therapeutics, Irvine, CA).Other example that is suitable for the fibre modification derivant is delivered to the material in the Venous system comprises polymer/solvent systems, wherein in case be injected in the vein, described solvent (for example spreads from polymeric matrix, degradable polymer system from Atrix, from the nondegradable polymer composition of ONYX and EMBOLYX with from Biocure, Angiotech Pharmaceuticals, Inc., 3M Company, the original position of and Neomend forms material).The suppository of commercially available other type comprises that the PVA granule is (from Cook, Inc. with Angiodynamics Inc.), and microspheres preparation is (for example from Biosphere, Inc. (Rockland, MA) EMBOSPHERE and EMBOGOLD and from BiocompatiblesLtd., the BEAD BLOCK of United Kingdom, described suppository can load to be used for veno-occlusive fibre modification derivant or to make of described fibre modification derivant.

In one embodiment, injectable angiogenic substance is made up of the Injectable polymer system of combination with the fibre modification derivant.Interested especially a kind of Injectable polymer systems produce is from 4-arm mercaptan PEG (10K), and 4-arm NHS PEG (10K) and methylated collagen protein are such as above-mentioned.Described injectable angiogenic substance can make up with fibre modification derivant (for example, Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin, CTGF, bone morphogenetic protein, transforming growth factor, platelet-derived somatomedin, fibroblast growth factor, and the analog of these chemical compounds and derivant) and be injected in the vein or Aranea vein of varicose.In addition, or alternatively, can also be with the fibre modification derivant, bone morphogenetic protein and somatomedin, injectable substance can be used for sclerosing agent is delivered to vein.Sclerosing agent comprises chemical compound such as ethanol, DMSO, surfactant, sucrose, sodium morrhuate, ethamolin (ester) NaCl (ethanolamine oleate NaCl), dextrose, glycerol, minocycline, tetracycline, doxycycline, Polidocanol, sodium tetradecyl sulfate, sodium morrhuate, Sotradecol and other.Described injectable material also can comprise reagent such as glycerol, glycerol, and PEG200, triethyl citrate and triacetin are as plasticizer.

In another embodiment, thus can also modify above-mentioned injectable intravascular mass and it is squeezed out form polymer " line " or comprise polymer line from conduit (or pin).Polymer line has the ability of condensing and inducing the fibroplasia reaction from blood vessel wall of inducing." line " that can inject can load with, coating is formed (for example forming the injectable implant that the polymerized form of agent itself is formed by silk fiber or fibrous tissue) with the fibre modification derivant or by the fibre modification derivant.These polymer lines can be degradable or nondegradable.Degradable line can be by degradable polyester, polyanhydride, poly-(acid anhydride ester), poly-(ester-amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, cyanoacrylate polymer, collagen protein, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose, cellulose esters, its admixture and copolymer, and other known degradable polymer is formed.Operable non-degradable polymer include, but not limited to polyester (for example, PET), polyurethane, siloxanes, PE, PP, PS, PAA, PMA, the silk, its admixture, copolymer and other known polymer.The line that uses can be made up of the admixture of single compositions or different components.Can come polymer line itself is further modified by the polymer coating that interpolation is applied on the described line.Be used to be coated with described line polymer can on to regard to described line itself described similar.Described polymer coating can also comprise bioactive fiber degeneration derivant.

In another embodiment, thereby injectable substance in the above-mentioned blood vessel can be prepared it is sent from conduit (or pin) as particulate matter, described particulate matter has to induce and condenses and fibrotic ability.Injectable granule can load with, the coating form with the fibre modification derivant or by the fibre modification derivant.These granules can be degradable or nondegradable and be similar to above-mentioned those at line in composition.Except above-mentioned polymer, the particulate matter that is effective to this embodiment practice comprises Talcum, starch, glass, silicate, Silicon stone, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic property mineral (VITOSS and CORTOSS), PMMA, silver nitrate, Inorganic Non-metallic Materials granule and other inorganic particle of inducing the fibroplasia reaction known in the art.The granule that is used in the present embodiment can be all same combinations or the admixture of different components.As mentioned above, can also be with these granules as the coating that is applied on the polymer chain.

As conspicuous, make it by polymer line and granulometric composition thereby can also make up to injectable intravascular mass.Used line and granule are similar to above-mentioned those and can be the compositions of uniform composition or fusion.In fact, the line of different components and particulate any combination of different components can be used in this embodiment.Described hydrogel, polymer line and granule can be used to send one or more fibre modification derivants.

Except above-mentioned injectable substance, exist to be suitable for intravascular administration some other Injectable compositions with treatment Aranea vein and cirso-.All all comprising is used for described venous chamber with biomaterial, follows or do not follow fibre modification derivant, bone morphogenetic protein, and/or the interpolation of the somatomedin that is fit to.Can pass through special delivery catheter, endoscope's (for example, angioscope; Typically send described material by the side of described device), pin or other applicator are with the access to plant of surgical operation placement, or access to plant is delivered to vein with following compositions in other transdermal blood vessel, and comprises and using: (a) fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microgranule, spray, aerosol, the preparation of solid implant and other release bioactive agent; (b) be injected into independent in the vein or load with additional fibers degeneration derivant, bone morphogenetic protein, and/or the microgranule silk of somatomedin and/or silk chain (linearity, side chain, and/or curl); (c) be injected into that injectable in the vein comprises preparation such as the COSTASIS of collagen protein or by 4-arm mercaptan PEG (10K), 4-arm NHS PEG (10K) and methylated collagen protein are such as the above-mentioned material of making, described preparation is independent or loads with the fibre modification derivant, bone morphogenetic protein, and/or somatomedin; (d) preparation that is injected into the injectable PEG of comprising in the vein is such as COSEAL, FOCALSEAL, and SPRAYGEL or DURASEAL, it is independent or loads with the fibre modification derivant bone morphogenetic protein, and/or somatomedin; (e) be injected into the preparation that comprises fibrinogen such as FLOSEAL or TISSEAL in the vein, described preparation is independent or loads with the fibre modification derivant bone morphogenetic protein, and/or somatomedin; (f) be injected into and comprise hyaluronic preparation such as RESTYLANE, HYLAFORM, PERLANE in the vein, SYNVISC, SEPRAFILM, SEPRACOAT, described preparation is independent or loads with the fibre modification derivant bone morphogenetic protein, and/or somatomedin; (g) be injected into polymer gel such as the REPEL or the FLOWGEL that implant at surgical operation in the vein, described gel is independent or loads with the fibre modification derivant bone morphogenetic protein, and/or somatomedin; (h) be injected into orthopedics's " cement " in the vein such as OSTEOBOND, LVC, SIMPLEX P, PALACOS, CORTOSS and ENDURANCE, described " cement " are independent or load with the fibre modification derivant, bone morphogenetic protein, and/or somatomedin; (i) be injected into the surgical operation binding agent that comprises cyanoacrylate in the vein such as DERMABOND, INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND, TISSUMEND II, HISTOACRYL BLUE and ORABASESOOTHE-N-SEAL LIQUID PROTECTANT or as mentioned above, described binding agent are independent or load with the fibre modification derivant, bone morphogenetic protein, and/or somatomedin; (j) be injected into the hydroxyapatite that comprises in the vein, calcium phosphate (such as VITOSS), or the surgical implants of calcium sulfate, described surgical implants are independent or load with the fibre modification derivant, bone morphogenetic protein, and/or somatomedin; (k) be injected into other biocompatible tissue filler in the vein, such as by BioCure, those that 3M Company and Neomend make, described filler are independent or load with the fibre modification derivant bone morphogenetic protein, and/or somatomedin; (1) be injected into the gel of polysaccharide gel such as the ADCON series in the vein, described polysaccharide gel is independent or loads with the fibre modification derivant bone morphogenetic protein, and/or somatomedin; (m) be injected into film in the vein, sponge, or mesh is such as INTERCEED, VICRYL mesh, and GELFOAM, and it is independent or loads with the fibre modification derivant bone morphogenetic protein, and/or somatomedin; And/or (n) form the hydrogel of Polyethylene Glycol from amino-functional (for example, 4-arm tetramino PEG[10k] and the functionalized PEG of 4-arm NHS) (for example, tetramethylolmethane gathers (ethylene glycol) ether four-succinimido glutarate [10K]).This hydrogel also can comprise collagen protein, methylated collagen protein and/or gelatin.This hydrogel also can comprise above-mentioned fibre modification derivant (for example, silk powder or silk thread).

In many these embodiments, add radiopaque material (for example, tantalum, barium, other metal or developing materials) thus make that injected material can by radiography or to be undertaken visual by MRI also be useful.In addition, during direct injection in proceeding to vein, can the employing technology increase visual by ultransonic pin (or conduit) by using with the pin of ECHO-COAT bag quilt or injection air (microbubble).

In a big varicose venous medication of preferred treatment, in the angioscope evaluation procedure of blood vessel, under directly showing, send described fibrous tissue and form agent.At this paper, will comprise the fibre modification derivant, bone morphogenetic protein, and/or the side of the compositions of somatomedin by angioscope is expelled in the cirso-.In some cases, can also in open surgery, the fibre modification derivant directly be delivered in the described venous chamber (or the tissue around the vein).

Should it is evident that to those skilled in the art, potentially, can any binding agent or fibre modification derivant is independent, or be combined and used in the practice of aforesaid embodiment.The exemplary fibers texturizer that is used in the vein Rogue program comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin, CTGF, bone morphogenetic protein, and/or osteogenic growth factor (such as transforming growth factor, platelet-derived somatomedin, fibroblast growth factor) and above-mentioned analog and derivant.In some clinical scenarios, may need the duplicate injection of following activating agent.

The exact dose of administration can depend on the concrete vein of being treated and change.Yet, some principle can be used for using of this area.Can be the function of the dosage of per unit volume (injected amount) with medication dose calculation, the total drug dose that can measure administration also can be determined the suitable surface concentration of active medicine.No matter to the venous method how described medicament administration, the exemplary fibers texturizer that is used alone or in combination, bone morphogenetic protein, and/or somatomedin is (such as transforming growth factor, platelet-derived somatomedin, fibroblast growth factor) should under instructing, following administration carry out administration:

Talcum is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming the injectable thing, or use without polymer support, the steatitic accumulated dose that is applied in any single injection in the Venous system should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the steatitic total amount that is applied should be in the scope of 10 μ g-50mg.The dosage of injected per unit volume should be at 0.05 μ g-10 μ g/mm ³In the scope.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge Talcum with different speed with concrete implant, thereby the Talcum that above-mentioned administration parameter should be used in combination the Cmin that makes 0.01nM-1000 μ M with the rate of release of medicine from carrier is continued to be delivered to described vein in treatment period of needs.In one embodiment, thus Talcum discharges the fibre modification that promotes in the vein in the period of a few hours to several months scope from the injectable thing.For example, Talcum can discharge the period that reaches 2-12 week scope with valid density.What consider that discussion provided herein it should be obvious that is to be used for purpose of the present invention with having active steatitic analog of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the Talcum effect with half of above-mentioned parameter, use half in chemical compound of Talcum effect etc.) with the twice of above-mentioned parameter.

Silk is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming the injectable thing, or use without polymer support, the accumulated dose that is delivered to the silk in the Venous system in any single injection should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, being applied should be in the scope of 10 μ g-50mg to the total amount of venous silk.The dosage of injected per unit volume should be at 0.05 μ g-10 μ g/mm ³In the scope.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge silk with different speed, thereby the silk that above-mentioned administration parameter should be used in combination the Cmin that makes 0.01nM-1000 μ M with the rate of release of medicine from carrier is continued to be delivered to described tissue in treatment period of needs.In one embodiment, thus silk is released in the venous chamber and promotes fibre modification in the period of a few hours to several months in the scope.For example, silk can discharge the period that reaches all scopes in 2 week-12 with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active silk of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles an effect with half of above-mentioned parameter, use half in chemical compound of silk effect etc.) with the twice of above-mentioned parameter.

Chitosan is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming the injectable thing, or use without polymer support, the accumulated dose that is delivered to the chitosan in the vein should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, being applied in any single injection should be in the scope of 10 μ g-50mg to the total amount of venous chitosan.The dosage of injected per unit volume should be at 0.05 μ g-10 μ g/mm ³In the scope.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge chitosan with different speed, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from carrier and makes the chitosan of 0.01nM-1000 μ M Cmin be continued to be delivered in the described vein.In one embodiment, thus chitosan is released in the venous chamber and promotes fibre modification in the period of a few hours to several months in the scope.For example, chitosan can discharge the period that reaches 2-12 week scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active chitosan of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the chitosan effect with half of above-mentioned parameter, use half in chemical compound of chitosan effect etc.) with the twice of above-mentioned parameter.

Polylysine is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming the injectable thing, or use without polymer support, the accumulated dose that is delivered to the polylysine in the vein in single injection should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, being delivered to the total amount of venous polylysine should be in the scope of 10 μ g-50mg.The dosage of injected per unit volume should be at 0.05 μ g-10 μ g/mm ³In the scope.In another embodiment, polylysine should be with 0.05-10 μ g/mm ³Dosage be expelled in the vein.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge polylysine with different speed, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from carrier and makes the polylysine of 0.01nM-1000 μ M Cmin be continued to be delivered in the described vein.In one embodiment, thus polylysine is applied in the described venous chamber and promotes fibre modification in the period of a few hours to several months in the scope.For example, polylysine can discharge the period that reaches 2-12 week scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active polylysine of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the polylysine effect with half of above-mentioned parameter, use half in chemical compound of polylysine effect etc.) with the twice of above-mentioned parameter.

Fibronectin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming the injectable thing, or use without polymer support, the accumulated dose that is delivered to the fibronectin in the vein in single injection should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, being injected into the total amount of the fibronectin in the vein should be in the scope of 10 μ g-50mg.The dosage of the per unit volume of injection should be at 0.05 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.05-10 μ g/mm ³Dosage by injection mass is used Talcum.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge fibronectin with different speed, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from carrier and makes the fibronectin of 0.01nM-1000 μ M Cmin be continued to be delivered to described vein.In one embodiment, thus fibronectin is released in the venous chamber and promotes fibre modification in the period of a few hours to several months in the scope.For example, fibronectin can discharge the period that reaches all scopes in 2 week-12 with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active fibronectin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the fibronectin effect with half of above-mentioned parameter, use half in chemical compound of fibronectin effect etc.) with the twice of above-mentioned parameter.

Bleomycin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming the injectable thing, or use without polymer support, the accumulated dose that is applied to the bleomycin in the vein in single injection should be no more than 100mg (scope of 0.01 μ g-100mg).In one embodiment, being injected into the total amount of the bleomycin in the vein should be in the scope of 0.10 μ g-50mg.The dosage of injected per unit volume should be at 0.005 μ g-10 μ g/mm ³Scope in.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge bleomycin with different speed, thereby above-mentioned administration parameter should be continued to be delivered in the described vein with the bleomycin that the rate of release of medicine from carrier is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, thus bleomycin discharges the fibre modification that promotes in the vein in the period of a few hours to several months scope from injection.For example, bleomycin can discharge the period that reaches all scopes in 2 week-12 with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active bleomycin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the bleomycin effect with half of above-mentioned parameter, use half in chemical compound of bleomycin effect etc.) with the twice of above-mentioned parameter.

CTGF is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming the injectable thing, or use without polymer support, the accumulated dose that is applied to the CTGF in the vein in single injection should be no more than 100mg (scope of 0.01 μ g-100mg).In one embodiment, being injected into the total amount of the CTGF in the vein should be in the scope of 0.10 μ g-50mg.The dosage of the per unit volume of injection should be at 0.005 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.005-10 μ g/mm ³Dosage CTGF is injected.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge CTGF with different speed, thereby above-mentioned administration parameter should be continued to be delivered in the described vein with the CTGF that the rate of release of medicine from carrier is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, thus CTGF discharges the fibre modification that promotes in the vein in the period of a few hours to several months scope from the injectable thing.For example, CTGF can discharge the period that reaches all scopes in 2 week-12 with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active CTGF of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the CTGF effect with half of above-mentioned parameter, use half in chemical compound of CTGF effect etc.) with the twice of above-mentioned parameter.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) in addition.Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of inflammatory cytokine from 0.0001 μ g/ml to about 20mg/ml is used in the preparation.Preferably, inflammatory cytokine discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 100mg); Preferred 0.001 μ g is to 50mg.When being used as the device coating, dosage is 0.0001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.001 μ g/mm ²-200 μ g/mm ²With 10 ^-10-10 ^-4The Cmin of the inflammatory cytokine of g/ml maintains on the apparatus surface.

In addition, described device can be separately or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA), and analog and derivant.Used dosage is to be proved to be those concentration (seeing that for example, embodiment 16) that stimulate cellular proliferation.Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of multiplication agent from 0.1ng/mL to 25mg/ml is used in the preparation.Preferably, multiplication agent discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 200mg); Preferred 0.001 μ g is to 100mg.When being used as the device coating, dosage is 0.00001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.0001 μ g/mm ²-200 μ g/mm ²With 10 ^-11-10 ^-6The Cmin of the multiplication agent of M maintains on the apparatus surface.

Should be that it is evident that can be with aforementioned fibers degeneration derivant for those skilled in the art, bone morphogenetic protein, or any of osteogenic growth factor or derivatives thereof and analog is used to produce the variation of above-mentioned composition under the situation that does not deviate from spirit and scope of the invention.

Also should it is evident that described reagent can be used in the compositions that has or do not have polymer support and change described carrier and not deviate from scope of the present invention.

8. The feces incontinence

The invention provides compositions and device is used in the incontinence of treatment feces.The feces incontinence is to control bowel movement.The reason of feces incontinence comprises, for example damage of pelvic floor nerve, and the wound of anus and/or rectal area, birth defect, reformed feces denseness, or unusual rectum capacity and disease be such as diabetes, multiple sclerosis and colorectum disease.In the women, the feces incontinence can be the result of difficult labour.

(i) anal sphincter filler

Can treat the feces incontinence with the closure of strengthening anal sphincter by near position filler being expelled to anal sphincter.Filler can make up with according to one or more fibre modification derivant of the present invention, comprises many products that can be purchased.For example, from Artes Medical, Inc. (SanDiego, CA) Injectable microspheres body, ENTERYX (from the ethylene vinyl alcohol polymer implant of Boston Scientific Corporation), and CONTIGEN (by C.R.Bard, what Billerica, MA obtained is dispersed in the collagen protein of the Corii Bovis seu Bubali glutaraldehyde cross-linking of the purification in the phosphate buffer normal saline with 35mg/ml) is widely used filler.Other the injectable product based on collagen protein can also be comprised being derived from non-cattle, the people, or those usefulness of recombinant sources are in this embodiment.Other representative example that can be used for the treatment of the commercially available filler of feces incontinence comprises the gel (COAPATITE) that hydroxyapatite loads; micronized alloderm acellular matrix (CYMETRA); the hyaluronic acid of non-animal stabilisation (NASHA) (DEFLUX); high temperature pyrolysis carbon coating microballon (DURASPHERE) in comprising the hydrogel of beta glucan; the collagen protein fibril (Organogenesis) of through engineering approaches; hylan polymer (HYLAGEL URO); MACROPLASTIQUE (polydimethylsiloxane in the hydrogel carrier); microsphere (for example; the acrylic acid pearl; such as can obtain from Biosphere Medical those); comprise the silk and the urethra filler of elastin laminin (such as can be) from those of Protein Polymer Technologies acquisition; crosslinked silicon microsphere of filling with biocompatible polymer (UROVIVE) and URYX filler and from Microtherapeutics; Inc.; San Clemente; CA and Genyx Medical; Inc.; Aliso Viejo, the Embolyx of CA.Other manufacturer who is suitable for use in the carrier in the filled compositions comprises C.R.Bard, Collagenesis, American Medical Systems, Mentor, Uromed, Boston ScientificCorporation, Johnson ﹠amp; Johnson (Ethicon, Inc.), Cook Group, W.L.Gore and SURx.

No matter their composition how, filler is designed to physical support is provided and stop the seepage of feces to anal sphincter.Unfortunately, for Most patients, alleviating of symptom often only is temporary transient and must repeats described method.Biodegradable injectable substance (such as collagen protein, hyaluronic acid and above-mentioned other) is absorbed and has lost their structural intergrity-must replace described material by duplicate injection in time by health.Nondegradable material (such as acrylic acid, hydroxyapatite, polymeric beads and above-mentioned other) is not reconstituted in the normal configuration anatomy or the biomechanics of the tissue around the anal sphincter.Add the fibre modification derivant in can addressing these problems in the filler some.The fibre modification derivant can promote the formation of the fibrous tissue (comprising collagen protein) of the health around anal sphincter itself.This causes the formation of the lasting connective tissue that can support, and described connective tissue is supported described anal sphincter in the mode of closer simulating normal rectum anatomy and biomechanics.Described result be continue longer, the treatment that better sx is provided and needs still less to intervene again.

On the one hand, the invention provides injectable compositions (filler) to be used in the incontinence of treatment feces.Particularly, the fibre modification derivant can with or do not prepare together with carrier (such as collagen protein, hyaluronic acid and/or other biocompatible polymer), thereby then be expelled to it in anal sphincter and provide support on every side and control.In one embodiment, thereby the fibre modification derivant directly can be attached in the preparation and produce suspension or solution (for example, silk powder, bleomycin) or its and (for example can be incorporated in the secondary carrier, micelle, liposome, microsphere, microgranule, the nanometer spheroid, microparticulates, Emulsion and/or microemulsion), described secondary carrier then is incorporated in the filled compositions.In another embodiment, the fibre modification derivant can be incorporated into statically or covalently original position forms in one or more component of polymer of compositions.To comprise that filler (many above-mentioned commercially available examples) that fibrous tissue forms agent is expelled to that space (alone or in combination with polymer support) around the muscle can increase cicatrization and for the support of anal sphincter and can cause endogenous collagen protein to produce.

In another embodiment, the fibre modification derivant can be attached in the filler in the process of the described reagent of preparation.For example can in the process of preparation, the silk powder be added as reagent as the microsphere of filler.

Tackling in those skilled in the art is to it is evident that potentially, above-mentioned any binding agent or fibre modification derivant can be used alone or in combination in the practice of the present embodiment.The exemplary fibrous tissue formation agent that is used in feces incontinence device and the compositions comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF, and above-mentioned analog and derivant.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or its analog or derivant in addition.

In addition, described device can comprise the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, all-trans retinoic acid (ATRA), and analog and derivant.

The dosage part below of suitable reagent and they can be further described in (iii).

(ii) prosthese anal sphincter

The other method of treatment feces incontinence comprises implanting prosthetic or device, such as ablating device, nerve stimulator, pump and stapling device.The device of treatment feces incontinence exists, and for example U.S. Patent number 6,428, and 467; 6,013,023; 5,421,827; 4,428,365; With 4,351,322 and in the disclosed patent application publication number 2002/0120219A1 of the U.S., describe to some extent.

Can make up with device and comprise many commercially available products according to the treatment feces incontinence of one or more fibre modification induced drugs of the present invention.For example, SECCA system (Curon Medical) uses radio-frequency ablation procedure to strain the muscle of anal sphincter.ACTICON Neosphincter (produced and sold by American Medical Systems by Acticon LLC) is implantable prosthese, and described prosthese comprises manual expansible pump, and described pump is connected with inflatable ring in artificial sphincter.(Minneapolis is to solve the neuropathic device that causes the feces incontinence MN) to the rumpbone nerve stimulator for Medtronic, Inc..PROXIMATE stapling device from Ethicon EndoSurgery promotes or puts back to again its initial position with mucosa or anus road tissue.

In the present invention, thus thereby fibre modification derivant combination increases the cicatrization around the device with the prosthese anal sphincter and strengthens rectum anatomy again and recover the feces restraining.Thereby the carrier system of aforementioned many polymer and non-polymer can be used to send the formation that one or more fibre modification derivants promote implanted device granulation tissue on every side.The fibre modification derivant is attached on the feces incontinence device or among method comprise: (a) directly will become fiber composition be attached to described device (for example, by aforesaid with or not with the spraying process or the dip coating of carrier); (b) directly will become fiber composition be attached in the described device (for example, by as mentioned above with or not with the spraying process or the dip coating of carrier); (c) by being coated with described device such as the hydrogel that can absorb into fiber composition again with material; (d) be woven in the described apparatus structure by the line (or polymer itself of formation line) that will become the fiber composition coating; (e) by described device is inserted in sleeve pipe or the mesh, described sleeve pipe or mesh are by becoming fiber composition to form or by its coating; (f) with becoming fiber composition construction device itself, or the part of described device; Or (g) directly be covalently bound to apparatus surface by fibrous tissue being formed agent, or on the joint (micromolecule or polymer), described joint is applied or be attached to apparatus surface.For these devices, can carry out coating process by this way, described mode is the outer surface of the described device of (a) coating, (b) inner surface of the described device of coating or (c) outer and inner surface all or part of of the described device of coating.

Except with becoming fiber composition to be coated with the described device, agent is mixed to be formed agent with the material that is used for preparing described device with fibrous tissue and is attached to resulting device thereby fibrous tissue can be formed.

Tackling in those skilled in the art is to it is evident that potentially, above-mentioned any binding agent or fibre modification derivant can be used alone or in combination in the practice of the present embodiment.The exemplary fibrous tissue formation agent that is used in feces incontinence device and the compositions comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF, and above-mentioned analog and derivant.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or its analog or derivant in addition.

In addition, described device can comprise the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, all-trans retinoic acid (ATRA), and analog and derivant.

Be used for being coated with the preferred concrete reagent of the implantable prosthetic appliance that is used in the incontinence of treatment feces and dosage be described in the following part that is right after (iii) in.

The fibre modification derivant that (iii) is used for the feces incontinence

Because the feces incontinence device is made with multiple configuration and size (comprising injectable thing and prosthetic implant), the exact dose of using can be with device or implant size, surface area and kind of design and change.Yet, some principle can be used for using of this area.Can be the function of the dosage of per unit volume/area (surface area of the part of the cumulative volume of injected filler or applied prosthetic appliance) with medication dose calculation, the total drug dose that can measure administration also can be determined the suitable surface concentration of active medicine.No matter the method that described fibre modification derivant is used in the incontinence of treatment feces is how, the exemplary fibers texturizer that is used alone or in combination should carry out administration under following administration is instructed:

Talcum is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from the filler injection, should be no more than 100mg (scope of 1 μ g-100mg) by steatitic accumulated dose that send or that be applied on feces incontinence implant or the apparatus surface.In one embodiment, d/d steatitic total amount should be in the scope of 10 μ g-50mg.The dosage of the injectable filler of the per unit volume steatitic dosage of the function of the volume of injected filler (that is, as) should be at 0.05 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to feces incontinence implant or apparatus surface with Talcum.In one embodiment, Talcum is from feces incontinence filler, thereby implant or device discharge the fibre modification in promoting to organize in the scope period of a few hours to several months.For example, in preferred embodiments, Talcum can discharge the period that reaches 3-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is to be used for purpose of the present invention with having active steatitic analog of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the Talcum effect with half of above-mentioned parameter, use half in chemical compound of Talcum effect etc.) with the twice of above-mentioned parameter.

Silk is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of being sent from the filler injection or be applied to the silk on feces incontinence implant or the apparatus surface should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the total amount of d/d silk should be in the scope of 10 μ g-50mg.The dosage of the injectable filler of the per unit volume dosage of the silk of the function of the volume of injected filler (that is, as) should be at 0.05 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to feces incontinence device surface with silk.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge silk with concrete filler with different speed with prosthetic appliance, above-mentioned administration parameter should with medicine from feces incontinence filler, be delivered in the described tissue thereby the rate of release in implant or the device is used in combination the silk of the Cmin that makes 0.01nM-1000 μ M.In one embodiment, silk is from feces incontinence filler, thereby implant or device discharge the fibre modification in promoting to organize in the scope period of a few hours to several months.For example, in preferred embodiments, silk can discharge the period that reaches 3-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active silk of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles an effect with half of above-mentioned parameter, use half in chemical compound of silk effect etc.) with the twice of above-mentioned parameter.

Chitosan is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from the filler injection, should be no more than 100mg (scope of 1 μ g-100mg) by accumulated dose that send or that be applied to the chitosan on feces incontinence implant or the apparatus surface.In one embodiment, the total amount of d/d chitosan should be in the scope of 10 μ g-50mg.The dosage of the injectable filler of the per unit volume dosage of the chitosan of the function of the volume of injected filler (that is, as) should be at 0.05 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to feces incontinence device surface with chitosan.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge chitosan with concrete filler with different speed with prosthetic appliance, above-mentioned administration parameter should with medicine from feces incontinence filler, thereby the rate of release in implant or the device is used in combination the chitosan of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, chitosan is from the agent of feces incontinence filling injection, thereby implant or device discharge the fibre modification in promoting to organize in the scope period of a few hours to several months.For example, in preferred embodiments, chitosan can discharge the period that reaches 3-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active chitosan of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the chitosan effect with half of above-mentioned parameter, use half in chemical compound of chitosan effect etc.) with the twice of above-mentioned parameter.

Polylysine is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, accumulated dose that send or that be applied to the polylysine on feces incontinence implant or the apparatus surface should be no more than 100mg (scope of 1 μ g-100mg) in the filler injection.In one embodiment, the total amount of d/d polylysine should be in the scope of 10 μ g-50mg.The dosage of the injectable filler of the per unit volume dosage of the polylysine of the function of the volume of injected filler (that is, as) should be at 0.05 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to feces incontinence device surface with polylysine.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge polylysine with concrete filler with different speed with prosthetic appliance, above-mentioned administration parameter should with medicine from feces incontinence filler, thereby the rate of release in device or the implant is used in combination the polylysine of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, polylysine is from feces incontinence filler, thus the fibre modification of release in promoting to organize in the scope period of a few hours to several months in implant or the device.For example, in preferred embodiments, polylysine can discharge the period that reaches 3-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active polylysine of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the polylysine effect with half of above-mentioned parameter, use half in chemical compound of polylysine effect etc.) with the twice of above-mentioned parameter.

Fibronectin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from the filler injection, should be no more than 100mg (scope of 1 μ g-100mg) by accumulated dose that send or that be applied to the fibronectin on feces incontinence implant or the apparatus surface.In one embodiment, the total amount of d/d fibronectin should be in the scope of 10 μ g-50mg.The dosage of the injectable filler of the per unit volume dosage of the fibronectin of the function of the volume of injected filler (that is, as) should be at 0.05 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to feces incontinence device surface with fibronectin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge fibronectin with concrete filler with different speed with prosthetic appliance, above-mentioned administration parameter should with medicine from feces incontinence filler, thereby the rate of release in implant or the device is used in combination the fibronectin of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, fibronectin is from feces incontinence filler, thus the fibre modification of release in promoting to organize in the scope period of a few hours to several months in implant or the device.For example, in a preferred embodiment, fibronectin can discharge the period that reaches 3-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active fibronectin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the fibronectin effect with half of above-mentioned parameter, use half in chemical compound of fibronectin effect etc.) with the twice of above-mentioned parameter.

Bleomycin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from the filler injection, should be no more than 100mg (scope of 0.01 μ g-100mg) by accumulated dose that send or that be applied to the bleomycin on feces incontinence implant or the apparatus surface.In one embodiment, the total amount of d/d bleomycin should be in the scope of 0.10 μ g-50mg.The dosage of the injectable filler of the per unit volume dosage of the bleomycin of the function of the volume of injected filler (that is, as) should be at 0.005 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to feces incontinence device surface with bleomycin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge bleomycin with concrete filler with different speed with prosthetic appliance, above-mentioned administration parameter should with medicine from feces incontinence filler, thereby the bleomycin that the rate of release in implant or the device is used in combination the Cmin that makes 0.001nM-1000 μ M is delivered in the described tissue.In one embodiment, bleomycin is from the agent of feces incontinence filling injection, thus the fibre modification of release in promoting to organize in the scope period of a few hours to several months in implant or the device.For example, in preferred embodiments, bleomycin can discharge the period that reaches 3-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active bleomycin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the bleomycin effect with half of above-mentioned parameter, use half in chemical compound of bleomycin effect etc.) with the twice of above-mentioned parameter.

CTGF is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from the filler injection, should be no more than 100mg (scope of 0.01 μ g-100mg) by accumulated dose that send or that be applied to the CTGF on feces incontinence implant or the apparatus surface.In one embodiment, the total amount of d/d CTGF should be in the scope of 0.10 μ g-50mg.The dosage of the injectable filler of per unit volume (that is, as the CTGF of the function of the volume of injected filler dosage) should be at 0.005 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to feces incontinence device surface with CTGF.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge CTGF with concrete filler with different speed with prosthetic appliance, above-mentioned administration parameter should with medicine from feces incontinence filler, thereby the CTGF that the rate of release in implant or the device is used in combination the Cmin that makes 0.001nM-1000 μ M is delivered in the described tissue.In one embodiment, CTGF is from the agent of feces incontinence filling injection, thus the fibre modification of release in promoting to organize in the scope period of a few hours to several months in implant or the device.For example, in preferred embodiments, CTGF can discharge the period that reaches 3-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active CTGF of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the CTGF effect with half of above-mentioned parameter, use half in chemical compound of CTGF effect etc.) with the twice of above-mentioned parameter.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or its analog or derivant in addition.According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of inflammatory cytokine from 0.0001 μ g/ml to about 20mg/ml is used in the preparation.Preferably, inflammatory cytokine discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 100mg); Preferred 0.001 μ g is to 50mg.When being used as the device coating, dosage is 0.0001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.001 μ g/mm ²-200 μ g/mm ²With 10 ^-10-10 ^-4The Cmin of the inflammatory cytokine of g/ml maintains on the apparatus surface.

In addition, described device can comprise the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA), and analog and derivant.Used dosage is to be proved to be those concentration (seeing that for example, embodiment 16) that stimulate cellular proliferation.According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of multiplication agent from 0.1ng/ml to 25mg/ml is used in the preparation.Preferably, multiplication agent discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 200mg); Preferred 0.001 μ g is to 100mg.When being used as the device coating, dosage is 0.00001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.0001 μ g/mm ²-200 μ g/mm ²With 10 ^-11-10 ^-6The Cmin of the multiplication agent of M maintains on the apparatus surface.

Should it will be apparent to one skilled in the art that aforementioned fibers degeneration derivant, any of or derivatives thereof and analog can be used to produce the variation of above-mentioned composition under the prerequisite that does not deviate from spirit and scope of the invention.Also should it is evident that described reagent can with or be not used in the compositions and change described carrier and do not depart from scope of the present invention with polymer support.

9. stomach esophagus adverse current disease (GERD)

The invention provides the compositions and the device that are used in the treatment stomach esophagus adverse current disease (GERD).GERD occurs in when lower esophageal sphincter (muscle between the harmonization of the stomach esophagus) can not stop the content adverse current of stomach to get back to esophagus.Gastric acid and enzyme have suitable corrosivity and can cause erosion, ulcer, cicatrization and esophagus to narrow down for the epithelial cell line of esophagus.Repetition adverse current in esophagus can cause irreversible damage and bring out the patient forming esophageal carcinoma.

(i) GERD filler

A kind of method of treatment GERD comprises the reinforcement of lower esophageal sphincter.A kind of method of strengthening lower esophageal sphincter with filler (for example comprises, the collagen protein filler) (for example sends, injection) to neighbouring (for example, to the muscle of LES space) on every side of lower esophageal sphincter (LES) thus recover the structure of described tissue and reduce to adverse current in the esophagus.Another kind method comprises the device of implanting filling device or sending distensible polymer composition (for example, hydrogel prosthesis).

As mentioned above, thus can near filler being expelled to lower esophageal sphincter, treat GERD with the closure of strengthening LES.Can make up with filler and comprise many commercially available products according to one or more fibre modification derivants of the present invention.For example, from Artes Medical, the Injectable microspheres body of ENTERYX and CONTIGEN (can pass through C.R.Bard, what Billerica, MA obtained is dispersed in the collagen protein of the Corii Bovis seu Bubali glutaraldehyde cross-linking of the purification in the phosphate buffer normal saline with 35mg/ml) is widely used filler.Other the product based on collagen protein can also be comprised from non-cattle that those of people or recombinant sources are with in this embodiment.Can load with fibre modification derivant and the other representative example that is used for the treatment of the commercially available filler of GERD and comprise COAPATITE, CYMETRA, DEFLUX, DURASPHERE, through engineering approaches collagen protein fibril from Organogenesis, HYLAGEL URO, MACROPLASTIQUE, microsphere (for example, the acrylic acid pearl, such as can obtain from Biosphere Medical those), comprise the LES filler (such as can be) of silk and elastin laminin from those of Protein Polymer Technologies acquisition, UROVIVE and URYX filler.The other device that is suitable for being used for the treatment of together with the fibre modification derivant GERD comprises by Medtronic Inc. (Minneapolis, MN) the GATEKEEPER Reflux Repair System of Zhi Zaoing.Other manufacturer who is suitable for sending the carrier of the fibre modification derivant that is used in the GERD filled compositions comprises C.R.Bard, Collagenesis, American Medical Systems, Mentor, Uromed, BSX, Johnson ﹠amp; Johnson (Ethicon, Inc.), Cook Inc., W.L.Gore ﹠amp; Associates, and SURx.The implantable example of esophagus filling device down also is described in WO 00/12027A1 and the U.S. Patent number 6,401,718.

No matter their composition how, the content adverse current that filler is designed to the physical support of lower esophageal sphincter is provided and stop stomach is in esophagus.Unfortunately, for Most patients, alleviating of symptom often only is temporary transient and must often repeats described method.Biodegradable injectable substance (such as collagen protein, hyaluronic acid and above-mentioned other) is absorbed and has lost their structural intergrity-must replace described material by duplicate injection in time by health.Nondegradable material (such as acrylic acid, hydroxyapatite, polymeric beads and above-mentioned other) is not reconstituted in the normal configuration anatomy or the biomechanics of the tissue around the lower esophageal sphincter.Add the fibre modification derivant in solving these problems in the filler some.The fibre modification derivant promotes the formation of the fibrous tissue (comprising collagen protein) of the health around lower esophageal sphincter itself.This causes the formation of the lasting connective tissue that can support, and described connective tissue is supported described LES in the mode of closer simulating normal stomach esophagus anatomy and biomechanics.The result be continue longer, the treatment that better sx is provided and needs still less to intervene again.

On the one hand, the invention provides injectable compositions (filler) to be used among the treatment GERD.Particularly, the fibre modification derivant can with or do not prepare together with carrier (such as collagen protein, hyaluronic acid and/or other biocompatible polymer), thereby then be expelled to it in anal sphincter and provide support on every side and control.In one embodiment, thereby the fibre modification derivant directly can be attached in the preparation and produce suspension or solution (for example, silk powder, bleomycin) or its and (for example can be incorporated in the secondary carrier, micelle, liposome, microsphere, microgranule, the nanometer spheroid, microparticulates, Emulsion and/or microemulsion), described secondary carrier then is incorporated in the filled compositions.In another embodiment, the fibre modification derivant can be incorporated into statically or covalently original position forms in one or more component of polymer of compositions.To comprise that filler (many above-mentioned commercially available examples) that fibrous tissue forms agent is expelled to that space (alone or in combination with polymer support) around the muscle can increase cicatrization and for the support of lower esophageal sphincter and can cause endogenous collagen protein to produce.

In another embodiment, the fibre modification derivant can be attached in the filler in the process of the described reagent of preparation.For example, can in the process of preparation, the silk powder be added as reagent as the microsphere of filler.

Tackling in those skilled in the art is to it is evident that potentially, above-mentioned any binding agent or fibre modification derivant can be used alone or in combination in the practice of the present embodiment.The exemplary fibrous tissue formation agent that is used in the GERD filler comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF, and above-mentioned analog and derivant.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or its analog or derivant in addition.

In addition, described device can comprise the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, all-trans retinoic acid (ATRA), and analog and derivant.

The dosage part below of suitable reagent and they can be further described in (iii).

The device that (ii) is used for GERD

The implantable apparatus and method of the multiple GERD of being used for the treatment of have been described.Representative therapeutic methods comprises, for example, and based on the Therapeutic Method of suture with use device based on energy.Method based on the treatment GERD of suture is described in, and for example U.S. Patent number 6,494,888, U.S. Patent Application Publication No. 2002/0138075A1, and they have described a kind of sphincter electrode potential plotting unit.U.S. Patent number 6,321,121 have described the lower esophageal sphincter take-up device.Other unit describe of treatment GERD exists, and for example U.S. Patent number 6,092, and 528,6,159,146; 6,113,609; 5,571,116; 6,432,040; With 6,264, in 700; Among U.S. Patent Application Publication No. 2003/0199731A1 and PCT publication number WO 99/44520A1 and the WO 01/24721A1.

The Therapeutic Method based on suture of treatment GERD can make up with one or more according to fibre modification derivant of the present invention.Some commercially available products can make up with the fibre modification derivant, comprising: (a) ENDOCINCH AND ENDOCINCH II Suturing System (C.R.Bard), and it uses to produce on lower esophageal sphincter and folds, or the program of pleat; (b) (Wilson-Cook, Winston-Salem NC) install ENDOSCOPICSuturing Device (ESD), and it is by flexible SEW-RIGHT device, and flexible TI-KNOT device and outer additional channel are formed; (c) PLICATORSYSTEM (NDO Surgical, Mansfield MA), it allows that the doctor produces the folding of maximum ga(u)ge (full-thichness) at gastroesophageal junction, allow serous coat-to the healing of-serous coat and adjust healing and transform LES again and (d) HISWIZ (Olympus is Inc.) based on the device of suture.

The another kind of method of treatment GERD is by using the device based on energy.The energy delivery apparatus of treatment esophageal sphincter is described in, and for example U.S. Patent number 6,613, in 047 and 6,009,877.The ablation of tissue unit describe exists, and for example U.S. Patent number 6,112, in 123 and 6,258,087.Can make up with one or more devices and comprise some commercially available products, such as STRETTA system (Curon Medical) radio frequency (RF) ablating device based on energy according to the treatment GERD of fibre modification derivant of the present invention.

In the present invention, thus fibre modification derivant combination is strengthened LES anatomy again and is stoped stomach esophagus adverse current to be increased in cicatrization around the device based on suture with based on the method for the treatment GERD of energy.The formation that the carrier system of aforesaid many polymer and non-polymer can be used to send one or more fibre modification derivants and promote the granulation tissue around implanted device.The fibre modification derivant is attached on the implanted GERD device or among method comprise: (a) directly will become fiber composition be attached to implanted suture (by aforesaid with or not with the spraying process or the dip coating of carrier); (b) directly will become fiber composition to be attached in the polymer of forming described suture itself; (c) by being coated with described device such as the hydrogel that can absorb into fiber composition again with material; (d) be woven in the stitching material by the line (or polymer itself of formation line) that will become the fiber composition coating; (e) with becoming fiber composition (particularly silk) to make up suture itself, or the part of described suture; Or (f) directly be covalently bound to suture surface or gastric mucosa surface (or using joint micromolecule or polymer to finish this) by fibrous tissue being formed agent; (g) by independent or in polymer support (for example, collagen protein, COSTASIS, mercaptan PEG (10K) by the 4-arm, the material of 4-arm NHS PEG (10K) and methylated collagen protein such as above-mentioned preparation, fibrin, PMMA, CORTOSS, cyanoacrylate, hyaluronic acid, EVA, PLA and other aforesaid polymer), the fibre modification derivant (is for example applied, infusion, spraying, injection) to LES or gastric mucosa (or serous coat) thus the surface induce in sphincter or pass through the cicatrization that folds that produces by stitching devices; And/or (h) with the fibre modification derivant, with or do not apply in the tissue that (for example, infusion, spraying, injection) be applied to energy (to increase cicatrization) with polymer support.

Tackling in those skilled in the art is to it is evident that potentially, above-mentioned any binding agent or fibre modification derivant can be used alone or in combination in the practice of the present embodiment.The exemplary fibrous tissue formation agent that is used among the treatment GERD comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF, and above-mentioned analog and derivant.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or its analog or derivant in addition.

In addition, described device can comprise the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, all-trans retinoic acid (ATRA), and analog and derivant.

Be used for being coated with the preferred concrete reagent of the implantable prosthetic appliance that is used in treatment GERD and dosage be described in following part (iii) in.

The fibre modification derivant that (iii) is used for GERD

Because the GERD device is made with multiple configuration and size (comprising injectable thing and implant), the exact dose of using can or be implanted the size of material with the amount of injection, surface area and kind of design and change.Yet, some principle can be used for using of this area.Can be the function of the dosage of per unit volume/area (surface area of the part of the cumulative volume of injected filler or applied implant) with medication dose calculation, the total drug dose that can measure administration also can be determined the suitable surface concentration of active medicine.No matter the method that described fibre modification derivant is used in treatment GERD is how, the exemplary fibers texturizer that is used alone or in combination should carry out administration under following administration is instructed:

Talcum is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, in the filler injection, should be no more than 100mg (scope of 1 μ g-100mg) by steatitic accumulated dose that send or that be applied on GERD implant or the apparatus surface.In one embodiment, d/d steatitic total amount should be in the scope of 10 μ g-50mg.The dosage of the injectable filler of the per unit volume steatitic dosage of the function of the volume of injected filler (that is, as) should be at 0.05 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to GERD implant or apparatus surface with Talcum.In one embodiment, Talcum is from the GERD filler, thereby device or implant discharge the fibre modification in promoting to organize in the scope period of a few hours to several months.For example, in preferred embodiments, Talcum can discharge the period that reaches 3-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is to be used for purpose of the present invention with having active steatitic analog of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the Talcum effect with half of above-mentioned parameter, use half in chemical compound of Talcum effect etc.) with the twice of above-mentioned parameter.

Silk is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of being sent in the filler injection or be applied to the silk on GERD implant or the apparatus surface should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the total amount of d/d silk should be in the scope of 10 μ g-50mg.The dosage of the injectable filler of the per unit volume dosage of the silk of the function of the volume of injected filler (that is, as) should be at 0.05 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to GERD implant or apparatus surface with silk.Because the drug delivery vehicle of concrete (polymer and non-polymer) and concrete filler, implant can discharge silk with different speed with device, above-mentioned administration parameter should with medicine from the GERD filler, be delivered in the described tissue thereby the rate of release in implant or the device is used in combination the silk of the Cmin that makes 0.01nM-1000 μ M.In one embodiment, silk is from the GERD filler, thereby implant or device discharge the fibre modification in promoting to organize in the scope period of a few hours to several months.For example, in preferred embodiments, silk can discharge the period that reaches 3-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active silk of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles an effect with half of above-mentioned parameter, use half in chemical compound of silk effect etc.) with the twice of above-mentioned parameter.

Chitosan is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from the filler injection, should be no more than 100mg (scope of 1 μ g-100mg) by accumulated dose that send or that be applied to the chitosan on GERD implant or the apparatus surface.In one embodiment, the total amount of d/d chitosan should be in the scope of 10 μ g-50mg.The dosage of the injectable filler of the per unit volume dosage of the chitosan of the function of the volume of injected filler (that is, as) should be at 0.05 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to GERD implant or apparatus surface with chitosan.Because the drug delivery vehicle of concrete (polymer and non-polymer) and concrete filler, implant can discharge chitosan with different speed with device, above-mentioned administration parameter should with medicine from the GERD filler, thereby the rate of release in implant or the device is used in combination the chitosan of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, chitosan is from the GERD filler, thereby implant or device discharge the fibre modification in promoting to organize in the scope period of a few hours to several months.For example, in preferred embodiments, chitosan can discharge the period that reaches 3-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active chitosan of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the chitosan effect with half of above-mentioned parameter, use half in chemical compound of chitosan effect etc.) with the twice of above-mentioned parameter.

Polylysine is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, in the filler injection, should be no more than 100mg (scope of 1 μ g-100mg) by accumulated dose that send or that be applied to the polylysine on GERD implant or the apparatus surface.In one embodiment, the total amount of d/d polylysine should be in the scope of 10 μ g-50mg.The dosage of the injectable filler of the per unit volume dosage of the polylysine of the function of the volume of injected filler (that is, as) should be at 0.05 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to GERD implant or apparatus surface with polylysine.Because the drug delivery vehicle of concrete (polymer and non-polymer) and concrete filler, implant can discharge polylysine with different speed with device, above-mentioned administration parameter should with medicine from the GERD filler, thereby the rate of release in device or the implant is used in combination the polylysine of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, polylysine is from the GERD filler, thus the fibre modification of release in promoting to organize in the scope period of a few hours to several months in implant or the device.For example, in preferred embodiments, polylysine can discharge the period that reaches 3-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active polylysine of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the polylysine effect with half of above-mentioned parameter, use half in chemical compound of polylysine effect etc.) with the twice of above-mentioned parameter.

Fibronectin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from the filler injection, should be no more than 100mg (scope of 1 μ g-100mg) by accumulated dose that send or that be applied to the fibronectin on GERD implant or the apparatus surface.In one embodiment, the total amount of d/d fibronectin should be in the scope of 10 μ g-50mg.The dosage of the injectable filler of the per unit volume dosage of the fibronectin of the function of the volume of injected filler (that is, as) should be at 0.05 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to GERD implant or apparatus surface with fibronectin.Because the drug delivery vehicle of concrete (polymer and non-polymer) and concrete filler, implant can discharge fibronectin with different speed with device, above-mentioned administration parameter should with medicine from the GERD filler, thereby the rate of release in implant or the device is used in combination the fibronectin of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, fibronectin is from the GERD filler, thus the fibre modification of release in promoting to organize in the scope period of a few hours to several months in implant or the device.For example, in preferred embodiments, fibronectin can discharge the period that reaches 3-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active fibronectin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the fibronectin effect with half of above-mentioned parameter, use half in chemical compound of fibronectin effect etc.) with the twice of above-mentioned parameter.

Bleomycin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from the filler injection, should be no more than 100mg (scope of 0.01 μ g-100mg) by accumulated dose that send or that be applied to the bleomycin on GERD implant or the apparatus surface.In one embodiment, the total amount of d/d bleomycin should be in the scope of 0.10 μ g-50mg.The dosage of the injectable filler of the per unit volume dosage of the bleomycin of the function of the volume of injected filler (that is, as) should be at 0.005 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to GERD implant or apparatus surface with bleomycin.Because the drug delivery vehicle of concrete (polymer and non-polymer) and concrete filler, implant can discharge bleomycin with different speed with device, above-mentioned administration parameter should with medicine from the GERD filler, thereby the bleomycin that the rate of release in implant or the device is used in combination the Cmin that makes 0.001nM-1000 μ M is delivered in the described tissue.In one embodiment, bleomycin is from the agent of GERD filling injection, thus the fibre modification of release in promoting to organize in the scope period of a few hours to several months in implant or the device.For example, in preferred embodiments, bleomycin can discharge the period that reaches 3-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active bleomycin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the bleomycin effect with half of above-mentioned parameter, use half in chemical compound of bleomycin effect etc.) with the twice of above-mentioned parameter.

CTGF is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from the filler injection, should be no more than 100mg (scope of 0.01 μ g-100mg) by accumulated dose that send or that be applied to the CTGF on GERD implant or the apparatus surface.In one embodiment, the total amount of d/d CTGF should be in the scope of 0.10 μ g-50mg.The dosage of the injectable filler of per unit volume (that is, as the CTGF of the function of the volume of injected filler dosage) should be at 0.005 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to GERD implant or apparatus surface with CTGF.Because the drug delivery vehicle of concrete (polymer and non-polymer) and concrete filler, implant can discharge CTGF with different speed with device, above-mentioned administration parameter should with medicine from the GERD filler, thereby the CTGF that the rate of release in implant or the device is used in combination the Cmin that makes 0.001nM-1000 μ M is delivered in the described tissue.In one embodiment, CTGF is from the agent of GERD filling injection, thus the fibre modification of release in promoting to organize in the scope period of a few hours to several months in implant or the device.For example, in preferred embodiments, CTGF can discharge the period that reaches 3-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active CTGF of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the CTGF effect with half of above-mentioned parameter, use half in chemical compound of CTGF effect etc.) with the twice of above-mentioned parameter.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or its analog or derivant in addition.

According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of inflammatory cytokine from 0.0001 μ g/ml to about 20mg/ml is used in the preparation.Preferably, inflammatory cytokine discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 100mg); Preferred 0.001 μ g is to 50mg.When being used as the device coating, dosage is 0.0001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.001 μ g/mm ²-200 μ g/mm ²With 10 ^-10-10 ^-4The Cmin of the inflammatory cytokine of g/ml maintains on the apparatus surface.

In addition, described device can be separately or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA), and analog and derivant.Used dosage is to be proved to be those concentration (seeing that for example, embodiment 16) that stimulate cellular proliferation.According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of multiplication agent from 0.1ng/ml to 25mg/ml is used in the preparation.Preferably, multiplication agent discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 200mg); Preferred 0.001 μ g is to 100mg.When being used as the device coating, dosage is 0.00001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.0001 μ g/mm ²-200 μ g/mm ²With 10 ^-11-10 ^-6The Cmin of the multiplication agent of M maintains on the apparatus surface.

Should it will be apparent to one skilled in the art that aforementioned fibers degeneration derivant, any of or derivatives thereof and analog can be used to produce the variation of above-mentioned composition under the prerequisite that does not deviate from spirit and scope of the invention.Also should it is evident that described reagent can with or be not used in the compositions and change described carrier and do not depart from scope of the present invention with polymer support.

10. morbid obesity

The invention provides fibre modification induces compositions and device to be used in the treatment morbid obesity.Morbid obesity (people who exceeds ideal body weight 50%) is important public health problem, and it influences the significantly ratio of (and increasing) of the Western countries country.Morbid obesity brings out patient's various remarkable health problem, comprises heart disease, diabetes, apoplexy, nephropathy, joint disease and the lost of life.Developed many interference methods and solved this problem, described interference method comprises that design reduces the size of stomach with surgical operation.This has limited the amount of the food that can consume from health, and satiety and final because food that reduces and heat absorption cause weight to reduce is provided.The invention describes the effectiveness that the fibre modification derivant that adds gastric restriction device (rescriction device) thereby make up improves described method.

The example of gastric restriction device is the expandable cover capsule of settling with peritoneoscope (being called stomach hoop (lap-band)), and described cover capsule is positioned in around the top of the stomach under the lower esophageal sphincter (LES).In order to further describe, see, for example, U.S. Patent number 5,601,604; 5,226,429; With 5,074,868.The other case description that is used for the treatment of the escapement of obesity exists, and for example U.S. Patent number 6,067, and 991; 6,454,699; 6,453,907; 6,450,946; 6,210,347; With 6,067, in 991.The device of other intrusion degree minimum includes, but not limited to the occupy-place device, is used to separate the endoluminal means based on suture of stomach, electrical stimulation device (for example, neural and non-nerve) and radio frequency antralplasty device.Occupy-place device (for example, intragastric balloon) is described in, and for example U.S. Patent number 5,259, and 399; 4,485,805; 5,129,915; 5,259,399; With 6,454, in 785.The electrical stimulation device that is used for the treatment of obesity is described in, for example, and U.S. Patent number 6,615,084; 6,129,685; 5,782,798,6,535,764; With 6,606, in 523.

On the one hand, thereby escapement can make up with the treatment of obesity of fibre modification derivant.Particularly, some commercially available interval products are suitable for practice of the present invention, the described LAP-BANDAdjustable Gastric Banding System (producing) that comprises by Inamed, it comprises the little ring of expandable siloxanes, described little ring can expand from the attached tube that is connected in subcutaneous part or dwindle), SWEDISH ADJUSTABLE GASTRIC BAND (Ethicon-Endosurgery production) is the low pressure inflatable device of strengthening with DACRON net, described inflatable device be suitable for peritoneoscope be installed on around the highest part of stomach and can be after installation by injection or remove fluid and adjust).

Be also included among the present invention, many devices that are used for the treatment of obesity can make up with one or more fibre modification derivants, and described device is commercially available and the device of intrusion degree minimum.Particularly, the device that is suitable for use in the occupy-place intrusion degree minimum in the present invention's practice comprises: BARIATRIC INTRAGASTRIC BALLOON (by Inamed) is the spherical silicon implant that is placed in the stomach and can be expanded to 400-800ml with saline, it can keep reaching in place 3-6 month), can be from Satiety, Inc. the air bag of the gastric of Huo Deing, BOWTIE occupy-place device (Wilson-Cook by successive polyester belt making, Inc.), with the endoluminal means that is used to separate stomach, such as EAGLE CLAW (Olympus America) based on suture.

Add the fibre modification derivant to stomach hoop device (gastric band device) or occupy-place device can increase described program on some modes effect and the life-span.For example, induce the fibrous tissue around the implant implant can be fixed on suitable position, allow that it keeps correct anatomical location under one's belt.In addition, that fibrous tissue can form under one's belt is persistent " hoop (band) ", and described " hoop " causes continuing of stomach, host tissue contraction.When the cicatrix maturation, it also can shrink, and further reduces the size of stomach and increases the effect of described method.

The many polymer described in detail previously and the carrier system of non-polymer can be used in the practice of the present invention.Thereby these compositionss can also comprise the formation that one or more fibre modification derivants promote granulation tissue.With become fiber composition be attached to stomach at interval or on the fat device of occupy-place or among method comprise: (a) directly will become fiber composition be attached to described device (for example, by aforesaid with or not with the spraying process or the dip coating of carrier); (b) directly will become fiber composition be attached in the described device (for example, by aforesaid with or not with the spraying process or the dip coating of carrier); (c) by being coated with described device such as the hydrogel that can absorb into fiber composition again with material; (d) be woven in the described apparatus structure by the line (or polymer itself of formation line) that will become the fiber composition coating; (e) by described device is inserted in sleeve pipe or the mesh, described sleeve pipe or mesh are by becoming fiber composition to form or by its coating; (f) with becoming fiber composition construction device itself, or the part of described device; And/or (g) directly be covalently bound to apparatus surface by fibrous tissue being formed agent, or on the joint (micromolecule or polymer), described joint is applied or be attached to apparatus surface.For these devices, can carry out coating process by this way, described mode is the outer surface of the described device of (a) coating, (b) inner surface of the described device of coating or (c) outer and inner surface all or part of of the described device of coating.Except with becoming fiber composition to be coated with the described device, agent is mixed to be formed agent with the material that is used for preparing described device with fibrous tissue and is attached to resulting device thereby fibrous tissue can be formed.

In one embodiment, thereby the fibre modification derivant directly can be attached in the preparation and produce suspension or solution (for example, silk powder, bleomycin) or its and (for example can be incorporated in the secondary carrier, micelle, liposome, microsphere, microgranule, the nanometer spheroid, microparticulates, Emulsion and/or microemulsion), described secondary carrier then is incorporated in gastric restriction device or the occupy-place device.In another embodiment, the fibre modification derivant can be incorporated into statically or covalently original position forms in one or more component of polymer of compositions.

Tackling in those skilled in the art is to it is evident that potentially, above-mentioned any binding agent or fibre modification derivant can be used alone or in combination in the practice of the present embodiment.The exemplary fibrous tissue formation agent that is used in obesity device and the compositions comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF, and above-mentioned analog and derivant.

Because the obesity device is made with multiple configuration and size, the exact dose of using can be with the device size, surface area and kind of design and change.Yet, some principle can be applied in the application of this area.Can be the function of per unit area (part of applied device) dosage with medication dose calculation, can measure the total drug dose of using, and can determine the suitable surface concentration of active medicine.No matter medicament administration is to the employed method of obesity device, the exemplary fibers texturizer that is used alone or in combination should use under following administration is instructed:

Talcum is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the lip-deep steatitic accumulated dose of sending from the obesity device or be applied to the obesity device should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the steatitic total amount that discharges from prosthese should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the steatitic dosage of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the obesity apparatus surface with Talcum.In one embodiment, thus Talcum discharges from the surface of obesity device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, Talcum can discharge the period that reaches 1-9 month scope with valid density.What consider that discussion provided herein it should be obvious that is to be used for purpose of the present invention with having active steatitic analog of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the Talcum effect with half of above-mentioned parameter, use half in chemical compound of Talcum effect etc.) with the twice of above-mentioned parameter.

Silk is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep silk of sending from the obesity device or be applied to the obesity device should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the silk that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the silk of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the obesity apparatus surface with silk.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge silk with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the silk that the rate of release of medicine from the obesity device is used in combination the Cmin that makes 0.01nM-1000 μ M.In one embodiment, thus silk discharges from the surface of obesity device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, silk can discharge the period that reaches 1-9 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active silk of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles an effect with half of above-mentioned parameter, use half in chemical compound of silk effect etc.) with the twice of above-mentioned parameter.

Chitosan is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep chitosan of sending from the obesity device or be applied to the obesity device should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the chitosan that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the chitosan of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the obesity apparatus surface with chitosan.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge chitosan with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be used in combination from the rate of release of obesity device with medicine the chitosan of 0.01nM-1000 μ M Cmin is delivered to the described tissue.In one embodiment, thus chitosan discharges from the surface of obesity device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, chitosan can discharge the period that reaches 1-9 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active chitosan of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the chitosan effect with half of above-mentioned parameter, use half in chemical compound of chitosan effect etc.) with the twice of above-mentioned parameter.

Polylysine is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep polylysine of sending from the obesity device or be applied to the obesity device should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the polylysine that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the polylysine of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the obesity apparatus surface with polylysine.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge polylysine with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be used in combination from the rate of release of obesity device with medicine and makes the polylysine of 0.01nM-1000 μ M Cmin be delivered to described tissue.In one embodiment, thus polylysine discharges from the surface of obesity device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, polylysine can discharge the period that reaches 1-9 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active polylysine of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the polylysine effect with half of above-mentioned parameter, use half in chemical compound of polylysine effect etc.) with the twice of above-mentioned parameter.

Fibronectin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep fibronectin of sending from the obesity device or be applied to the obesity device should be no more than 100mg (scope of 1 μ g-100mg).The total amount of the fibronectin that discharges from prosthese in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the fibronectin of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the obesity apparatus surface with fibronectin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge fibronectin with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from the obesity device fibronectin of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, thus fibronectin discharges from the surface of obesity device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, fibronectin can discharge the period that reaches 1-9 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active fibronectin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the fibronectin effect with half of above-mentioned parameter, use half in chemical compound of fibronectin effect etc.) with the twice of above-mentioned parameter.

Bleomycin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep bleomycin of sending from the obesity device or be applied to the obesity device should be no more than 100mg (scope of 0.01 μ g-100mg).In one embodiment, the total amount of the bleomycin that discharges from prosthese should be in the scope of 0.10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the bleomycin of the function of the surface area of the part of bonded device) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the obesity apparatus surface with bleomycin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge bleomycin with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered in the described tissue with the bleomycin that the rate of release of medicine from the obesity device is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, thus bleomycin discharges from the surface of obesity device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, bleomycin can discharge the period that reaches 1-9 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active bleomycin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the bleomycin effect with half of above-mentioned parameter, use half in chemical compound of bleomycin effect etc.) with the twice of above-mentioned parameter.

CTGF is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of the lip-deep CTGF that sends from the obesity device or be applied to the obesity device should be no more than 100mg (scope of 0.01 μ g-100mg).In one embodiment, the total amount of the CTGF that discharges from prosthese should be in the scope of 0.10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the CTGF of the function of the surface area of the part of bonded device) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the obesity apparatus surface with CTGF.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge CTGF with different speed with concrete medical apparatus, thereby above-mentioned administration parameter should be delivered to described tissue with the CTGF that the rate of release of medicine from the obesity device is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, thus CTGF discharges from the surface of obesity device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, CTGF can discharge the period that reaches 1-9 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active CTGF of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the CTGF effect with half of above-mentioned parameter, use half in chemical compound of CTGF effect etc.) with the twice of above-mentioned parameter.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6 and growth hormone or its analog or derivant) in addition.Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of inflammatory cytokine from 0.0001 μ g/ml to about 20mg/ml is used in the preparation.Preferably, inflammatory cytokine discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 100mg); Preferred 0.001 μ g is to 50mg.When being used as the device coating, dosage is 0.0001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.001 μ g/mm ²-200 μ g/mm ²With 10 ^-10-10 ^-4The Cmin of the inflammatory cytokine of g/ml maintains on the apparatus surface.

In addition, described device can be separately or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA), and analog and derivant.Used dosage is to be proved to be those concentration (seeing that for example, embodiment 16) that stimulate cellular proliferation.Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of multiplication agent from 0.1ng/ml to 25mg/ml is used in the preparation.Preferably, multiplication agent discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 200mg); Preferred 0.001 μ g is to 100mg.When being used as the device coating, dosage is 0.00001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.0001 μ g/mm ²-200 μ g/mm ²With 10 ^-11-10 ^-6The Cmin of the multiplication agent of M maintains on the apparatus surface.

Should be that it is evident that can be with aforementioned fibers degeneration derivant for those skilled in the art, any of or derivatives thereof and analog be used to produce the variation of above-mentioned composition under the situation that does not deviate from spirit and scope of the invention.Also should it is evident that described reagent can be used in the compositions that has or do not have polymer support and change described carrier and not deviate from scope of the present invention.

11. soft palate implant

The combination that the invention provides fibre modification derivant and soft palate implant device is to be used for the treatment of snoring and sleep apnea (being also referred to as occlusive sleep apnea (OSA)).Sleep apnea refers to can not keep normal breathing and Oxygenation in sleep.The feature of occlusive sleep apnea is the air flue obturation in frequent cycle when sleep, follows the obturation of inspiratory airflow, the decline of blood oxygen and the interruption of sleep, and this moment, the patient was clear-headed to use muscle contraction initiatively to open air flue and do some deep breathing.What also will consider is the very big snoring of sound (often reaching the decibel level that equates when taking off) to the patient's that suffers from the occlusive sleep apnea companion's the sleep pattern and the influence of life style.The cause of sleep apnea is the mechanicalness obturation of air flue and can comprises painful and/or insufficient breathing, unusual heart beating, and hypertension.Inaccessible machinery location and reasons in structure are various.Modal mechanism comprises tongue, uvula, soft palate or other be organized in air-breathing relevant negative pressure process at the arrangement of air flue.This can with accumulation of adipose tissue, the shortage of flesh sound or to the insufficient maincenter of tongue and/or other attached breathing muscle around the oropharynx air flue breathe advance relevant.The treatment of sleep apnea comprises that surgical method is (such as staphylectomy or staphyleus removal, the surgical removal of the soft tissue in air flue, or by removing tissue and inducing cicatrization to make the soft palate hardening), the behavior control of sleeping posture, apply positive airway pressure by mask, and use transplantable sleep apnea device (such as the soft palate implant).

Thereby the present invention describes the efficient that the combination of soft palate implant and fibre modification derivant is increased in the cicatrization around the implant and increases described device.Can with in part (i) thus in the interpolation described or the Injectable composition that does not add the fibre modification derivant inject the physical support that described tissue is provided under the mucosa of leading described palate.The combination of fibre modification derivant and soft palate prosthese (or solid implant) be described in the part (ii) in.

No matter their kind of design how, thereby soft palate injectable thing and graft design are provided for staphyleus physical support and prevent soft palate inaccessible air flue in sleep.Unfortunately, for many patients, alleviating of symptom only is temporary transient, because the support of soft palate is inadequate or does not have enough cicatrizations to produce permanent result around implant.The fibre modification derivant is added quantity that can be increased in implant scar tissue on every side in the palate implant and the long-term effect that improves described method.The fibre modification derivant promote the health itself around the soft palate implant fibrous tissue (comprising collagen protein) thus formation provide support; Cicatrix natural contracture in time further improves uvula and increases the size of air flue.This has caused the formation of the lasting connective tissue that can support, and it supports uvula in the mode of closer simulating nasopharynx anatomy and biomechanics.The result be continue longer, the treatment that better sx is provided and needs still less to intervene again.

(i) injectablely induce fibrotic palate implant

The invention describes degradable and nondegradable injectable biomaterial and implant, remove the treatment sleep apnea thereby described injectable biomaterial and implant are independent or be used for being expelled to soft palate with fibre modification derivant, somatomedin or sclerosing agent combination.Typically, the mucosa that pin or conduit is advanced to soft palate down and use injectable implant.Fibre modification derivant, sclerosing agent and/or somatomedin added to having produced nonvolatil cicatrix in the material that is injected in the soft palate, it supports uvula also to open air flue.

Developed many present invention of being suitable for practice injectable based on polymer product and they can be used in combination separately or with the fibre modification derivant.Separately or with the combination of fibre modification derivant, be suitable for being expelled to the example of the product in the soft palate, comprise: TRUFILL normal-butyl cyanoacrylate (n-BCA) Liquid Embolic System (Cordis, a division of Johnsonand Johnson, Miami, FL); EMBOSPHERE and EMBOGOLD Microspheres; ONYX Liquid Embolic System; BEAD BLOCK; From Cook, Inc. and Angiodynamics, the PVA granule of Inc.; With from Biocure, AngiotechPharmaceuticals, Inc., the original position of 3M Company and Neomend forms material.

Thereby some other Injectable composition is suitable for being expelled to the treatment of carrying out sleep apnea in the soft palate.All all comprising is applied to biomaterial in the tissue of soft palate, follows or do not follow the fibre modification derivant, the interpolation of sclerosing agent and/or suitable somatomedin.Following compositions can be passed through special delivery catheter under direct or endoscopic observation, pin or other applicator, or the access to plant that surgical operation is laid is sent.The example that can be injected into the injectable substance that is fit in the soft palate comprises: (a) fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microparticulates, spray, aerosol, other preparation of solid implant and release bioactive agent; (b) be injected into independent in the soft palate or load with additional fibers degeneration derivant, sclerosing agent, and/or the microgranule silk of somatomedin and/or silk chain (linearity, side chain, and/or curl); (c) injectablely comprise preparation such as the COSTASIS of collagen protein or by 4-arm mercaptan PEG (10K), 4-arm NHS PEG (10K) and methylated collagen protein are such as the above-mentioned material of making, described preparation is independent or loads with the fibre modification derivant sclerosing agent, and/or somatomedin; (d) the injectable preparation that comprises PEG is such as COSEAL, and FOCALSEAL, SPRAYGEL or DURASEAL, described preparation are independent or load with the fibre modification derivant sclerosing agent, and/or somatomedin; (e) comprise preparation such as the FLOSEAL or the TISSEAL of fibrinogen, described preparation is independent or loads with the fibre modification derivant sclerosing agent, and/or somatomedin; (f) comprise hyaluronic preparation such as RESTYLANE, HYLAFORM, PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT, described preparation are independent or load with the fibre modification derivant sclerosing agent, and/or somatomedin; (g) at polymer gel such as the REPEL or the FLOWGEL of surgical implants, described gel is independent or loads with the fibre modification derivant sclerosing agent, and/or somatomedin; (h) orthopedics's " cement " is such as OSTEOBOND, and LVC, SIMPLEXP, PALACOS, CORTOSS and ENDURANCE, described " cement " are independent or load with the fibre modification derivant sclerosing agent, and/or somatomedin; (i) be injected into the surgical operation binding agent that comprises cyanoacrylate in the soft palate such as DERMABOND, INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL BLUE and ORABASESOOTHE-N-SEAL LIQUID PROTECTANT, it is independent or loads with the fibre modification derivant sclerosing agent, and/or somatomedin; (j) comprise hydroxyapatite, calcium phosphate (such as VITOSS), or the surgical implants of calcium sulfate, described surgical implants are independent or load with the fibre modification derivant sclerosing agent, and/or somatomedin; (k) other biocompatible tissue filler, such as by BioCure, those that 3M Company and Neomend make, it is independent or loads with the fibre modification derivant sclerosing agent, and/or somatomedin; (l) polysaccharide gel is such as the gel of ADCON series, and described polysaccharide gel is independent or loads with the fibre modification derivant sclerosing agent, and/or somatomedin; (m) film, sponge, or mesh is such as INTERCEED, VICRYL mesh, and GELFOAM, and it is independent or loads with the fibre modification derivant sclerosing agent, and/or somatomedin; And/or (n) form the hydrogel of Polyethylene Glycol from amino-functional (for example, 4-arm tetramino PEG[10k] and the functionalized PEG of 4-arm NHS) (for example, tetramethylolmethane gathers (ethylene glycol) ether four-succinimido glutarate [10K]).This hydrogel also can comprise collagen protein, methylated collagen protein and/or gelatin.This hydrogel also can comprise above-mentioned fibre modification derivant (for example, silk powder or silk chain).Can be with film, sponge and mesh place soft palate.That also be used for being expelled to soft palate is nondegradable polymer such as polyester (for example PET), polyurethane, siloxanes, PE, PP, PS, PAA, PMA, silk, its admixture, copolymer and other known in the art nondegradable polymer.Be injected in the soft palate and comprise polyester with the degradable polymer that tissue support is provided, poly-(acid anhydride), poly-(acid anhydride-ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, cyanoacrylate polymer, collagen protein, chitosan, hyaluronic acid, chromic catgut, alginate, starch, cellulose, cellulose esters, its admixture and copolymer, and other known degradable polymer.

In one embodiment, injectable polymer system preparation is from 4-arm mercaptan PEG (10K), and 4-arm NHS PEG (10K) and methylated collagen protein are such as above-mentioned.Injectable polymer system can make up that (for example, the fibre modification derivant is such as Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin, CTGF with bioactivator; Sclerosing agent is such as ethanol, DMSO, surfactant, sucrose, sodium morrhuate, ethamolin (ester) NaCl, dextrose, glycerol, minocycline, tetracycline, doxycycline, Polidocanol, sodium tetradecyl sulfate, sodium morrhuate, Sotradecol; Somatomedin is such as transforming growth factor, platelet-derived somatomedin, fibroblast growth factor and bone morphogenetic protein; And/or the analog of these chemical compounds and derivant) and be injected in the soft palate.The Injectable polymer system can also comprise reagent such as glycerol, glycerol, and PEG200, triethyl citrate and triacetin are as plasticizer.

In another embodiment, thus can prepare and it is used as have the particulate matter of inducing fibrotic ability and from conduit (or pin), send being delivered to injectable substance in the soft palate.Injectable substance can load with, applied with, or comprise the fibre modification derivant.These granules can be degradable or nondegradable and on forming to above-mentioned those are similar.Except above-mentioned polymer, the particulate matter useful for putting into practice of the present embodiment comprises Talcum, starch, glass, silicate, Silicon stone, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic property mineral (VITOSS and CORTOSS), PMMA, silver nitrate, Inorganic Non-metallic Materials granule and other inorganic particle of inducing the fibroplasia reaction known in the art).The granule that is used in the present embodiment can be all same combinations or the admixture of different components.These granules can also be used in combination with above-mentioned Injectable polymer matter.

In the embodiment on many, add radiopaque material (for example, tantalum, barium, other metal or developing materials) thus it also is useful making injected material be undertaken visual by radiography.In addition, during direct injection in proceeding to soft palate, can the employing technology increase visual by ultransonic pin (or conduit) by using with the pin of ECHO-COAT bag quilt or injection air (microbubble).

Tackling in those skilled in the art is to it is evident that potentially, can be with above-mentioned any binding agent or fibre modification derivant, and sclerosing agent, or somatomedin is used alone or in combination in the practice of the present embodiment.The exemplary fibrous tissue formation agent that is used in the injectable soft palate implant method comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF, sclerosing agent, and/or somatomedin is (such as transforming growth factor, platelet-derived somatomedin, fibroblast growth factor, bone morphogenetic protein) and above-mentioned analog and derivant.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF in addition, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or bone morphogenetic protein (BMP) is (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant).

In addition, described device can comprise the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, all-trans retinoic acid (ATRA), and analog and derivant.

In some clinical scenarios, may need the duplicate injection of activating agent.Can be used in concrete reagent in the injectable soft palate implant and dosage be described in detail in following part (iii) in.

(ii) with the soft palate implant of fibre modification derivant combination

The soft palate implant is the SM device that is designed to insert in individual's the soft palate of palate, and described individual suffers from snoring or sleep apnea.The soft palate implant is described in, and for example U.S. Patent number 6,626, and 181; In 6,571,798 and 6,578,580.Other the medical apparatus that is used for the treatment of sleep apnea comprises provides the soft palate of electricity irritation implant (to see for example 6,240,316; 6,574,507; 5,284,161 and 5,792,067).

Can make up with one or more according to fibre modification derivant of the present invention, the soft palate implant of sclerosing agent and/or somatomedin comprises some commercially available products.For example, from Restore Medical Inc. (St.Paul, MN) the PILLAR Palatal Implant System that is used for the treatment of snoring is the woven polyester species of implanted soft palate, described material is strengthened and is supported described palate (reduce vibration and soft palate thus and " fall " the also tendency of inaccessible described air flue), and need not heat or remove tissue.

The carrier system of above-mentioned many polymer and non-polymer can be used for send the fibre modification derivant from the soft palate implant, sclerosing agent and somatomedin.To become fiber, sclerosis with on growth factor combination is attached to the soft palate implant or among method comprise: a) directly will become fiber, sclerosis and/or growth factor combination are attached to the palate implant (for example, by being sprayed in the surface of implant or the implant immersion being comprised in the solution of activating agent; Described reagent can be used separately or with polymer support); (b) directly will become fiber, sclerosis and/or growth factor combination are attached in the composition or polymer of forming the palate implant (for example, by with or not with the spray method or the immersion method of polymer support); (c) by with material such as can absorbing into fiber again, the hydrogel of sclerosis and/or growth factor combination is coated on the palate implant; (d) by becoming fiber with (or be made up of it), the line of sclerosis and/or somatomedin coating is woven in the structure of palate implant; (e) by the palate implant being inserted in sleeve pipe or the mesh, described sleeve pipe or mesh be by becoming fiber, and sclerosis and/or growth factor combination are formed or by its coating; (f) with becoming fiber, sclerosis and/or growth factor combination make up palate implant itself, or the part of described implant (is effective especially for silk); And/or (g) by fibrous tissue being formed agent, sclerosing agent and/or somatomedin directly are covalently bonded in palate implant surface or joint (micromolecule or polymer), and described joint is applied or be attached to described implant surface.For the palate implant, described coating process can carry out by this way, as a) outer surface of implant as described in the coating, b) inner surface or the c of the described implant of coating) all or part on the outer and inner surface of the described implant of coating.Except with becoming fiber, outside sclerosis and/or the growth factor combination coating palate implant, thereby the material that activating agent can be mixed to be used to prepare described implant will become fiber, harden and/or somatomedin is attached in the final implant.

Should it is evident that to those skilled in the art potentially, can be with the fibre modification derivant, any of sclerosing agent or somatomedin is independent, or combined administration is in the practice of the present embodiment.The exemplary fibers texturizer that is used in combination with the soft palate implant comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin, CTGF; Sclerosing agent is such as sodium morrhuate, ethamolin (ester), ethanol, DMSO, surfactant, sucrose, NaCl, dextrose, glycerol, minocycline, tetracycline, doxycycline, Polidocanol, sodium tetradecyl sulfate, sodium morrhuate, Sotradecol; And/or somatomedin is such as transforming growth factor, platelet-derived somatomedin, fibroblast growth factor and bone morphogenetic protein; And above-mentioned analog and derivant.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF in addition, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or bone morphogenetic protein (BMP) is (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant).

In addition, described device can comprise the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, all-trans retinoic acid (ATRA), and analog and derivant.

In some clinical scenarios, may need the duplicate injection of activating agent.Can be used in concrete reagent in the injectable soft palate implant and dosage be described in detail in following part (iii) in.

(iii) use the reagent in the treatment sleep apnea

Existence can be suitable for some the commercially available sclerosing agents according to use of the present invention.Can from WyethPharmaceuticals (Collegeville, PA), a division of Wyeth (Madison, NJ) example of Huo Deing is SOTRADECOL, it is a sodium tetradecyl sulfate.Other sclerosing agent comprises sodium morrhuate, and ethamolin (ester) comprises alcoholic acid compositions, DMSO, surfactant, sucrose, NaCl, dextrose, glycerol, minocycline, tetracycline, doxycycline, Polidocanol, sodium morrhuate, Sotradecol and other.Be suitable for being expelled in the soft palate or combination comprises by the fibre modification derivant with other example of the compositions of soft palate implant, silk (for example, microgranule silk) that sclerosing agent and somatomedin are formed and polymer gel (such as can be) from those of PolymerixCorporation acquisition.

Because soft palate implant and device be with the making of multiple configuration and size (comprising injectable thing and implant), the exact dose of using can be with injected amount, or big or small, surface area and described implant design type and change.Yet, some principle can be used for using of this area.Can be the function of the dosage of per unit volume/area (surface area of the part of the cumulative volume of injected material or applied palate implant) with medication dose calculation, the total drug dose that can measure administration also can be determined the suitable surface concentration of active medicine.No matter the method that described fibre modification derivant is used in the treatment sleep apnea is how, the exemplary fibers texturizer that is used alone or in combination should carry out administration under following administration is instructed:

Talcum is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, in soft palate injectable, should be no more than 100mg (scope of 1 μ g-100mg) by steatitic accumulated dose that send or that be applied on palate implant or the apparatus surface.In one embodiment, d/d steatitic total amount should be in the scope of 10 μ g-50mg.The dosage of the soft palate injectable thing of the per unit volume steatitic dosage of the function of the volume of injected material (that is, as) should be at 0.05 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to palate implant or apparatus surface with Talcum.In one embodiment, Talcum is from soft palate injectable thing, thereby device or implant discharge the fibre modification in promoting to organize in the scope period of a few hours to several months.For example, in preferred embodiments, Talcum can discharge the period that reaches 3-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is to be used for purpose of the present invention with having active steatitic analog of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the Talcum effect with half of above-mentioned parameter, use half in chemical compound of Talcum effect etc.) with the twice of above-mentioned parameter.

Silk is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of being sent from soft palate injectable or be applied to the silk on soft palate implant or the apparatus surface should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the total amount of d/d silk should be in the scope of 10 μ g-50mg.The dosage of the soft palate injectable thing of the per unit volume dosage of the silk of the function of the volume of injected material (that is, as) should be at 0.05 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to soft palate implant or apparatus surface with silk.Because the drug delivery vehicle of concrete (polymer and non-polymer) and concrete soft palate injectable thing, implant can discharge silk with different speed with device, above-mentioned administration parameter should with medicine from soft palate injectable thing, be delivered in the described tissue thereby the rate of release in implant or the device is used in combination the silk of the Cmin that makes 0.01nM-1000 μ M.In one embodiment, silk is from soft palate injectable thing, thereby implant or device discharge the fibre modification in promoting to organize in the scope period of a few hours to several months.For example, in preferred embodiments, silk can discharge the period that reaches 3-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active silk of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles an effect with half of above-mentioned parameter, use half in chemical compound of silk effect etc.) with the twice of above-mentioned parameter.

Chitosan is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from soft palate injectable, should be no more than 100mg (scope of 1 μ g-100mg) by accumulated dose that send or that be applied to the chitosan on soft palate implant or the apparatus surface.In one embodiment, the total amount of d/d chitosan should be in the scope of 10 μ g-50mg.The dosage of the soft palate injectable thing of the per unit volume dosage of the chitosan of the function of the volume of injected material (that is, as) should be at 0.05 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to soft palate implant or apparatus surface with chitosan.Because the drug delivery vehicle of concrete (polymer and non-polymer) and concrete soft palate injectable thing, implant can discharge chitosan with different speed with device, above-mentioned administration parameter should with medicine from soft palate injectable thing, thereby the rate of release in implant or the device is used in combination and makes the chitosan of 0.01nM-1000 μ M Cmin be delivered to described tissue.In one embodiment, chitosan is from soft palate injectable thing, thereby implant or device discharge the fibre modification in promoting to organize in the scope period of a few hours to several months.For example, in preferred embodiments, chitosan can discharge the period that reaches 3-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active chitosan of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the chitosan effect with half of above-mentioned parameter, use half in chemical compound of chitosan effect etc.) with the twice of above-mentioned parameter.

Polylysine is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, the accumulated dose of sending in soft palate injectable or be applied to the polylysine on soft palate implant or the apparatus surface should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the total amount of d/d polylysine should be in the scope of 10 μ g-50mg.The dosage of the soft palate injectable thing of the per unit volume dosage of the polylysine of the function of the volume of injected material (that is, as) should be at 0.05 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to soft palate implant or apparatus surface with polylysine.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge polylysine with different speed with concrete palate injectable thing, implant and device, above-mentioned administration parameter should with medicine from soft palate injectable thing, thereby the device or the rate of release of implant are used in combination and make the polylysine of 0.01nM-1000 μ M Cmin be delivered to described tissue.In one embodiment, polylysine is from soft palate injectable thing, thereby implant or device discharge the fibre modification in promoting to organize in the scope period of a few hours to several months.For example, in preferred embodiments, polylysine can discharge the period that reaches 3-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active polylysine of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the polylysine effect with half of above-mentioned parameter, use half in chemical compound of polylysine effect etc.) with the twice of above-mentioned parameter.

Fibronectin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from soft palate injectable, should be no more than 100mg (scope of 1 μ g-100mg) by accumulated dose that send or that be applied to the fibronectin on soft palate implant or the apparatus surface.In one embodiment, the total amount of d/d fibronectin should be in the scope of 10 μ g-50mg.The dosage of the soft palate injectable thing of the per unit volume dosage of the fibronectin of the function of the volume of injected material (that is, as) should be at 0.05 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to soft palate implant or apparatus surface with fibronectin.Because the drug delivery vehicle of concrete (polymer and non-polymer) and concrete soft palate injectable thing, implant can discharge fibronectin with different speed with device, above-mentioned administration parameter should with medicine from soft palate injectable thing, thereby the rate of release of implant or device is used in combination and makes the fibronectin of 0.01nM-1000 μ M Cmin be delivered to described tissue.In one embodiment, fibronectin is from soft palate injectable thing, thereby implant or device discharge the fibre modification in promoting to organize in the scope period of a few hours to several months.For example, in a preferred embodiment, fibronectin can discharge the period that reaches 3-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active fibronectin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the fibronectin effect with half of above-mentioned parameter, use half in chemical compound of fibronectin effect etc.) with the twice of above-mentioned parameter.

Bleomycin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from soft palate injectable, should be no more than 100mg (scope of 0.01 μ g-100mg) by accumulated dose that send or that be applied to the bleomycin on soft palate implant or the apparatus surface.In one embodiment, the total amount of d/d bleomycin should be in the scope of 0.10 μ g-50mg.The dosage of the soft palate injectable thing of the per unit volume dosage of the bleomycin of the function of the volume of injected material (that is, as) should be at 0.005 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to soft palate implant or apparatus surface with bleomycin.Because the drug delivery vehicle of concrete (polymer and non-polymer) and concrete soft palate injectable thing, implant can discharge bleomycin with different speed with device, above-mentioned administration parameter should with medicine from soft palate injectable thing, thereby the bleomycin that the rate of release in implant or the device is used in combination the Cmin that makes 0.001nM-1000 μ M is delivered in the described tissue.In one embodiment, bleomycin is from soft palate injectable thing, thus the fibre modification of release in promoting to organize in the scope period of a few hours to several months in implant or the device.For example, in preferred embodiments, bleomycin can discharge the period that reaches 3-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active bleomycin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the bleomycin effect with half of above-mentioned parameter, use half in chemical compound of bleomycin effect etc.) with the twice of above-mentioned parameter.

CTGF is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from soft palate injectable, should be no more than 100mg (scope of 0.01 μ g-100mg) by accumulated dose that send or that be applied to the CTGF on soft palate implant or the apparatus surface.In one embodiment, the total amount of d/d CTGF should be in the scope of 0.10 μ g-50mg.The dosage of the soft palate injectable thing of per unit volume (that is, as the CTGF of the function of the volume of injected material dosage) should be at 0.005 μ g-10 μ g/mm ³Scope in.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to soft palate implant or apparatus surface with CTGF.Because the drug delivery vehicle of concrete (polymer and non-polymer) and concrete soft palate injectable thing, implant can discharge CTGF with different speed with apparatus surface, above-mentioned administration parameter should with medicine from soft palate injectable thing, thereby the CTGF that the rate of release in implant or the device is used in combination the Cmin that makes 0.001nM-1000 μ M is delivered in the described tissue.In one embodiment, CTGF is from soft palate injectable thing, thus the fibre modification of release in promoting to organize in the scope period of a few hours to several months in implant or the device.For example, in preferred embodiments, CTGF can discharge the period that reaches 3-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active CTGF of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the CTGF effect with half of above-mentioned parameter, use half in chemical compound of CTGF effect etc.) with the twice of above-mentioned parameter.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF in addition, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or bone morphogenetic protein (BMP) is (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant.Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, with bone morphogenetic protein (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant) be used in the preparation with concentration range from 0.001 μ g/ml to about 20mg/ml.Preferably, bone morphogenetic protein is discharged 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.001 μ g is to the scope of 500mg); Preferred 1 μ g is to 250mg.When being used as the device coating, dosage is 0.001 μ g-1000 μ g/mm of per unit area ²Preferred dosage is 0.01 μ g/mm ²-200 μ g/mm ²With 10 ^-9-10 ^-4The Cmin of the bone morphogenetic protein of M maintains on the apparatus surface.

According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of inflammatory cytokine from 0.0001 μ g/ml to about 20mg/ml is used in the preparation.Preferably, inflammatory cytokine discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 100mg); Preferred 0.001 μ g is to 50mg.When being used as the device coating, dosage is 0.0001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.001 μ g/mm ²-200 μ g/mm ²With 10 ^-10-10 ^-4The Cmin of the inflammatory cytokine of g/ml maintains on the apparatus surface.

In addition, described device can be separately or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA), and analog and derivant.Used dosage is to be proved to be those concentration (seeing that for example, embodiment 16) that stimulate cellular proliferation.According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of multiplication agent from 0.1ng/ml to 25mg/ml is used in the preparation.Preferably, multiplication agent discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 200mg); Preferred 0.001 μ g is to 100mg.When being used as the device coating, dosage is 0.00001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.0001 μ g/mm ²-200 μ g/mm ²With 10 ^-11-10 ^-6The Cmin of the multiplication agent of M maintains on the apparatus surface.

Should it will be apparent to one skilled in the art that aforementioned fibers degeneration derivant, any of or derivatives thereof and analog can be used to produce the variation of above-mentioned composition under the prerequisite that does not deviate from spirit and scope of the invention.Also should it is evident that described reagent can with or be not used in the compositions and change described carrier and do not depart from scope of the present invention with polymer support.

12. suppository and embolization device

On the one hand, the invention provides the combination that fibrous tissue forms agent and embolization device and aneurysm coil (coil).Thereby to embolization device design slow down or eliminate blood flow to tissue and can use it for the treatment multiple medical conditions, described disease comprises, but be not limited to, uncontrolled vascular hemorrhage (such as dysmenorrhea), the vascular aneurysm is (such as the breast aortic aneurysm, abdominal aortic aneurysm, the aneurysm of brain), benign tumor growth (such as leiomyoma of uterus), malignant growth (liver particularly, kidney with other solid tumor) and vascular malformation (AV deformity, vascular tumor).

Embolization device refer to be designed to be placed on patient's vascular system (typically tremulous pulse) thus in make blood pass through the mobile of the blood vessel part of the blood vessel in the situation (or in aneurysm) by most of or thoroughly inaccessible device.Thereby can insert suppository or device it is housed inside in the lumen of artery on health, has caused flowing to the interruption of the blood flow of tissue.Described suppository or device can also induction of vascular (or part of blood vessel) thus condense and make blood flow by grumeleuse (or combination of device and grumeleuse) obturation.In arbitrary situation, the blood supply in particular anatomical zone (for example, tumor, aneurysmal sack, vascular malformation) is reduced, or eliminates, and has caused the ischemic injury of defective (unwanted) tissue or thoroughly inaccessible.

The example of embolization device includes, but not limited to vascular coil, vascular occluding device, blood vessel tinsel, vascular peg stay plug device, vascular occluding device, little coil, injectable suppository, the suppository of polymerization rerum natura, suppository, vascular embolization implant, the suberification plug, distensible implant, prosthese and embolism microball body in the vascular plug, blood vessel.

On the one hand, described embolization device is blood vessel (blood vessel) occlusive device.Vascular occluding device can be inserted in the vascular system or some other by in the zone of obturation, such as fallopian tube and bile duct.Vascular occluding device can adopt various ways.For example, the original shape of blood vessel (blood vessel) locking device can exist with the form of coil (for example, vertical coil or spiral), is also referred to as vascular occlusion coil implant in this article.Perhaps, described vascular occlusion device can exist with (non-coiled) (that is non-perpendicular or non-helical shape) form of non-coiling.The representative shape example of non-coiling form vascular occlusion implant can be with fabric, randomly shaped implant, and spheroid form, avette, fibrous (seeing that for example U.S. Patent number 5,226,911), chain, flower shape, spheroid, linear and other non-helical shape form exists.The vascular occlusion device of helical form and non-helical shape can also have multiple second shape.The instantiation of the embolization device of embolic coil and other type is described in detail in the following part.

On the one hand, described vascular occlusion device can be distensible vascular occluding device.Distensible vascular occluding device can include material resilience force or shape memory, and when being exposed to or be heated to body temperature, described material will carry out self expandable from its configuration that works by the resilience force of himself or by the experience inversion of phases.Perhaps, such device can comprise the plastically deformable material, can be by exerting pressure or power compresses configuration with it from its radiation shape and is deformed into the configuration that it works.Perhaps, some in these devices can compress configuration from its radiation shape and be expanded to their configuration that works.The example of distensible embolization device is the chamber locking device, described device comprises blood vessel bonding part and the expansible chamber of radiation shape enclosure portion, work described device be anchored on the surrounding wall of blood vessel in described bonding part, the expansible chamber of described radiation shape enclosure portion works at least one direction, by the chamber prevention blood flow of blood vessel.(see, for example, U.S. Patent number 6,638,293).After implanting described device, the expansible part of radiation shape can be expanded the configuration for working, wherein Zhuan Zhi the blood vessel bonding part chamber enclosure portion that will engage blood vessel wall and described device with the chamber of sealing blood vessels at least one direction, to stop blood flow.

Unfortunately, in many situations, blood flow recovers (being called logical again process) in time, causes the treatment failure.This places the patient under the danger of consequence of disease potential threat life once more, and such as hemorrhage, aneurysm rupture, cerebral hemorrhage or tumor growth, described disease is treated with initial intervention.The treatment that occurs in some clinical scenarios is failed part because present obtainable reagent does not produce fibre modification (the real chamber cicatrization of permanent shape, wherein blood vessel wall sticks to each other and the inaccessible described blood vessel of nonvolatil fibrous tissue), caused the probability of logical again, restoration of blood flow and final palindromia.The invention describes the material (or implanted device) that the adding of fibre modification derivant is injected in the vascular system and produce purpose permanent, the occlusive cicatrix to satisfy in lumen of vessels (or aneurysmal sack), it has caused the degeneration and the absorption of defective blood vessel (or part of blood vessel).If blood flow since the occlusive fibre modification in blood vessel by permanent prevention, health can absorb non-functional vascular tissue and can eliminate blood vessel once more, the chance that makes recurrence seldom or do not have.

(i) with the aneurysm " coil " of fibre modification derivant combination

Vascular aneurysms is that it finally causes the projection (being called as aneurysm " capsule ") of blood vessel owing to the reduction of the focus of the part of arterial wall.Under the pressure of artery blood flow, the thin and weak wall of aneurysmal sack is in the risk of rupture that increases; Dangerous increase day by day with the increase of capsule size.Aneurysm rupture can have catastrophic consequence, and described consequence comprises subarachnoid hemorrhage, apoplexy, permanent neurological handicap and because cerebral aneurysm and dead and because the death of aortic aneurysm of bleeding profusely and causing.Depending on aneurysmal anatomy location, treat this disease, particularly be arranged in the surgical method (being known as aneurysm " montage ") of this disease of brain, may be breakneck or or even impossible.As operating alternative, developed the intervention of intrusion degree minimum, wherein can use embolization device that disruptive and uncracked aneurysm is treated.Can use the conduit and the tinsel that are advanced to the aneurysm zone from groin that embolization device is delivered to the aneurysm.Then, by conduit embolization device is inserted and is inserted in the aneurysm.In case in aneurysm, it occupies the space in the aneurysmal sack physically, induces the formation of grumeleuse, " filling " described aneurysmal sack, and stop artery blood flow to enter aneurysm and therefore further damage of prevention.Many implants that are used for being inserted into aneurysmal sack have been described and they are suitable for combination with the fibre modification derivant.One of common treatment method of cerebral aneurysm comprises blood vessel " coil " (that is aneurysm coil) is implanted in the aneurysmal sack.Described coil under radiology instructs, is advanced in the described capsule by delivery catheter, from delivery catheter, breaks away from (inducing by electric current in wire coil usually), and be released in the described capsule; Then repeat described method up to sufficient coil " packing " in the aneurysmal sack with thorough filling it.Although the obvious progress that obtains in aneurysm treatment, separable coil are not the limitations that does not have them.The complication relevant with these methods comprises be not intended to inaccessible (about 21% the frequency) of higher level's tremulous pulse, the persistent filling of lumen of artery (thoroughly not inaccessible), logical again (that is, after beginning successfully obturation, blood flow is got back in the aneurysm) with annual 2-5% ratio.Thoroughly inaccessible (occur in for little carotid aneurysm in 38% the case, occur in for wide carotid aneurysm in the case of 60-85%) and the consequence of leading to again are the danger of the increase that aneurysm can be hemorrhage again.Particularly, be considered to unsettled at the coil-thrombosis complex that begins to form after the successful use.Logical again can be that described compression and rearrangement have the tendency that is returned to their initial spiral forms (particularly when closely not wrapped up) owing to the compression of coil bundle and the rearrangement of individual coil loop.Tong clinical effectiveness is that the patient is in the danger of aneurysm rupture and hemorrhage (subarachnoid hemorrhage) again, and it is relevant with high incidence (50% survivor has tangible neurological handicap) with high mortality (25-50%).Relatively, think that the aneurysm of being entirely shut has low (or nothing) risk of bleeding again.The fibre modification derivant is added in the aneurysm coil and can also fill described capsule (stoping again logical) with nonvolatil scar tissue by the danger (stoping halfway obturation) that helps to reduce failure with fibrous tissue ballast coil-thrombosis complex.

Thereby multiple intra-arterial tumor coil can make up with the fibre modification derivant and satisfy purpose of the present invention.Should be to it is evident that the accurate physical form of described coil is not crucial for practice of the present invention to those skilled in the art, yet Shuo Ming mode illustrate the kind of design of many coils by way of example.On the one hand, described aneurysm coil can be made up of biocompatible metal alloy (for example, platinum or tungsten) and/or biodegradable or not biodegradable biocompatible polymer.On the one hand, provide aneurysm coil and tinsel, described coil and tinsel are made up of such as polymer biodegradable material, and described material is a flexibility (ductility is arranged) and strong.Described polymer can be expanded after use in size.The representative example that is used in the distensible polymer in aneurysm coil and the tinsel is crosslinked poly-(vinyl alcohol), crosslinked poly-(ethylene glycol), poly-(acrylic acid), poly-(hydroxyethyl meth acrylate), and copolymer and admixture.The degraded of the coil of polymerization rerum natura in a couple of days to several weeks after use has some advantages.For example, relative with the metallicity coil, the aneurysm coil of polymerization rerum natura can in use reduce the danger of aneurysm operation.Because described coil is not lasting, the probability that they are moved in the circulation of higher level's blood vessel also can be less.In addition, degradable coil can be incorporated in thrombosis-coil complex, has therefore reduced logical again incidence rate.

The vascular aneurysms coil can be coated or not coated, and/or can comprise other component (for example, chain, filament, mesh and/or other granule) along coil.On the one hand, aneurysm coil can be applied with or comprise non-thrombosis material (for example, heparin, antithrombase, antithrombase-heparin complex), described material stop device is final place before the formation thrombosis.Can depend on the time of using described matching requirements, thereby this temporary transient coating design is kept several minutes to a few hours.

Described aneurysm coil can be by porous, and flexible PTFE material is formed such as the PTFE (ePTFE) that extends.Described PTFE material can be taked various ways.For example, described material can be taked the form of thin chain or band and can strengthen with metallic bond or biodegradable chain.Described PTFE material can be applied with water-soluble polymer, and described polymer provide some rigidity being used to send purposes can also for described material, but at it from described material after the stripping, it is very flexible that described material becomes.Described material can be impregnated or coating form a kind of of agent or its combination and other bioactivator (for example, promoting the reagent of thrombosis or cell growth) with fibrous tissue, follow or do not follow the use of carrier.Use above-mentioned delivery system based on conduit, can be in aneurysm with described substance delivery.With suitable kind of design, described conduit can be sent the material of regular length the chain that continues that maybe can send described material, and described chain is cut into the size that needs by the cutter sweep at catheter tip.In a single day thereby described material enough approaches to make it have very much flexible and be used it and do not apply very significantly pressure on aneurysm wall.For the material of being sent by conduit that does not have structural strength, thin metallic bond can be incorporated in the material to produce more inflexible material.Described metallic bond can prepare certainly, for example rustless steel, titanium, platinum, gold, nickel, nitinol or other metal alloy.Biodegradable polymer chain can be replaced metallic bond.In case be used, described polymer chain can be degraded, and eliminates the probability of later stage aneurysm strage perforation thus.Polymer chain can prepare from, for example polyester (for example, PLGA, PLA, PCL, PGA, etc.), polyanhydride, poe, poly-phosphazine based on the polymer of tyrosine, polyamide (for example, protein is such as gelatin), carbohydrate, polysaccharide and admixture thereof.Can be by they being passed described material or by their layerings are incorporated into described link in the described material being fused in the described material between described material two-layer or by heat.Described chain can also by nondegradable polymer such as, for example, polyurethane, siloxanes, PE, PP, polyacrylate or, polyamide polymer, or based on the polymer manufacture of vinyl based on the polymer of poly-(methacrylate).Can also make it have more rigidity by making in the core that polymer is added described material.This polymer can be water miscible or water-insoluble and can be biodegradable or nondegradable.Water miscible, the example of nondegradable polymer is PEG.Polymer such as DTE based on tyrosine is the example of insoluble polymer, and it has relatively short degradation time.Hole by filling porous property PTFE can polymer be provided provide to a certain degree structural rigidity to be used for use, but after use, it will can not degraded or stripping fast, thereby make described material will return to its flexible state and can more closely be packaged in the aneurysmal sack.

It maybe can be biologically inert that described blood vessel coil can be made up of bioactive ingredients.Because the blood vessel coil can be delivered to described vascular site by microtubular, they can be designed to have elementary phase with mutually secondary.The blood vessel coil can be characterized by different shapes or configuration, compositions, physical state and/or bioactive level mutually.Typically, the state (that is secondary phase) after these are illustrated in the state (being elementary phase) that inserts preceding blood vessel coil mutually and follow the insertion of blood vessel coil.For example, can be to have the device that the external helicoid of the polymer filament that stretches resistance twines with the blood vessel coil design, wherein form secondary shape and with heat treatment to keep this shape.See U.S.6 for example, 193,728.The blood vessel coil can be designed to have the configuration of spiraling when being stretched and having linear helical configuration when folding when loosening.See U.S.4 for example, 994,069.Described blood vessel coil can be made up of coil flexible, that spiral twines, and the coil that described spiral twines has two primary coil ends and initial diameter, and it comprises at least two vertical focal axis in the secondary configuration that loosens.See U.S.5 for example, 639,277.Described blood vessel coil can have the fibre element that adheres to, and described element extends in hole shape mode and therefore, produces multiple secondary shape along the length of coil.See U.S.5 for example, 304,194.Described blood vessel coil can be a wire coil, and described wire coil has one or more fibre bundles with serpentine configuration, and wherein said ring extends around the individual pen of described coil.See that for example, US 5,226,911.Described embolization device (for example, the blood vessel coil) can form by the spiral winding with a plurality of windings (winding) and the bolt of thermoplastic biocompatible polymer, the adopted tube chamber of described delineation, described bolt is positioned in the space of described tube chamber at the two ends of coil.See U.S.5 for example, 690,667.Described blood vessel coil can be made up of the spiral winding that is elongated of biocompatibility metal, and described coil has the winding of a plurality of axial spacings and a plurality ofly extends axially polymer by described coil, bioactive, the chain that causes inaccessible material.See, for example, U.S.5,658,308.Described embolization device can be distensible supporting element and the thromboembolism element that is placed on the supporting element, described supporting element has the swelling state that loosens and the contraction state of tension, described thromboembolism element (for example, polymer mesh) works in fact the prevention blood flow.See U.S.6 for example, 554,849.Described embolization device can be by being elongated, flexible thread carrier and form with the thromboembolism element that distensible polymer form (for example, the porous hydrogel) exists, and described thromboembolism element is fixed in described carrier.See U.S.6 for example, 602,261.Described blood vessel coil can comprise the positive charge that promotes thromboembolism, electric current, or magnetic field on coil.See, for example, U.S.5,122,136,6,066,133 and 6,603,994.The coil of other vascular group is described in, and for example U.S. Patent number 5,133, and 731; 5,312,415; 5,354,294; 5,382,259; 5,382,260; 5,417,708; 5,423,849; 5,476,472; 5,578,074; 5,582,619; 5,624,461; In 5,645,558 and 5,718,711.

Can make up with one or more aneurysm coils and comprise some commercially available products according to fibre modification derivant of the present invention.For example, GDC (GUGLIELMI DETACHABLE COIL) and MATRIX detachable coil (from Boston Scientific Corporation) are useful especially for the practice of the present embodiment.MICROPLEX and HYDROCOIL Coil System are (from MicroVention, Inc., Aliso Viejo, CA), from Cook Diagnostic andInterventional Products (Bloomington, IN) TORNADO EmbolizationMicrocoils, from Micrus Corp. (Sunnyvale, CA) HELIPAQ spiral and the spherical coil of MICRUSPHERE, from Target Therapeutics, and Inc. (Fremont, CA)/GDC Coils 2D and the 3D of Boston Scientific Corporation, with from CordisCorporation (Miami Lakes, FL)/Johnson ﹠amp; The TRUFILL PushableCoils of Johnson also is fit to.

Some Injectable polymer systems that are used for being expelled to aneurysmal sack and suppository have been described carrying out the aneurysmal treatment of brain and breast.With these blood vessels " filler " further describe below part (ii) in.In the treatment aneurysm, blood vessel polymerization rerum natura implant can be made up with the fibre modification derivant to be used for purpose of the present invention.Should be it is evident that to those skilled in the art, the composition of polymerization rerum natura aneurysm graft be the key that the present invention puts into practice.

Above-mentioned many polymerization rerum naturas and non-polymeric rerum natura carrier system can be used for sending the fibre modification derivant from implantable aneurysm treatment methods such as coil and polymerization rerum natura implant.Induce compositions to be attached on aneurysm coil and the implant fibre modification or among method comprise: (a) directly will become fiber composition to be attached to described aneurysm coil or implant and (for example, comprise in the solution of activating agent by being sprayed in the surface of described implant or described implant being immersed; Described reagent can be used separately or with polymer support); (b) (for example directly will become fiber composition to be attached to form in the component of aneurysm coil or implant or the polymer, by with not with the nebulization of carrier or immersion method-for having component of polymer such as above-mentioned coating, the coil of mesh and hydrogel is effective especially); (c) by being coated with described aneurysm coil or implant such as the hydrogel that can absorb into fiber composition again with material; Thereby described hydrogel can also swelling be filled described aneurysmal sack better; (d) by weaving or be attached in the structure of aneurysm coil or implant with " line " (or special in the situation of silk by its line of forming) that fibrous tissue forms agent coating; Described line can be again side chain or " bifurcated " to increase surface area; (e) by aneurysm coil or implant are inserted in sleeve pipe or the mesh, described sleeve pipe or mesh are made up of the one-tenth fiber composition or are coated with by it; (f) use the part (for the polymeric medicine compositions, silk and EVA are especially effectively-for example, thereby produce silk and/or EVA aneurysm coil) that makes up aneurysm coil or implant itself or described coil or implant into fiber composition; This can have the additional benefit of generation " flexible coil ", and described flexible coil can not be by by the perforation of the aneurysm wall that weakened (the aneurysm perforation that wire coil causes occurs in 5% the case); Described flexible coil can further be coated with hard polymer surfaces (so that rigidity in use to be provided), and described polymer surfaces rapidly disappears after use to stay flexible coil; In an especially preferred embodiment, aneurysm coil is made up of to increase surface area silk and/or EVA main chain (can exist the side chain on the side chain, that is, polybasic bifurcated), wherein said EVA main chain has the silk of multiple " side chain " and/or by its EVA that sends; Or (g) by fibrous tissue being formed surface or the joint (micromolecule or polymer) that agent directly is covalently bound to aneurysm coil or implant, described joint is applied or be attached to described surface.For aneurysm coil and implant, can carry out described coating process by this way, described mode is: (a) outer surface of the described device of coating; (b) inner surface of the described device of coating, (c) the outer and inner surface of the described device of coating is all or part of, or (d) (for example with non-formation thrombosis material, heparin, antithrombase, multiple and the thing of antithrombase-heparin) be coated with described coil, described non-formation thrombosis material stops thrombosis to form before the final arrangement of device and then disappears to allow that thrombosis takes place.Except with becoming fiber composition coating aneurysm coil or the implant, thereby described activating agent can mix and makes fibrous tissue form agent with the material that is used for preparing coil or implant to be attached to final implant.

In one embodiment, described aneurysm coil can comprise starch (for example, cereal starch or corn starch).Described starch material can be attached in the described device as coating and/or combination to be attached to the polymer line (for example, silk) in the aneurysm coil.Can starch or the compositions that comprises starch be applied on the described device by starch powder being applied directly to apparatus surface.Perhaps, can use solvent method or pressing method that starch is put on described device.Whole device or the part of only installing can be applied with starch.For example, starch can be made solution (for example), it can be coated on the outer surface of described device by placing autoclave to reach 45 minutes 5% aqueous solution.Thereby then removing described solvent stays starch and is coated on the described device.In another method, described starch can be attached to (for example, degradable or nondegradable polymer, wax, lipid, wet goods) in the secondary carrier, described secondary carrier can be by randomly crosslinked.Described secondary carrier (for example, polymer) can be coated on the described device.On the other hand, described starch can be attached to nondegradable polymer (for example, silk or DACRON) or biodegradable polymer (for example, PLGA) among or on, then with described polymer-coated to described device.When depolymerization, the tissue around starch is released in, it causes required biologically in described tissue.Perhaps, or in addition, described starch can be attached to the material that is used for preparation facilities.

Described aneurysm coil can comprise polymer line, thereby makes the existence of polymer line cause replying at the cell and the extracellular matrix of the outside increase of device.Described polymer line can prepare any polymer from cell that causes increasing and/or fibre modification reaction.For example, described line can be the biocompatible polymer (for example, starch) of silk suture material or another kind of type, the applied polymer with the cell response that causes increasing of described line.Described polymer line can be attached to the aneurysm coil of various configurations, and this can cause partially or completely the covering to the aneurysm coil outside.Any combination of said method can be used in the practice of the present embodiment.

Use any suitable method, for example gluing, thermal weld, roll extrusion, parcel, woven, any combination of knotting or these methods can be attached to described aneurysm coil with the line that comprises fibrous tissue formation agent.

Described line can be coated with material, and described material delays the time that the line material contacts with surrounding tissue.This allows the placement of described device and need not consider the caused thrombosis incident of polymer line.Coating can be from degradable material, the in a single day implanted i.e. dissolving of described material (for example, gelatin, polyester, such as PLGA, PLA, MePEG-PLGA, PLGA-PEG-PLGA and copolymer thereof and admixture, lipid, fatty acid, sugar ester, the nucleic acid ester, polyanhydride, poe, PVA etc.).These coatings can comprise the fibre modification derivant and/or reduce the reagent of the probability of thrombosed incident (for example, heparin and heparin derivatives are such as hydrophobic quaternary amine heparin complex) immediately.

Should it is evident that to those skilled in the art potentially, can any of fibre modification derivant is independent, or be combined and used in the practice of the present embodiment.The exemplary fibers texturizer that is used in combination with aneurysm coil and implant comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF and above-mentioned analog and derivant.These can further make up with other reagent such as sclerosing agent (sodium morrhuate, ethamolin (ester), ethanol, DMSO, surfactant, sucrose, NaCl, dextrose, glycerol, minocycline, tetracycline, doxycycline, Polidocanol, sodium tetradecyl sulfate, sodium morrhuate, Sotradecol) and/or somatomedin (transforming growth factor, platelet-derived somatomedin, fibroblast growth factor and bone morphogenetic protein) thus further improve effect.

Randomly, described device can comprise inflammatory cytokine (for example, TGF β, PDGF in addition, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or bone morphogenetic protein (BMP) is (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant).

In addition, described device can be separately or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, all-trans retinoic acid (ATRA), and analog and derivant.

The suppository that (ii) comprises the fibre modification derivant

The thromboembolism product is used to reduce or eliminate blood flows to certain organs or tissue.Typically, with they be used for the treatment of hemorrhage (for example, thereby the thromboembolism uterine artery is treated serious hemorrhage), benign tumor growth (for example, leiomyoma of uterus thromboembolism), malignant growth (liver tumor, renal cell carcinoma, solid tumor), varicoseals, or treat unusual vascular structure (artery-vein deformity, vascular tumor).Traditionally, carry out described program by following: conduit is inserted vascular system (normally femoral artery), thereby under the lonizing radiation guiding it being advanced to tremulous pulse makes tissue by thromboembolism, on guide wire, advance delivery catheter, and granule/microsphere/gel delivery delivered in the lumen of vessels, described granule/microsphere/gel is propagated in blood flow up to them and is arrived downstream blood vessel (its relative aperture embolic particles littler).This has hindered blood and has flow to target tissue, makes described target tissue deficiency of oxigen and nutritional labeling, cause ischemia and, in some cases, cause tissue necrosis and death.

Manyly be used for the granule of intravascular injection as suppository, microsphere and Injectable polymer system have been carried out to be described and they are suitable for combination with the fibre modification derivant.Although, in inaccessible blood flow, obtained initial success, many suppositories can be kept their effect, because by logical again (that is, after the successful obturation originally, by the restoration of blood flow of tremulous pulse) of treatment blood vessel.As logical again consequence, existence can be recurred hemorrhage and the danger recoverable increase of tumor growth.Relative therewith, think that the blood vessel of thorough obturation has the hemorrhage again of low (or nothing) and forces tumor cell to raise the danger of neovasculature to tissue.The fibre modification derivant added to can help in the suppository to reduce the danger of failure by fill lumen of artery (stoping again logical) with permanent scar tissue.If because the occlusive fibre modification, blood flow longer period by obturation, blood vessel is degenerated, health absorbs the vascular tissue that does not have function again, described blood vessel is eliminated and the danger of recurring is reduced.

Can make up with one or more suppositories and comprise that some are purchased product according to fibre modification derivant of the present invention.For example, and TRUFILL n-Butyl Cyanoacrylate (n-BCA) LiquidEmbolic System (Cordis, a division of Johnson and Johnson, Miami, FL); EMBOSPHERE Microspheres and EMBOGOLD Microspheres (Biosphere, Rockland, MA); (Micro Therapeutics, Irvine CA) are the polymer plug system that is suitable for making up with the fibre modification derivant with ONYX Liquid Embolic System.The example of the embolization device that other is fit to comprises the polymer/solvent systems that comprises the fibre modification derivant, in case wherein it is injected into the treatment site, described solvent from the polymeric matrix diffusion (for example, degradable polymer system from Atrix, nondegradable polymer composition such as ONYX and EMBOLYX and original position form material such as can be from Biocure, Angiotech Pharmaceuticals, Inc., those of 3M Companyand Neomend acquisition).Can load with the fibre modification derivant or with the commercially available suppository of other type of its making and comprise PVA granule (Cook, Inc.and Angiodynamics, Inc.) and microspheres preparation (for example, from Biosphere, Inc. EMBOSPHERE is from the Contour SE of BostonScientific with from the BEAD BLOCK of Biocompatibles).

Many other vascular occluding devices can make up with the fibre modification derivant.Described embolization device can be made up of distensible implant or bolt, and described implant or bolt are directed in the vascular site and are separated in desired location.For example, described distensible implant can be the capsule of being sent by catheter in blood vessel, and when described capsule was expanded, it served as the thromboembolism element.See U.S.4 for example, 819,637.Described distensible blood vessel implant can be made up of the hydrogel stent, and the use microtubular is directed to vascular site with described hydrogel stent and its hydration is also expanded up to its inaccessible described blood vessel.See U.S.5 for example, 258,042.Expansion is with the foam of polymers (for example, polyvinyl alcohol, polyurethane foam or polyethylene) of induction of vascular obturation behind the contact blood flow, and ball or granule also are suitable for combination with fibre modification derivant (seeing U.S.5 for example, 823,198).The another kind of expandable implant that is fit to is made up of multiple expansible thromboembolism element and the thread carrier that is elongated that (flexible material by the elastic memory shape forms ring structure, thus from discharging described element along the space interval that encircles; See U.S.6 for example, 238,403).

The injectable liquids suppository that changes their physical property (for example, curing and/or expansion) in response to heating, enzymatic reaction and/or chemical polymerization can make up with the fibre modification derivant.Can also use injectable suppository, described suppository is the Emulsion of granule or microsphere and has the concretion of blood constituent and/or each other in the combination of vascular site.For example, described suppository can be by the cellulose diacetate polymer, and biocompatible solvent and the contrast agent that is insoluble in water are formed, and it is in case sent, and described solvent dispersion is in blood flow and stay the gel that remaining composition forms the described blood vessel of thromboembolism.See U.S.5 for example, 580,568.The another kind of suppository that is fit to is by polymer and solvent composition, described suppository when body temperature be liquid and at non-particulate reagent (for example, blood vessel coil) in-situ precipitate becomes solid when existing.See U.S.6 for example, 017,977.The another kind of suppository that is fit to is made up of thermosensitive polymer, and described polymer is sent as aqueous solution when certain temperature (that is, being higher or lower than body temperature), and when reaching (or being cooled to) body temperature in heating, it forms solid.See U.S.5 for example, 525,334.The another kind of liquid embolizing agent that is fit to be Emulsion (by at the bottom of the aqueous base and liquid oil forms), when heating, enzymatic reaction or chemical polymerization, the substrate that described Emulsion formation can not be water-soluble.See U.S.5 for example, 894,022.Described suppository can also be injectable microsphere solution, and described solution is made up of the copolymer of cytoadherence promoter coating.See US.5 for example, 648,100.Will be as the other substance description of injectable liquids suppository at U.S.4, in 551,132 and 4,795,741.

On the one hand, the invention provides direct combination, or combination forms the suppository of compositions (for example, the carrier of polymer or non-polymer) of agent to be used for the purpose of permanent occlusion's blood vessel to comprise fibrous tissue with the fibre modification derivant.Can come to send the fibre modification derivant in some modes with suppository, described mode comprises: (a) fluid, suspension, Emulsion, microemulsion, microsphere, paste, gel, microparticulates, spray, aerosol, solid implant and other discharge the preparation (see above-mentioned those) of fibre modification derivant; (b) microgranule silk and/or silk chain (linear, side chain and/or curling), it is independent, or loading is injected with additional fibers degeneration derivant (or embolization material) and as suppository; (c) form from fibrous tissue form the polymer formulations of agent gel, microsphere or microgranule (for example, polymeric medicine such as describe by Polymerix Corporation those); (d) with or not with polymer support, the fibre modification derivant is applied on microsphere or the microparticle surfaces; (e) the fibre modification derivant is loaded into the liquid embolic system (seeing above-mentioned) of one or more phases; (f) send described fibre modification derivant (that is, as to by the infusion in the tissue for the treatment of) with thromboembolism method combination (before the thromboembolism method, among or afterwards) at aqueous phase; (g) embolizing compositions that forms for original position can directly be attached to (for example, silk powder in the preparation as suspension or solution with the fibre modification derivant, bleomycin), or be loaded into secondary carrier (for example, micelle, liposome, microsphere, microgranule, nanometer spheroid, micriparticulates, Emulsion and/or microemulsion) in, described secondary carrier then is incorporated in the compositions of original position formation; (h) the fibre modification derivant can be attached to statically or covalently in one or more component of polymer of the embolizing compositions that original position forms; And/or (i) described fibrous tissue forms agent and can mix to be used for the material of manufacturing installation, is attached in the suppository in production process (for example, the silk powder can be added into as reagent in the process of producing microsphere) thereby fibrous tissue is formed agent.

Tackling in those skilled in the art is to it is evident that potentially, above-mentioned any fibre modification derivant can be used alone or in combination in the practice of the present embodiment.The exemplary fibrous tissue formation agent that is used in embolization device and the compositions comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF and above-mentioned analog and derivant.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF in addition, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or bone morphogenetic protein (BMP) is (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant).

In addition, described device can be separately or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, all-trans retinoic acid (ATRA), and analog and derivant.

In some clinical scenarios, may need the duplicate injection of activating agent.Can be used in concrete reagent in aneurysm coil and the implant and dosage be described in detail in following part (iii) in.

(iii) be used in the reagent in thromboembolism reagent and the aneurysm coil

Because thromboembolism reagent and aneurysm treatment device are made with multiple configuration and size, the exact dose of using can be with implant or device size, surface area and kind of design and change.Yet, some principle can be applied in the application of this area.Can be the function of per unit area (part of applied embolization material or aneurysm device) dosage with medication dose calculation, can measure the total drug dose of using, and can determine the suitable surface concentration of active medicine.No matter to thromboembolism or the employed method of aneurysm device how medicament administration, the exemplary fibers texturizer that is used alone or in combination should use under following administration is instructed:

Talcum is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, should be no more than 100mg (scope of 1 μ g-100mg) from thromboembolism reagent or aneurysm device lip-deep steatitic accumulated dose that send or that be applied to thromboembolism or aneurysm device.In one embodiment, should be in the scope of 10 μ g-50mg from thromboembolism reagent or the d/d steatitic total amount of aneurysm coil.The dosage of the per unit area of thromboembolism reagent or aneurysm device (that is, be applied as medicine and/or the steatitic dosage of the function of the surface area of the part of bonded implant or device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to thromboembolism reagent or aneurysm apparatus surface with Talcum.In one embodiment, thus Talcum discharges from the surface of thromboembolism or aneurysm device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, Talcum can discharge the period that reaches 1-9 month scope with valid density.What consider that discussion provided herein it should be obvious that is to be used for purpose of the present invention with having active steatitic analog of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the Talcum effect with half of above-mentioned parameter, use half in chemical compound of Talcum effect etc.) with the twice of above-mentioned parameter.

Silk is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, should be no more than 100mg (scope of 1 μ g-100mg) from the accumulated dose of thromboembolism reagent or the lip-deep silk that the aneurysm device is sent or be applied to suppository or aneurysm device.In one embodiment, the total amount of the silk that discharges from suppository or aneurysm coil should be in the scope of 10 μ g-50mg.The dosage of the per unit area of described implant or device (that is, be applied as medicine and/or the dosage of the silk of the function of the surface area of the part of bonded device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to thromboembolism or aneurysm apparatus surface with silk.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge silk with concrete suppository with different speed with the aneurysm device, thereby above-mentioned administration parameter should be delivered to the described tissue from the silk that the rate of release of thromboembolism or aneurysm device is used in combination the Cmin that makes 0.01nM-1000 μ M with medicine.In one embodiment, thus silk discharges from the surface of thromboembolism or aneurysm device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, silk can discharge the period that reaches 1-9 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active silk of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles an effect with half of above-mentioned parameter, use half in chemical compound of silk effect etc.) with the twice of above-mentioned parameter.

Chitosan is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, should be no more than 100mg (scope of 1 μ g-100mg) from suppository or aneurysm device accumulated dose that send or that be applied to the lip-deep chitosan of suppository or aneurysm device.In one embodiment, the total amount of the chitosan that discharges from suppository or aneurysm coil should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the chitosan of the function of the surface area of the part of bonded implant or device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to thromboembolism or aneurysm apparatus surface with chitosan.Because the drug delivery vehicle of concrete (polymer and non-polymer) and concrete implant and device can be with different speed release chitosans, thereby above-mentioned administration parameter should be used in combination from the rate of release of thromboembolism or aneurysm device with medicine the chitosan of 0.01nM-1000 μ M Cmin is delivered to the described tissue.In one embodiment, thus chitosan discharges from the surface of thromboembolism or aneurysm device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, chitosan can discharge the period that reaches 1-9 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active chitosan of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the chitosan effect with half of above-mentioned parameter, use half in chemical compound of chitosan effect etc.) with the twice of above-mentioned parameter.

Polylysine is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, should be no more than 100mg (scope of 1 μ g-100mg) from suppository or aneurysm device accumulated dose that send or that be applied to the lip-deep polylysine of suppository or aneurysm device.In one embodiment, the total amount of the polylysine that discharges from suppository or aneurysm coil should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the polylysine of the function of the surface area of the part of bonded implant or device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to thromboembolism or aneurysm apparatus surface with polylysine.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge polylysine with concrete suppository with different speed with the aneurysm device, thereby above-mentioned administration parameter should be used in combination from the rate of release of thromboembolism or aneurysm device with medicine and makes the polylysine of 0.01nM-1000 μ M Cmin be delivered to described tissue.In one embodiment, thus polylysine discharges from the surface of thromboembolism or aneurysm device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, polylysine can discharge the period that reaches 1-9 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active polylysine of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the polylysine effect with half of above-mentioned parameter, use half in chemical compound of polylysine effect etc.) with the twice of above-mentioned parameter.

Fibronectin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, should be no more than 100mg (scope of 1 μ g-100mg) from suppository or aneurysm device accumulated dose that send or that be applied to the lip-deep fibronectin of thromboembolism or aneurysm device.In one embodiment, the total amount of the fibronectin that discharges from suppository or aneurysm coil should be in the scope of 10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the fibronectin of the function of the surface area of the part of bonded implant or device) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to suppository or aneurysm apparatus surface with Talcum.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge fibronectin with concrete suppository with different speed with the aneurysm device, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from thromboembolism or aneurysm device the fibronectin of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, thus fibronectin discharges from the surface of suppository or aneurysm device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, fibronectin can discharge the period that reaches 1-9 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active fibronectin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the fibronectin effect with half of above-mentioned parameter, use half in chemical compound of fibronectin effect etc.) with the twice of above-mentioned parameter.

Bleomycin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, should be no more than 100mg (scope of 0.01 μ g-100mg) from suppository or aneurysm device accumulated dose that send or that be applied to the lip-deep bleomycin of suppository or aneurysm device.In one embodiment, the total amount of the bleomycin that discharges from suppository or aneurysm coil should be in the scope of 0.10 μ g-50mg.The dosage of the per unit area of device (that is, be applied as medicine and/or the dosage of the bleomycin of the function of the surface area of the part of bonded implant or device) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to suppository or aneurysm apparatus surface with bleomycin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge bleomycin with concrete suppository with different speed with the aneurysm device, thereby above-mentioned administration parameter should be delivered in the described tissue with the bleomycin that the rate of release of medicine from thromboembolism or aneurysm device is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, thus bleomycin discharges from the surface of thromboembolism or aneurysm device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, bleomycin can discharge the period that reaches 1-9 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active bleomycin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the bleomycin effect with half of above-mentioned parameter, use half in chemical compound of bleomycin effect etc.) with the twice of above-mentioned parameter.

CTGF is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, should be no more than 100mg (scope of 0.01 μ g-100mg) from suppository or aneurysm device accumulated dose that send or that be applied to the lip-deep CTGF of thromboembolism or aneurysm device.In one embodiment, the total amount of the CTGF that discharges from suppository or aneurysm coil should be in the scope of 0.10 μ g-50mg.The dosage of the per unit area of implant or device (that is, be applied as medicine and/or the dosage of the CTGF of the function of the surface area of the part of bonded device) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to suppository or aneurysm apparatus surface with CTGF.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge CTGF with concrete suppository with different speed with the aneurysm device, thereby above-mentioned administration parameter should be delivered to described tissue with the CTGF that the rate of release of medicine from suppository or aneurysm device is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, thus CTGF discharges from the surface of suppository or aneurysm device and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, CTGF can discharge the period that reaches 1-9 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active CTGF of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the CTGF effect with half of above-mentioned parameter, use half in chemical compound of CTGF effect etc.) with the twice of above-mentioned parameter.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF in addition, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or bone morphogenetic protein (BMP) is (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant).

Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, with bone morphogenetic protein (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant) be used in the preparation with concentration range from 0.001 μ g/ml to about 20mg/ml.Preferably, bone morphogenetic protein discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.001 μ g is to the scope of 500mg); Preferred 1 μ g is to 250mg.When being used as the device coating, dosage is 0.001 μ g-1000 μ g/mm of per unit area ²Preferred dosage is 0.01 μ g/mm ²-200 μ g/mm ²With 10 ^-9-10 ^-4The Cmin of the bone morphogenetic protein of M maintains on the apparatus surface.

Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of inflammatory cytokine from 0.0001 μ g/ml to about 20mg/ml is used in the preparation.Preferably, inflammatory cytokine discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 100mg); Preferred 0.001 μ g is to 50mg.When being used as the device coating, dosage is 0.0001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.001 μ g/mm ²-200 μ g/mm ²With 10 ^-10-10 ^-4The Cmin of the inflammatory cytokine of g/ml maintains on the apparatus surface.

In addition, described device can be separately or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA), and analog and derivant.Used dosage is to be proved to be those concentration (embodiment 16) that stimulate cellular proliferation.Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of multiplication agent from 0.01ng/ml to 25mg/ml is used in the preparation.Preferably, multiplication agent discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 200mg); Preferred 0.001 μ g is to 100mg.When being used as the device coating, dosage is 0.00001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.0001 μ g/mm ²-200 μ g/mm ²With 10 ^-11-10 ^-6The Cmin of the multiplication agent of M maintains on the apparatus surface.

Should be that it is evident that can be with aforementioned fibers degeneration derivant for those skilled in the art, any of or derivatives thereof and analog be used to produce the variation of above-mentioned composition under the situation that does not deviate from spirit and scope of the invention.Also should it is evident that described reagent can be used in the compositions that has or do not have polymer support and change described carrier and not deviate from scope of the present invention.

13. lung sealant

The invention provides compositions and device subtracts to hold in the surgical operation (lungreduction surgery) at open or endoscope type lung and is used as the lung sealant.Lung is in the air leaks of treatment operation back lung with the initial clinical practice of sealant.If air can leak into many spaces from lung by the aperture that produces in surgical procedures, it can strengthen, and exerts pressure on lung, and stops lung fully expansion in breathing process.This has stoped normal ventilation to take place, and if serious, can produce condition, need promptly exhaust apparatus be placed plura by the breast pipe is inserted and enters to come in the airbag through rib.For example, the air leaks that continues is a recurrent complication and can cause severe complications after pulmonary carcinoma or emophysematous open or endoscope's pulmonary resection, and such as empyema, the breast pipe inserts and the time of hospitalization prolongation.Thereby developed dissimilar surgical sealants with air leaks after being used to be administered to the prevention of lung surface or reducing operation.With the fibre modification derivant add to can induce in the lung sealant stable, the formation of fibre modification cicatrix, the wall surface that is formed on surgical site sealed-for-life lung of described cicatrix (if or subtract to hold in the surgical procedures at lung and sent with endoscope, the vesicle surface of lung), reduce hospital stays and stop the recurrence of air leaks.Clinically, fibre modification can be induced the lung sealant to be used to improve open pneumochirurgia operation, subtract at the endoscope type lung of emophysematous (serious COPD) and to hold operating effect, be used for the esophagus seepage after splanchnoscopy or the excision, treat the complication of other intrathoracic malignant tumor, leural effusion, hemothorax, pneumothorax, chylothorax, the complication and the phthisical result that suck.

When being used for this paper, term " sealant " refers to reduce or stop the material of fluid or air (for example, many spaces) middle migration from a tissue cavity (for example lung) to another tissue cavity.Sealant carries out the in-situ locally polymerization subsequently and forms typically by precursor molecule is administered to tissue.When being applied between them and then carrying out polymerization, or when using and being embedded between the tissue simultaneously, identical sealant material can also be used for together tissue " gluing ".Usually, surgical sealants is absorbable material, and described material is mainly used in the inner hemorrhage and seal tissue (thereby stoping seepage) of control.

Thereby send sealant material sealant material used in this invention and unit describe for example, U.S. Patent number 6,624,245; 6,534,591; 6,495,127; 6,482,179; 6,458,889; 6,323,278; 6,312,725; 6,280,727; 6,277,394; 6,166,130; 6,110,484; 6,096,309; 6,051,648; With 5,874,500; 6,063,061; 5,895,412; In 5,900,245 and 6,379,373.Can increase the performance of these materials by adding the fibre modification derivant.

On the one hand, the invention provides the lung sealant that comprises the fibre modification derivant.The carrier system of above-mentioned many polymer and non-polymer can be used in the practice of the present embodiment.Thereby these compositionss can also comprise the formation that one or more fibre modification derivants promote granulation tissue.An examples preparation of the sealant that is fit to is from 4-arm mercaptan PEG (10K), and 4-arm NHS PEG (10K) and methylated collagen protein are such as above-mentioned.Be suitable for making up with one or more commercially available sealants and comprise: COSEAL according to fibre modification derivant of the present invention; FLOSEAL; SPRAYGEL or its variant; And FOCALSEAL.

In one aspect of the invention, can will become fiber (cicatrization) agent to be included in the polymerization rerum natura sealant spray, thereby described spray film-forming or coating promote fibre modification and sealing air seepage.On the other hand, can in open and endoscope type LD method, induce the lung sealant to be used to seal alveolar sprayable fibre modification.In another embodiment, described spray comprises and comprises organizing mucoadhesive polymers and can preparing from microsphere of fibre modification derivant.

For sprayable original position forms compositions, produce suspension or solution (for example, silk powder in the preparation thereby the fibre modification derivant directly can be attached to, bleomycin), or they can be incorporated into secondary carrier (for example, micelle, liposome, microsphere, microparticle, nanometer spheroid, microparticulates, Emulsion and/or microemulsion) in, described secondary carrier then is incorporated in the compositions of original position formation.

In another embodiment, described fibre modification derivant can be statically or covalently is attached in one or more component of polymer of original position formation compositions.

In another embodiment, can be attached to (for example, hyaluronic acid, PLURONIC F127, polyester-PEG-polyester (for example, PLGA-PEG-PLGA)) in gel or the hot gel with the direct combination of fibre modification derivant or by secondary carrier.Can before or after the using of lung sealant, these gels then be administered to the treatment site.

In another embodiment, the fibre modification derivant can be attached in the biodegradable or soluble film (or mesh) that is applied to lung subsequently.Then, the composition spray that original position can be formed seals lung and thus to the film (or mesh) on required lung surface to film.In the variation of these embodiments, can be before the biodegradable film that will comprise the fibre modification derivant or mesh be applied to area for treatment, the sealant of original position is administered to lung.The exemplary material that is used to prepare these films or mesh is hyaluronic acid (crosslinked or noncrosslinking), cellulose derivative (for example, hydroxypropyl cellulose) and crosslinked poly-(ethylene glycol).

Should it is evident that to those skilled in the art, above-mentioned any binding agent or fibre modification derivant can be used alone or in combination in the practice of the present embodiment potentially.The exemplary fibers texturizer that is used in the lung sealant comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin, and CTGF, and aforesaid analog and derivant.

Because the lung sealant is made in a variety of forms, the exact dose of using can change with form.Yet, some principle can be applied in the application of this area.Can be the function of per unit area dosage (amount of the sealant that is applied) with medication dose calculation, can measure the total drug dose of using, and can determine the suitable surface concentration of active medicine.No matter how medicine is attached in the lung sealant employed method, the exemplary fibers texturizer that is used alone or in combination should use under following administration is instructed:

As exemplary fibers degeneration derivant, the lip-deep steatitic accumulated dose of being sent from the lung sealant or be applied to lung should be no more than 100mg (scope of 1 μ g-100mg) with Talcum.In one embodiment, the steatitic accumulated dose that discharges from sealant should be in the scope of 10 μ g-50mg.The dosage of per unit area (that is the steatitic dosage of the function of the surface area of the lung that is applied to as medicine) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the lung surface with Talcum.In one embodiment, thus Talcum discharges from the lung sealant and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, Talcum can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is to be used for purpose of the present invention with having active steatitic analog of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the Talcum effect with half of above-mentioned parameter, use half in chemical compound of Talcum effect etc.) with the twice of above-mentioned parameter.

As exemplary fibers degeneration derivant, the accumulated dose of the lip-deep silk of being sent from the lung sealant or be applied to lung should be no more than 100mg (scope of 1 μ g-100mg) with silk.The total amount of the silk that discharges from sealant in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of per unit area (that is the dosage of the silk of the function of the surface area of the lung that is applied to as medicine) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to silk on the surface of lung.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge silk with different speed with concrete lung sealant, thereby above-mentioned administration parameter should be delivered in the described tissue with the silk that the rate of release of medicine from sealant is used in combination the Cmin that makes 0.01nM-1000 μ M.In one embodiment, thus silk discharges from the lung sealant and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, silk can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active silk of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles an effect with half of above-mentioned parameter, use half in chemical compound of silk effect etc.) with the twice of above-mentioned parameter.

Chitosan as exemplary fibers degeneration derivant, should be no more than 100mg (scope of 1 μ g-100mg) from the accumulated dose of lung sealant lip-deep chitosan that sent or that be applied to lung.In one embodiment, the total amount of the chitosan that discharges from sealant should be in the scope of 10 μ g-50mg.The dosage of per unit area (that is the dosage of the chitosan of the function of the surface area of the lung that is applied to as medicine) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the lung surface with chitosan.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge chitosan with different speed with concrete lung sealant, thereby above-mentioned administration parameter should be used in combination from the rate of release of sealant with medicine the chitosan of 0.01nM-1000 μ M Cmin is delivered to the described tissue.In one embodiment, thus chitosan discharges from the lung sealant and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, chitosan can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active chitosan of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the chitosan effect with half of above-mentioned parameter, use half in chemical compound of chitosan effect etc.) with the twice of above-mentioned parameter.

Polylysine as exemplary fibers degeneration derivant, should be no more than 100mg (scope of 1 μ g-100mg) from the accumulated dose of lung sealant lip-deep polylysine that sent or that be applied to lung.The total amount of the polylysine that discharges from sealant in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of per unit area (that is the dosage of the polylysine of the function of the surface area of the lung that is applied to as medicine) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the lung surface with polylysine.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge polylysine with different speed with concrete lung sealant, thereby above-mentioned administration parameter should be used in combination from the rate of release of lung sealant with medicine and makes the polylysine of 0.01nM-1000 μ M Cmin be delivered to described tissue.In one embodiment, thus polylysine discharges from the lung sealant and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, polylysine can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active polylysine of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the polylysine effect with half of above-mentioned parameter, use half in chemical compound of polylysine effect etc.) with the twice of above-mentioned parameter.

Fibronectin as exemplary fibers degeneration derivant, should be no more than 100mg (scope of 1 μ g-100mg) from the accumulated dose of lung sealant lip-deep fibronectin that sent or that be applied to lung.The total amount of the fibronectin that discharges from sealant in one embodiment, should be in the scope of 10 μ g-50mg.The dosage of per unit area (that is the dosage of the fibronectin of the function of the surface area of the lung that is applied to as medicine) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the lung surface with fibronectin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge fibronectin with different speed with concrete lung sealant, thereby above-mentioned administration parameter should be used in combination with the rate of release of medicine from sealant the fibronectin of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, thus fibronectin discharges from the lung sealant and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, fibronectin can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active fibronectin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the fibronectin effect with half of above-mentioned parameter, use half in chemical compound of fibronectin effect etc.) with the twice of above-mentioned parameter.

Bleomycin as exemplary fibers degeneration derivant, should be no more than 100mg (scope of 0.01 μ g-100mg) from the accumulated dose of lung sealant lip-deep bleomycin that sent or that be applied to lung.In one embodiment, the total amount of the bleomycin that discharges from sealant should be in the scope of 0.10 μ g-50mg.The dosage of per unit area (that is the dosage of the silk of the function of the surface area of the lung that is applied to as medicine) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the lung surface with bleomycin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge bleomycin with different speed with concrete lung sealant, thereby above-mentioned administration parameter should be delivered in the described tissue with the bleomycin that the rate of release of medicine from the lung sealant is used in combination the Cmin that makes 0.001nM-1000 μ M.In one embodiment, thus bleomycin discharges from the lung sealant and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, bleomycin can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active bleomycin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the bleomycin effect with half of above-mentioned parameter, use half in chemical compound of bleomycin effect etc.) with the twice of above-mentioned parameter.

CTGF as exemplary fibers degeneration derivant, should be no more than 100mg (scope of 0.01 μ g-100mg) from the accumulated dose of lung sealant lip-deep CTGF that sent or that be applied to lung.In one embodiment, the total amount of the CTGF that discharges from sealant should be in the scope of 0.10 μ g-50mg.The dosage of per unit area (that is the dosage of the CTGF of the function of the surface area of the lung that is applied to as medicine) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the lung surface with CTGF.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge CTGF with different speed with concrete lung sealant, thereby above-mentioned administration parameter should be delivered to the described tissue from the CTGF that the rate of release of sealant is used in combination the Cmin that makes 0.001nM-1000 μ M with medicine.In one embodiment, thus CTGF discharges from the lung sealant and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, CTGF can discharge the period that reaches 1 hour-30 days scopes with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active CTGF of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the CTGF effect with half of above-mentioned parameter, use half in chemical compound of CTGF effect etc.) with the twice of above-mentioned parameter.

Randomly, described sealant can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or its analog or derivant in addition).Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of inflammatory cytokine from 0.0001 μ g/ml to about 20mg/ml is used in the preparation.Preferably, inflammatory cytokine discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 100mg); Preferred 0.001 μ g is to 50mg.When being used as the device coating, dosage is 0.0001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.001 μ g/mm ²-200 μ g/mm ²With 10 ^-10-10 ^-4The Cmin of the inflammatory cytokine of g/ml maintains on the apparatus surface.

In addition, described sealant can be separately or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA), and analog and derivant.Used dosage is to be proved to be those concentration (seeing that for example embodiment 16) that stimulate cellular proliferation.Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of multiplication agent from 0.0000001 to 25mg/ml is used in the preparation.Preferably, multiplication agent discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 200mg); Preferred 0.001 μ g is to 100mg.When being used as the device coating, dosage is 0.00001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.0001 μ g/mm ²-200 μ g/mm ²With 10 ^-11-10 ^-6The Cmin of the multiplication agent of M maintains on the apparatus surface.

Should be that it is evident that can be with aforementioned fibers degeneration derivant for those skilled in the art, or derivatives thereof and analog any under the situation that does not deviate from spirit and scope of the invention be used to produce the variation of above-mentioned composition.Also should it is evident that described reagent can be used in the compositions that has or do not have polymer support and change described carrier and not deviate from scope of the present invention.

14. hernia mesh (mesh)

The invention provides fibre modification derivant and being used to and strengthen the combination of the damaged implantable mesh such as hernia of tissue wall.Hernia is that organ or other body structure pass through at coverlay outstanding unusually (the turning up) of the damaged or natural openings in muscle or the bone.Hernia often is caused by the activity that causes overexertion (typically increasing the activity of intra-abdominal pressure), or they can be used as result's generation of childbirth.Wherein may need to use the disease of hernia mesh to include, but not limited to groin (that is, groin), umbilicus, veutro, femur, abdominal part, diaphragm, epigastrium, the stomach esophagus, ceasma, between flesh, mesentery, by the peritoneum, rectum vagina, rectum caecum, the repairing of uterus and cystocele.

Inguinal hernia is the type of modal hernia among the adult and can tears crack or opening and form because of the weakness in hypogastric region or groin (inguinal canal) muscular wall.Therefore, the content of abdominal part can be outstanding by opening such as intestinal, produces bulging and/or pain.Inguinal hernia can be inborn and can be in life whenever become obvious because of pain and bulging.They can also be because of the repetition pressure to abdominal wall muscle, overexertion or injury and obtain.

Umbilical hernia is in the formation of in the umbilicus (that is umbilicus) and peripheral region and influence those people that have congenital defect in the stomach wall around umbilicus (zone that the fetal cord blood vessel breaks away from by abdominal wall muscle) gradually.Hernia can the zone that whenever occurs in this weakness after from be born to growing up in.Described S﹠S is included in umbilicus location or near pain and relevant protrusion or the odd-shaped formation of umbilicus.This bulging is extruded on subcutaneous or on every side umbilicus, distortion Qizhong or on every side normal profile and structure.

Otch or veutro hernia can occur in the zone of any surgical incision the preceding, and can be in size from very for a short time change to very big and complicated.The reason that they form is edge or near the destruction the abdomen wall sewing zone, normally places structural stretching or other inhibitory action to abundant healing (infecting poor nutrition, obesity or metabolic disease) subsequently.These hernias are as bulging or be projected on incisional scar place or near zone appearance the preceding.The abdominal operation of many types (for example, enterochirurgia operation, vascular operation, appendectomy or laparoscopy) can form incisional hernia in the cicatrix zone subsequently.

The femur hernia forms at inguinal region as inguinal hernia.The lower limb fold place or near these hernias of formation.The damaged inguinal ligament (producing the tendon band of lower limb gauffer) that occurs in itself is between pubis downside and the femur vein (mainline of lower limb).Because the shape and the angle of pelvis, this crack are big a little in the women, therefore make the femur hernia more common in the women.

Hernia itself is not dangerous, in case still they will be produced extreme problem by incarceration.In by the hernia of incarceration, outstanding internal organs can not be withdrawn into their normal anatomy location and can " be held back " in hernical sac.If increased by the internal organs of incarceration, organ (intestinal typically) can be closed (causing intestinal obstruction) and/or the blood supply in organ is destroyed, and this can cause necrosis and by the death of the part of incarceration.Hernia like this is often repaired to stop complication with surgical operation.For its simplest form, described internal organs are got back to its normal location and damaged in wall mainly carries out closure with suture, but for bigger crack, thereby mesh is placed the damaged closed described hernia opening of.Be used in the surgical prosthesis (be referred to herein as " hernia mesh ") of hernia in repairing and comprise prosthese mesh-or gauze sample material, it supports the hernia that is repaired or other body structure in agglutination.With the fibre modification derivant add to can promote in the implant strong, development and the inwardly growth of fibrous tissue around mesh neutralization.This can enhanced tissue, forms scar tissue and produce the reparation that continues that can reduce relapse rate on abdominal-wall defect.For littler crack, thereby the combination of fibre modification derivant can be produced identical effect with the suture material.

On the one hand, described hernia mesh can comprise biodegradable or not biodegradable material.In certain embodiments, described mesh fabric can be responsive for the formation with the adhesion of surrounding tissue or organ and/or can promote the tissue ingrowth that increases.

The representative example that is used in the nondegradable material in the hernia reparation mesh comprises following: the tantalum screening, the rustless steel mesh, polyamide, polyolefin (for example, polypropylene and polyethylene), polyurethane, the polyester and polyether block copolymer, polyester (PET, polybutylene terephthalate and polyhexamethylene terephthalate), mylar (such as DACRON), polyester sheet (such as can be, Wilmington, the MYLAR that DE obtains) from E.I.DuPont DeNemours and Company, the nylon mesh, the DACRON mesh (such as can be from Ethicon, Inc., a Johnson ﹠amp; Johnson Company, Somerville, the MERSILENE that NJ obtains), acrylic acid cloth (ORLON that can obtain from E.I.DuPont DeNemours and Company), polyvinyl sponge (IVALON), polyethylene base cloth (VINYON-N), the polypropylene mesh (can be from CR Bard, Inc., Cranston, MARLEX or BARD mesh that RI obtains) and can be from Ethicon, Inc., a Johnson ﹠amp; JohnsonCompany, Somerville, the PROLENE that NJ obtains), siloxanes, or fluoropolymer polymer such as PEP (FEP) or politef (PTFE; Such as can be from E.I.DuPont De Nemoursand Company (Wilmington, DE) TEFLON mesh of Huo Deing and cloth or sell from W.L.Gore ﹠amp with trade (brand) name GORE-TEX; Associates, the PTFE that is extended that Inc. obtains.

Hernia is repaired mesh can comprise biodegradable or not biodegradable polymer such as polyglactin (VICRYL; Ethicon, Inc., a Johnson ﹠amp; Johnson Company (Somerville, NJ)), polyglycolic acid is (such as DEXON; United States Surgical/Syneture (Norwalk, CT)), the carbon fiber mesh, from body, heterogeneous and heteroplasm's (for example, pericardium or submucous layer of small intestine), or oxidation, regenerated cellulose.

Be used in the hernia reparation the surgical operation mesh can by knotting in supporting screen work, woven, weave or form the alternate manner of multiple yarn (for example, monofilament body or the polymitus silk thread that forms by polymer material such as polypropylene and polyester) and make.The mesh fabric that is used in combination with the hernia reparation is disclosed in U.S. Patent number 6,638,284; 5,292,328; In 4,769,038 and 2,671,444.Knitting and woven fabric makes up from multiple synthetic fibers and fabric the use in surgical repair also in U.S. Patent number 3,054,406; 3,124,136; 4,193,137; 4,347,847; 4,452,245; 4,520,821; 4,633,873; 4,652,264; 4,655,221; 4,838,884 and 5,002,551 and European Patent Application No. 334,046 in discuss to some extent.Implantable hernia mesh is in U.S. Patent number 6,610,006; Describe to some extent in 6,368,541 and 6,319,264.The hernia mesh that is used to repair the ceasma hernia exists, and for example U.S. Patent number 6,436, describes to some extent in 030.The hernia mesh that is used for the reparation of abdominal part (for example, veutro and umbilicus) hernia is described in U.S. Patent number 6,383, in 201.Anti-infective hernia mesh is described in, and for example U.S. Patent number 6,375, in 662.Thereby the hernia mesh is suitable for making up with the fibre modification derivant and produces the mesh that promotes the fibrous tissue growth such as being described in the patent of listing above those.

Commercially available hernia mesh can also make up with one or more according to fibre modification induced drug of the present invention.Can make up with the fibre modification derivant be used in hernia repair in (for example, other hernia of inguinal hernia and stomach wall) commercially available example comprises: (a) MARLEX or BARD mesh (CR Bard, Inc., Cranston, RI)), described mesh is the knit goods structure with very dense of low porosity; (b) monofilament body polypropylene mesh is such as can be from Ethicon, Inc., a Johnson; JohnsonCompany, Somerville, the PROLENE (seeing that for example U.S. Patent number 5,634,931 and 5,824,082) that NJ obtains); (c) (all from Cook Surgical, Inc.), described graft is that the device of specific assembling is to be used for strengthening soft tissue in the open and reparation of abdominal cavity mirror method in inguinal hernia for SURGISIS GOLD and SURGISIS IHM soft tissue graft thing; (d) the polypropylene surgical operation mesh of thin-walled is such as obtaining trade (brand) name PROLITE, PROLITE ULTRA, and LITEMESH from Atrium; (e) COMPOSIX hernia mesh (C.R.Bard, Murray Hill, NJ), (described paster comprises the two-layer synthetic mesh of being made by polypropylene usually of inertia in conjunction with the mesh paster for it, and at U.S. Patent number 6, describe to some extent in 280,453), described mesh paster comprises filament and maintains flat configuration with sclerosis and with device; (f) VISILEX mesh (from C.R.Bard), it is the polypropylene mesh that makes up with monofilament body polypropylene; (g) can be from C.R.Bard, other hernia mesh that Inc. obtains, it comprises PERFIX Plug, KUGEL Hernia Patch, 3D MAX mesh, LHI mesh, DULEX mesh and VENTRALEX Hernia Patch; (h) the polypropylene monofilament body hernia mesh and the bolt product of other type, described hernia mesh and bolt product comprise the USA from Herniamesh, Inc (Great Neck, NY). HERTRA mesh 1,2, and 2A, HERMESH3,4; 5 and 3-dimension Plugs T1, T2, and T3.Another kind be suitable for use in implant in the present embodiment be have can biological resorbent coating prosthese polypropylene mesh, be known as SEPRAMESH BiosurgicalComposite (Genzyme Corporation, Cambridge, MA).One side of described mesh applied with hyaluronate sodium and carboxymethyl cellulose can biology absorbed layer again, temporary transient physical barriers is provided, tissue that described barrier will be below and organ surface and described mesh are separated.The opposite side of described mesh does not have applied, is similar to naked polypropylene mesh and allows tissue ingrowth completely.In one embodiment, can only the fibre modification derivant be put on the uncoated side of SEPRAMESH and not put on a side of hyaluronate sodium and carboxymethyl cellulose coating.

Also other commercially available material can be used as the hernia mesh.(Natick MA) sells the TRELEX NATURALMesh that is made up of the knitting polypropylene material of uniqueness to Boston Scientific Corporation.(Hudson, NH) sale is used for the treatment of the hernia reparation by the thin-walled polypropylene with by 3 PROLITE Mesh and the PROLITE Ultra Mesh that tie up the making of PROLOOP bolts that polyacrylic monofilament body ring is formed to Atrium Medical Corporation.Ethicon, Inc. produce absorbable VICRYL (polyglactin 910) mesh (knitting and woven), PROLENE Polypropylene HerniaMeshes and MERSILENE Polyester Fiber Mesh.(Midland MI) sells the mesh material that is formed by silicone elastomer to Dow Corning Corporation, is called SILASTIC RxMedical Grade Sheeting (Platinum Cured).(Norwalk CT) sells the mesh of being made by absorbable polyglycolic acid with trade name DEXON Mesh Products to United States Surgical/Syneture.(Obernburg Germany) sells microporous polypropylene fibre of CELGARD and film to Membrana Accurel Systems.Gynecare Worldwide, a division ofEthicon, Inc., a Johnson ﹠amp; Johnson Company (Somerville NJ) sells by oxidation, the mesh material that regenerated cellulose is made, and it is called as INTERCEED TC7.

On the one hand, thus the invention provides the hernia that comprises the fibre modification derivant repairs cicatrization and the closure that mesh promotes abdominal-wall defect.Can with the coating of described hernia mesh with fibrous tissue form agent (with or not with carrier).For example, the fibre modification induced drug can be applied to meshed surface or be woven in the fabric.Perhaps, or in addition, described hernia mesh can be completely or partially fibrotic fibrous by inducing.For example, can with the silk chain or the silk woven in the hernia mesh or described hernia mesh can form by silk fully.

On the other hand, the invention provides the sprayable compositions that comprises the fibre modification derivant, thereby described compositions can be used in the closure that promotes cicatrization and abdominal-wall defect in the endoscope type hernia restorative procedure.

The carrier system of above-mentioned many polymer and non-polymer can be used in the practice of the present embodiment.Thereby these compositionss also can comprise the formation that one or more fibre modification derivants promote the fibroid scar tissue.With become fiber composition to be attached on the hernia mesh or among method comprise: (a) directly will become fiber composition to be attached to implant (for example, with or not with carrier, by aforesaid spraying process or dip coating); (b) directly will become fiber composition to be attached in the device (for example, with or not with carrier, by aforesaid spraying process or dip coating); (c) by being coated with described device with material such as hydrogel, described hydrogel can absorb into fiber composition again; (d) be woven in the apparatus structure by the line (or polymer itself of formation line) that will become the fiber composition coating; (e) by film or netting knot are incorporated in the described hernia mesh, described film or mesh are made up of the one-tenth fiber composition or are coated with; (f) use part into fiber composition construction device itself or described device; And/or (g) fibrous tissue being formed surface or the joint (micromolecule or polymer) that agent directly is covalently bound to the hernia mesh, described joint is applied or be attached to described meshed surface.For the hernia mesh, can carry out coating process by this way, (a) outer surface of the described mesh of coating or (b) the described mesh inner surface of coating or (c) the coating outer surface of described device and inner surface all or part of.

Except inducing compositions to be coated with the described device with fibre modification, can mix and make fibrous tissue form agent with the material that is used for manufacturing installation to be attached to final device thereby fibrous tissue forms agent.

Except (or as alternative) is administered to the fibre modification agent the hernia mesh, the original position that comprises the fibre modification derivant can be formed compositions, gel or hot gel combination are used (as gel, solid implant, liquid or spray) in the placement site of hernia mesh, following arbitrary: (a) before placing described mesh; (b) after placing described hernia mesh; (c) in placing described mesh process; Or (d) above-mentioned three arbitrary combination.Hot gel and gel combination for original position formation, fibre modification derivant (for example, silk powder, bleomycin) directly can be attached in the preparation to produce suspension or solution or its and (for example can be incorporated in the secondary carrier, micelle, liposome, microsphere, microgranule, the nanometer spheroid, microparticulates, Emulsion and/or microemulsion), described secondary carrier then is incorporated in the compositions of original position formation.In another embodiment, the fibre modification derivant can be incorporated into statically or covalently original position forms in one or more component of polymer of compositions.

In an especially preferred embodiment, described compositions can prepare from 4-arm mercaptan PEG (10K), 4-arm NHS PEG (10K) and methylated collagen protein be such as above-mentioned and comprise the fibre modification derivant, thereby described compositions is sprayed to and on the surgical sites described hernia mesh is attached to suitable position and fibre modification is induced in the mesh.

In another embodiment, the fibre modification derivant can be attached in biodegradable or soluble film or the mesh, follow before implanting described hernia mesh, or afterwards described film or mesh are administered to the treatment site.The exemplary material that is used to prepare these films or mesh is hyaluronic acid (crosslinked or noncrosslinking), cellulose derivative (for example, hydroxypropyl cellulose), collagen protein and crosslinked poly-(ethylene glycol).

Tackling in those skilled in the art is to it is evident that potentially, above-mentioned any binding agent or fibre modification derivant can be used alone or in combination in the practice of the present embodiment.The exemplary fibers texturizer that is used in the hernia reparation mesh comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF and above-mentioned analog and derivant.

Because hernia mesh and the compositions of using with the hernia mesh are made with multiple configuration and size, the exact dose of using can be with width of mesh, surface area and kind of design and change.Yet, some principle can be applied in the application of this area.Can be the function of per unit area (part of applied mesh) dosage with medication dose calculation, can measure the total drug dose of using, and can determine the suitable surface concentration of active medicine.No matter to the method for hernia mesh how medicament administration, the exemplary fibers texturizer that is used alone or in combination should use under following administration is instructed:

Talcum is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming the hernia mesh, or use without polymer support, the steatitic accumulated dose of sending from the hernia mesh or be applied to the hernia meshed surface should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the steatitic accumulated dose that discharges from prosthese should be in the scope of 10 μ g-50mg.The dosage of the per unit area of implanted mesh (that is, be applied as medicine and/or the steatitic dosage of the function of the surface area of the part of bonded mesh) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the hernia meshed surface with Talcum.In one embodiment, thus Talcum discharges from the surface of hernia mesh and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, Talcum can discharge the period that reaches 1 week-9 a month scope with valid density.What consider that discussion provided herein it should be obvious that is to be used for purpose of the present invention with having active steatitic analog of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the Talcum effect with half of above-mentioned parameter, use half in chemical compound of Talcum effect etc.) with the twice of above-mentioned parameter.

Silk is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming the hernia mesh, or use without polymer support, the accumulated dose of sending from the hernia mesh or be applied to the silk on the hernia meshed surface should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the total amount of the silk that discharges from the hernia mesh should be in the scope of 10 μ g-50mg.The dosage of the per unit area of implanted mesh (that is, be applied as medicine and/or the dosage of the silk of the function of the surface area of the part of bonded mesh) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the hernia meshed surface with silk.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge silk with different speed with concrete hernia mesh, thereby above-mentioned administration parameter should be delivered to the described tissue from the silk that the rate of release of hernia mesh is used in combination the Cmin that makes 0.01nM-1000 μ M with medicine.In one embodiment, thus silk discharges from the surface of hernia mesh and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, silk can discharge the period that reaches 1 week-9 a month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active silk of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles an effect with half of above-mentioned parameter, use half in chemical compound of silk effect etc.) with the twice of above-mentioned parameter.

Chitosan is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming the hernia mesh, or use without polymer support, the accumulated dose of sending from the hernia mesh or be applied to the chitosan on the hernia meshed surface should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the total amount of the chitosan that discharges from the hernia mesh should be in the scope of 10 μ g-50mg.The dosage of the per unit area of implanted mesh (that is, be applied as medicine and/or the dosage of the chitosan of the function of the surface area of the part of bonded mesh) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the hernia meshed surface with chitosan.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge chitosan with different speed with concrete hernia mesh, thereby above-mentioned administration parameter should be used in combination from the rate of release of hernia mesh with medicine the chitosan of 0.01nM-1000 μ M Cmin is delivered to the described tissue.In one embodiment, thus chitosan discharges from the surface of hernia mesh and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, chitosan can discharge the period that reaches 1 week-9 a month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active chitosan of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the chitosan effect with half of above-mentioned parameter, use half in chemical compound of chitosan effect etc.) with the twice of above-mentioned parameter.

Polylysine is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming the hernia mesh, or use without polymer support, the accumulated dose of sending from the hernia mesh or be applied to the polylysine on the hernia meshed surface should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the total amount of the polylysine that discharges from the hernia mesh should be in the scope of 10 μ g-50mg.The dosage of the per unit area of implanted mesh (that is, be applied as medicine and/or the dosage of the polylysine of the function of the surface area of the part of bonded mesh) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the hernia meshed surface with polylysine.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge polylysine with different speed with concrete hernia mesh, thereby above-mentioned administration parameter should be used in combination from the rate of release of hernia mesh with medicine the polylysine of 0.01nM-1000 μ M Cmin is delivered to the described tissue.In one embodiment, thus polylysine discharges from the surface of hernia mesh and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, polylysine can discharge the period that reaches 1 week-9 a month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active polylysine of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the polylysine effect with half of above-mentioned parameter, use half in chemical compound of polylysine effect etc.) with the twice of above-mentioned parameter.

Fibronectin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming the hernia mesh, or use without polymer support, the accumulated dose of sending from the hernia mesh or be applied to the fibronectin on the hernia meshed surface should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the total amount of the fibronectin that discharges from the hernia mesh should be in the scope of 10 μ g-50mg.The dosage of the per unit area of implanted mesh (that is, be applied as medicine and/or the dosage of the fibronectin of the function of the surface area of the part of bonded mesh) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the hernia meshed surface with fibronectin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge fibronectin with different speed with concrete hernia mesh, thereby above-mentioned administration parameter should be used in combination from the rate of release of hernia mesh with medicine the fibronectin of 0.01nM-1000 μ M Cmin is delivered to the described tissue.In one embodiment, thus fibronectin discharges from the surface of hernia mesh and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, fibronectin can discharge the period that reaches 1 week-9 a month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active fibronectin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the fibronectin effect with half of above-mentioned parameter, use half in chemical compound of fibronectin effect etc.) with the twice of above-mentioned parameter.

Bleomycin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming the hernia mesh, or use without polymer support, the accumulated dose of sending from the hernia mesh or be applied to the bleomycin on the hernia meshed surface should be no more than 100mg (scope of 0.01 μ g-100mg).In one embodiment, the total amount of the bleomycin that discharges from the hernia mesh should be in the scope of 0.10 μ g-50mg.The dosage of the per unit area of implanted mesh (that is, be applied as medicine and/or the dosage of the bleomycin of the function of the surface area of the part of bonded mesh) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the hernia meshed surface with bleomycin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge bleomycin with different speed with concrete hernia mesh, thereby above-mentioned administration parameter should be delivered to the described tissue from the bleomycin that the rate of release of hernia mesh is used in combination the Cmin that makes 0.001nM-1000 μ M with medicine.In one embodiment, thus bleomycin discharges from the surface of hernia mesh and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, bleomycin can discharge the period that reaches 1 week-9 a month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active bleomycin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the bleomycin effect with half of above-mentioned parameter, use half in chemical compound of bleomycin effect etc.) with the twice of above-mentioned parameter.

CTGF is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming the hernia mesh, or use without polymer support, the accumulated dose of sending from the hernia mesh or be applied to the CTGF on the hernia meshed surface should be no more than 100mg (scope of 0.01 μ g-100mg).In one embodiment, the total amount of the CTGF that discharges from the hernia mesh should be in the scope of 0.10 μ g-50mg.The dosage of the per unit area of implanted mesh (that is, be applied as medicine and/or the dosage of the CTGF of the function of the surface area of the part of bonded mesh) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the hernia meshed surface with CTGF.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge CTGF with different speed with concrete hernia mesh, thereby above-mentioned administration parameter should be delivered to the described tissue from the CTGF that the rate of release of hernia mesh is used in combination the Cmin that makes 0.001nM-1000 μ M with medicine.In one embodiment, thus CTGF discharges from the surface of hernia mesh and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, CTGF can discharge the period that reaches 1 week-9 a month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active CTGF of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the CTGF effect with half of above-mentioned parameter, use half in chemical compound of CTGF effect etc.) with the twice of above-mentioned parameter.

Randomly, described device or compositions can be separately or are comprised inflammatory cytokine (for example, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or its analog or derivant in addition.According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of inflammatory cytokine from 0.0001 μ g/ml to about 20mg/ml is used in the preparation.Preferably, inflammatory cytokine discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 100mg); Preferred 0.001 μ g is to 50mg.When being used as the device coating, dosage is 0.0001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.001 μ g/mm ²-200 μ g/mm ²With 10 ^-10-10 ^-4The Cmin of the inflammatory cytokine of g/ml maintains on the apparatus surface.

In addition, described device or compositions can be separately or are comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA), and analog and derivant.Used dosage is to be proved to be those concentration (seeing that for example, embodiment 16) that stimulate cellular proliferation.According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of multiplication agent from 0.1ng/ml to 25mg/ml is used in the preparation.Preferably, multiplication agent discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 200mg); Preferred 0.001 μ g is to 100mg.When being used as the device coating, dosage is 0.00001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.0001 μ g/mm ²-200 μ g/mm ²With 10 ^-11-10 ^-6The Cmin of the multiplication agent of M maintains on the apparatus surface.

Should it will be apparent to one skilled in the art that aforementioned fibers degeneration derivant, any of or derivatives thereof and analog can be used to produce the variation of above-mentioned composition under the prerequisite that does not deviate from spirit and scope of the invention.Also should it is evident that described reagent can with or be not used in the compositions and change described carrier and do not depart from scope of the present invention with polymer support.

15. capsula articularis humeri (shoulder capsule), ligament and tendon reparation

On the one hand, the invention provides compositions and device to be used in capsula articularis humeri, during ligament and tendon reconstructive surgery are performed the operation.Term " ligament " refers to the band of fibrous connective tissue, and described band is connected in cartilage with bone, and the effect of described ligament is to support and the reinforcement joint.Term " tendon " refers to the fiber sex cords of connective tissue, and wherein meat fiber ends at described tendon and is attached to bone or other structure by described tendon muscle.In the U.S., surpass 700,000 ligament and tendon kposthesis every year, comprising: the foot and the kposthesis of ankle (altogether 11%, particularly heel string also has diseased tendon, the plantar fascia kposthesis, toe extensor tendon, tendon before the shin, ligament is stablized in the outside of ankle, inferior ligament before the shin calf, inboard deltoid ligament), the knee joint kposthesis (altogether 38%, medial collateral ligament particularly, lateral collateral ligament, anterior cruciate ligament, posterior cruciate ligament and meniscus kposthesis also have the cartilage surface kposthesis, patella tendon kposthesis, the biceps femoral muscle kposthesis), the kposthesis of hip (rectus femoris origin or beginning, the other tendon origin of muscle of gracilis tendon popliteal avulsion), the kposthesis of pelvis (gracilis muscle origin or beginning, adductor muscle origin or beginning, rectus femoris insert, pelvisternum), the kposthesis of shoulder (altogether 25%; Rotator cuff tendon particularly; Shoulder lock is stablized ligament, biceps tendon in addition), back kposthesis (the sacrum ilium is stablized ligament), elbow (biceps tendon, outside epicondyle-extensor origin or beginning, inboard epicondyle-bent origin of muscle, triceps muscle complex), and hands (altogether 26%; The bent flesh and the extensor tendon of wrist and hands).With the fibre modification derivant add to soft tissue kposthesis method (such as list above those) in can increase cicatrization and cause for the patient more can be durable, that can support and effect practicality.

Produced some surgical operation meshes, thereby described mesh is used in the open surgery process as tissue repairing's product performance function and is suitable for sending the fibre modification derivant based on collagen protein.For example, the collagen protein surgical patches, (Organogenesis Inc., Canton MA), repair in the surgical operation enhanced tissue in surgery operative repair and agglutination thereby be used in tendon, ligament and cartilage such as FORTAFLEX Patch.Tendon and ligament are repaired surgical operation and are typically comprised using suture anchor or sewing up by (suture-passing) thereby install impaired tendon is fixed in bone.According to the size of tearing, the collagen protein paster can be used to fill up the damaged of tendon or ligament.The collagen protein implant is served as can resorbent support, and described support provides biomechanical strength, supports and strengthens soft tissue with the surgery operative repair.Finally, collagen protein soaks into and is replaced by host tissue cell (mainly being fibroblast), and this can repair the also tissue (mainly being organized connective tissue) of regeneration of damaged.

Unfortunately, for many these surgical intervention, the durability of collagen protein implant becomes the important clinical problem.In tendon and repair of ligament, it is desirable to provide structural intergrity up to healing and natural tissues replace and can take place fully for the collagen protein implant.In meeting needed big tissue defect situation that the several months heals to the time that surpasses 1 year, the limited durability of collagen protein implant can become clinical problem, if its before healing is finished, thorough words that absorb.In the trial that addresses this problem, the manufacturer has attempted to produce the collagen protein implant with raising durability by being increased in amount crosslinked between the collagen fabric.Yet highly cross-linked collagen substance has the support different with natural collagen protein and degradation model and do not have optimum performance function in agglutination.One or more fibre modification derivants are added to have some important clinical meanings in the collagen protein paster.At first, because it does not need the change of collagen substance itself, collagen scaffold keeps its native state and can support the normal inwardly growth of reparation property fibrous connective tissue.Secondly, described fibre modification derivant stimulates the inside growth of the fibrous connective tissue of health itself, healing acceleration process and allow that repairing took place before the implant breakage.Described result by the connective tissue of health itself form faster, stronger, the repairing that the persistent period is longer, this has caused better clinical effectiveness and lower risk of failure.

On the one hand, the invention provides the compositions and the device that comprise the fibre modification derivant, thereby wherein said reagent can promote cicatrization with the ligament of surgery operative repair (for example to strengthen, before and posterior cruciate ligament), tendon (for example, or joint capsule (for example, preventing the anterior capsule of recurrent shoulder dislocation) heel string).Multiple embodiments is suitable for practice of the present invention, comprise to sending of operation on soft tissue site following: (1) comprises " hot paste (thermopaste) " of fibre modification derivant, described hot paste at actual temp (for example, body temperature) be applied to required site as fluid, and harden into the solid of required form; (2) (promptly as the spray that comprises the fibre modification derivant, " nanometer spray (nanospray) "), it can be in open surgery, or (for example by special surgery device, endoscope) is delivered to required site, and harden into solid subsequently, adhere to the tissue that it is applied to; (3) as adherent, softish, the elastic polymeric film that comprises the fibre modification derivant, described film directly or by special device is administered to the site that needs, and it preferably is attached to the site that it is applied to; And/or (4) as the fluid of being made up of the suspension that comprises the microsphere of fibre modification derivant in suitable mounting medium, described fluid by directly or by special device be administered to need the site, and this stays the microsphere layer and uses the site.The representative example of above-mentioned each embodiment proposes below in more detail.

In another embodiment, can come tendon, ligament or capsula articularis humeri are handled with the fibre modification derivant that original position forms the compositions of gel with combination.These can be crosslinked gels, hot gel or conventional gel combination.For original position forms gel, hot gel and gel combination, thereby the fibre modification derivant can directly be attached in the preparation and to produce suspension or solution (for example, silk powder, bleomycin) or its and (for example can be incorporated into secondary carrier, micelle, liposome, microsphere, microgranule, the nanometer spheroid, microparticulates, Emulsion and/or microemulsion) in, described secondary carrier then is incorporated in the gel combination of original position formation.In certain embodiments, described fibre modification derivant can be statically or covalently is incorporated into one or more component of polymer that original position forms gel combination.

In another embodiment, the fibre modification derivant can be attached in biodegradable or soluble film or the mesh, described film or mesh the treatment before, among or be applied to afterwards the treatment site.Described film or mesh can be applied to whole treatment site, be used for bridging or fill tissue defect, or they can be used as paster and are applied to very concrete position in the treatment site.The preferred material that is used to prepare these films or mesh is hyaluronic acid (crosslinked or noncrosslinking), cellulose derivative (for example, hydroxypropyl cellulose), collagen protein and crosslinked poly-(ethylene glycol).

In another embodiment, the fibre modification derivant can exist with injectable or sprayable form (being particularly useful in endoscope sends), described fibre modification derivant can directly be delivered to the treatment site, be administered on tendon, ligament or the capsule with the surgery operative repair, it is damaged to be used for repair tissue, or is applied to the tissue around the treatment site.Described compositions can be used easily as " spray ", and described spray is cured as film or coating subsequently.The sprayable preparation that fibrous tissue forms agent can be used in, for example knee joint surgical operation (for example, MCL and ACL) thus strengthen ligament in the kposthesis or be used in the ankle surgical operation to strengthen tendon (for example, heel string).Described compositions can also be used to the purpose of making up, such as strengthening or (for example strengthening Cooper's ligament.Be used for supporting or promoting breast).For example, thus described ligament can be applied forms agent with the cicatrization fibrous tissue to be caused ligament to shrink (that is, shortening) and promotes breast tissue.The fibre modification derivant (for example, the silk powder, bleomycin) thus can directly be attached in the preparation and to produce suspension or solution or its and can be incorporated into secondary carrier (for example, micelle, liposome, microsphere, microgranule, nanometer spheroid, microparticuclates, Emulsion and/or microemulsion) in, described secondary carrier then is incorporated in injectable or the sprayable compositions.Comprise that the spray of organizing mucoadhesive polymers that contains the fibre modification derivant can prepare the microsphere of extensively arranging from size.In another embodiment, described fibre modification derivant can be statically or covalently is incorporated into one or more component of polymer of injectable or sprayable compositions.

Injectable and sprayable compositions also can comprise polymer to strengthen the viscosity of solution.The polymer that is used for this purpose comprises hyaluronic acid, CMC, PLURONICS, such as PLURONIC F127, and X-Y, X-Y-X, or the gel of Y-X-Y form (comprising hot gel) (wherein X is that degradable polyester and Y are polyalkylene oxides, preferably Polyethylene Glycol or its monomethyl ether).In another embodiment, injectable or sprayable preparation also can comprise one or more biocompatible solvents.These can comprise ethanol, DMSO, NMP, poly-(ethylene glycol)-200, and/or poly-(ethylene glycol)-300.

A kind of interested especially material preparation that is used for the present embodiment is from 4-arm mercaptan PEG (10K), and 4-arm NHS PEG (10K) and methylated collagen protein are such as above-mentioned.In one embodiment, preparation is from 4-arm mercaptan PEG (10K), the material of 4-arm NHS PEG (10K) and methylated collagen protein load with the fibre modification derivant and by directly spraying (directly or pass through endoscope) to the treatment site, it is damaged to be used for repair tissue, be applied to the tissue of treatment around the site, or be administered to impaired tendon, ligament or capsule with tissue adhesion to together and induce fibre modification.

Tackling in those skilled in the art is to it is evident that potentially, above-mentioned any fibre modification derivant can be used alone or in combination in the practice of the present embodiment.Be used in capsule, the exemplary fibers texturizer in ligament and tendon repair apparatus and the graft comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF and above-mentioned analog and derivant.

Because depend on the position and the degree of damage, capsula articularis humeri, ligament and tendon repair apparatus and compositions are made with multiple configuration and size, and the exact dose of using can be with the implant size, surface area and kind of design and change.Yet, some principle can be applied in the application of this area.Can be the function of implant per unit area (or volume) dosage with medication dose calculation, can measure the total drug dose of using, and can determine the suitable surface concentration of active medicine.No matter medicament administration is to joint capsule, the method for ligament or tendon repair apparatus or implant is how, and the exemplary fibers texturizer that is used alone or in combination should use under following administration is instructed:

Talcum is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from joint capsule, ligament or tendon are repaired that implant is sent or are applied to joint capsule, and the steatitic accumulated dose that ligament or tendon are repaired implant surface should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the steatitic total amount that discharges from implant should be in the scope of 10 μ g-50mg.The dosage of the implant of per unit volume (that is, be applied as medicine and/or the steatitic dosage of the function of the volume of the part of bonded implant) should be at 0.05 μ g-10 μ g/mm ³In the implanted material scope.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to joint capsule with Talcum, and ligament or tendon are repaired implant surface.In one embodiment, Talcum is from joint capsule, thereby ligament or tendon are repaired the fibre modification of surface release in promoting to organize in the scope period of a few hours to several months of implant.For example, Talcum can discharge the period that reaches 1-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is to be used for purpose of the present invention with having active steatitic analog of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the Talcum effect with half of above-mentioned parameter, use half in chemical compound of Talcum effect etc.) with the twice of above-mentioned parameter.

Silk is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from joint capsule, ligament or tendon are repaired that implant is sent or are applied to joint capsule, and the accumulated dose that ligament or tendon are repaired the silk on the implant surface should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the total amount of the silk that discharges from implant should be in the scope of 10 μ g-50mg.The dosage of the implant of per unit volume (that is, be applied as medicine and/or the dosage of the silk of the function of the volume of the part of bonded implant) should be at 0.05 μ g-10 μ g/mm ³In the implanted material scope.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to joint capsule with silk, and ligament or tendon are repaired implant surface.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge silk with different speed with concrete medical implant, above-mentioned administration parameter should with medicine from joint capsule, thereby ligament or tendon are repaired the silk that the rate of release of implant is used in combination the Cmin that makes 0.01nM-1000 μ M and are delivered to described tissue.In one embodiment, silk is from joint capsule, thereby ligament or tendon are repaired the fibre modification of surface release in promoting to organize in the scope period of a few hours to several months of implant.For example, silk can discharge the period that reaches 1-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active silk of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles an effect with half of above-mentioned parameter, use half in chemical compound of silk effect etc.) with the twice of above-mentioned parameter.

Chitosan is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from joint capsule, ligament or tendon are repaired that implant is sent or are applied to joint capsule, and the accumulated dose that ligament or tendon are repaired the chitosan on the implant surface should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the total amount of the chitosan that discharges from implant should be in the scope of 10 μ g-50mg.The dosage of the implant of per unit volume (that is, be applied as medicine and/or the dosage of the chitosan of the function of the volume of the part of bonded implant) should be at 0.05 μ g-10 μ g/mm ³In the implanted material scope.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to joint capsule with chitosan, and ligament or tendon are repaired implant surface.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge chitosan with different speed with concrete medical implant, above-mentioned administration parameter should with medicine from joint capsule, thereby ligament or tendon are repaired the rate of release of implant and are used in combination the chitosan of 0.01nM-1000 μ M Cmin is delivered in the described tissue.In one embodiment, chitosan is from joint capsule, thereby ligament or tendon are repaired the fibre modification of surface release in promoting to organize in the scope period of a few hours to several months of implant.For example, chitosan can discharge the period that reaches 1-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active chitosan of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the chitosan effect with half of above-mentioned parameter, use half in chemical compound of chitosan effect etc.) with the twice of above-mentioned parameter.

Polylysine is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from joint capsule, ligament or tendon are repaired that implant is sent or are applied to joint capsule, and the accumulated dose that ligament or tendon are repaired the polylysine on the implant surface should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the total amount of the polylysine that discharges from implant should be in the scope of 10 μ g-50mg.The dosage of the implant of per unit volume (that is, be applied as medicine and/or the dosage of the polylysine of the function of the volume of the part of bonded implant) should be at 0.05 μ g-10 μ g/mm ³In the implanted material scope.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to joint capsule with polylysine, and ligament or tendon are repaired implant surface.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge polylysine with different speed with concrete medical implant, above-mentioned administration parameter should with medicine from joint capsule, thereby ligament or tendon are repaired the rate of release of implant and are used in combination and make the polylysine of 0.01nM-1000 μ M Cmin be delivered to described tissue.In one embodiment, polylysine is from joint capsule, thereby ligament or tendon are repaired the fibre modification of surface release in promoting to organize in the scope period of a few hours to several months of implant.For example, polylysine can discharge the period that reaches 1-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active polylysine of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the polylysine effect with half of above-mentioned parameter, use half in chemical compound of polylysine effect etc.) with the twice of above-mentioned parameter.

Fibronectin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from joint capsule, ligament or tendon are repaired that implant is sent or are applied to joint capsule, and the accumulated dose that ligament or tendon are repaired the fibronectin on the implant surface should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the total amount of the fibronectin that discharges from implant should be in the scope of 10 μ g-50mg.The dosage of the implant of per unit volume (that is, be applied as medicine and/or the dosage of the fibronectin of the function of the volume of the part of bonded implant) should be at 0.05 μ g-10 μ g/mm ³In the implanted material scope.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to joint capsule with fibronectin, and ligament or tendon are repaired implant surface.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge fibronectin with different speed with concrete medical implant, above-mentioned administration parameter should with medicine from joint capsule, thereby ligament or tendon are repaired the rate of release of implant and are used in combination and make the fibronectin of 0.01nM-1000 μ M Cmin be delivered to described tissue.In one embodiment, fibronectin is from joint capsule, thereby ligament or tendon are repaired the fibre modification of surface release in promoting to organize in the scope period of a few hours to several months of implant.For example, fibronectin can discharge the period that reaches 1-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active fibronectin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the fibronectin effect with half of above-mentioned parameter, use half in chemical compound of fibronectin effect etc.) with the twice of above-mentioned parameter.

Bleomycin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from joint capsule, ligament or tendon are repaired that implant is sent or are applied to joint capsule, and the accumulated dose that ligament or tendon are repaired the bleomycin on the implant surface should be no more than 100mg (scope of 0.01 μ g-100mg).In one embodiment, the total amount of the bleomycin that discharges from implant should be in the scope of 0.10 μ g-50mg.The dosage of the implant of per unit volume (that is, the dosage of bleomycin is applied as medicine and/or the function of the volume of the part of bonded implant) should be at 0.005 μ g-10 μ g/mm ³In the implanted material scope.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to joint capsule with bleomycin, and ligament or tendon are repaired implant surface.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge bleomycin with different speed with concrete medical implant, above-mentioned administration parameter should with medicine from joint capsule, thereby ligament or tendon are repaired the bleomycin that the rate of release of implant is used in combination the Cmin that makes 0.001nM-1000 μ M and are delivered in the described tissue.In one embodiment, bleomycin is from joint capsule, thereby ligament or tendon are repaired the fibre modification of surface release in promoting to organize in the scope period of a few hours to several months of implant.For example, bleomycin can discharge the period that reaches 1-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active bleomycin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the bleomycin effect with half of above-mentioned parameter, use half in chemical compound of bleomycin effect etc.) with the twice of above-mentioned parameter.

CTGF is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of component devices or implant, or use without polymer support, from joint capsule, ligament or tendon are repaired that implant is sent or are applied to joint capsule, and the accumulated dose that ligament or tendon are repaired the CTGF on the implant surface should be no more than 100mg (scope of 0.01 μ g-100mg).In one embodiment, the total amount of the CTGF that discharges from implant should be in the scope of 0.10 μ g-50mg.The dosage of the implant of per unit volume (that is, be applied as medicine and/or the dosage of the CTGF of the function of the volume of the part of bonded implant) should be at 0.005 μ g-10 μ g/mm ²In the implanted material scope.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to joint capsule with CTGF, and ligament or tendon are repaired implant surface.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge CTGF with different speed with concrete medical implant, above-mentioned administration parameter should with medicine from joint capsule, thereby ligament or tendon are repaired the CTGF that the rate of release of implant is used in combination the Cmin that makes 0.001nM-1000 μ M and are delivered in the described tissue.In one embodiment, CTGF is from joint capsule, thereby ligament or tendon are repaired the fibre modification of surface release in promoting to organize in the scope period of a few hours to several months of implant.For example, CTGF can discharge the period that reaches 1-12 month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active CTGF of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the CTGF effect with half of above-mentioned parameter, use half in chemical compound of CTGF effect etc.) with the twice of above-mentioned parameter.

Randomly, described device can be separately or is comprised inflammatory cytokine (for example, TGF β, PDGF in addition, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) and/or bone morphogenetic protein (BMP) is (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant).

Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, with bone morphogenetic protein (for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, or BMP-7 or its analog or derivant) be used in the preparation with concentration range from 0.001 μ g/ml to about 20mg/ml.Preferably, bone morphogenetic protein discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.001 μ g is to the scope of 500mg); Preferred 1 μ g is to 250mg.When being used as the device coating, dosage is 0.001 μ g-1000 μ g/mm of per unit area ²Preferred dosage is 0.01 μ g/mm ²-200 μ g/mm ²With 10 ^-9-10 ^-4The Cmin of the bone morphogenetic protein of M maintains on the apparatus surface.

Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of inflammatory cytokine from 0.0001 μ g/ml to about 20mg/ml is used in the preparation.Preferably, inflammatory cytokine discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 100mg); Preferred 0.001 μ g is to 50mg.When being used as the device coating, dosage is 0.0001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.001 μ g/mm ²-200 μ g/mm ²With 10 ^-10-10 ^-4The Cmin of the inflammatory cytokine of g/ml maintains on the apparatus surface.

In addition, described device can be separately or is comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA), and analog and derivant.Used dosage is to be proved to be those concentration (seeing that for example, embodiment 16) that stimulate cellular proliferation.Depend on concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of multiplication agent from 0.0000001 to 25mg/ml is used in the preparation.Preferably, multiplication agent discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 200mg); Preferred 0.001 μ g is to 100mg.When being used as the device coating, dosage is 0.00001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.0001 μ g/mm ²-200 μ g/mm ²With 10 ^-11-10 ^-6The Cmin of the multiplication agent of M maintains on the apparatus surface.

Should be that it is evident that can be with aforementioned fibers degeneration derivant for those skilled in the art, or derivatives thereof and analog any under the situation that does not deviate from spirit and scope of the invention be used to produce the variation of above-mentioned composition.Also should it is evident that described reagent can be used in the compositions that has or do not have polymer support and change described carrier and not deviate from scope of the present invention.

16. in every inaccessible paster

The invention provides the fibre modification derivant and in every the combination of inaccessible paster.With fibrous tissue form agent be attached in every among the inaccessible paster or on can promote tissue growth, therefore this is anchored to barrier film with device and better sealing is provided, and reduces the incidence rate of seepage.

The damaged obstruction blood of only about half of congenital cardiovascular flows in the right ventricle of heart and left chamber.Two kinds of the damaged of common type are atrial septal defect and ventricular septal defect, and described atrial septal defect is included in the opening of two walls between the atrium, and described ventricular septal defect is included in the opening of the wall between the ventricle.Other similar heart defect is patent foramen ovale (patent foramen ovale) and patent ductus arteriosus.Only in the U.S., annual just have 20,000 children with one of these deformities to be born approximately.In addition, have 100 ten thousand to suffer from the damaged American of congenital cardiovascular still survival and nowadays approximately with the complication of development need treatment, such as pulmonary hypertension, congestive heart failure, atrial arrhythmia, aerobic capacity weaken (impaired aerobic capacity) and apoplexy.

Heart defect become the attractive alternative of surgical closure through vessel occlusion because it has reduced inherent danger of cardiac operation and sickness rate.Developed some transcatheter technology and in every locking device and use clinically.The latest generation of device is made up of two plates that stem in two quilts connects.The inaccessible described damaged and described plate of described stem is attached to each side of wall.The device of contraction state discharges by catheter positioning and under fluoroscopic guidance.Yet the size of these devices limits the application of this technology in little patient.And, typically, have big damaged patient and have around damaged inadequate in the edge edge the patient can not with in treat every locking device.In addition, with in comprise incomplete closure (seepage) every the relevant unfavorable complication of locking device, friction pathological changes and cardiac perforation.

With the fibre modification derivant add to can promote in the implant in the development and the inwardly growth of strong fibrous tissue around locking device neutralization.This can enhanced tissue, forms scar tissue and produce the repairing that continues on implant.During tissue growth can be anchored to described device every and the sealing of improvement is provided, therefore make minimizing of seepage.In addition, device is broken and cardiac perforation in conjunction with preventing to rub by heart tissue.Among the device and/or on tissue growth can intensifier and allow the application of thinner device, therefore reduce volume and be fit to the patient group of wider scope.The intensity of the increase of device can also be allowed bigger damaged treatment.Finally, transcatheter therapy is that the patient with little middle edge edge who is not enough to treat will make device be anchored to the appropriate location because of tissue growth optional this method usually.

Thereby in the term among inaccessible paster refers to be designed to place host's vascular system or near retardance blood by the mobile device of vascular defects.In include, but not limited to damaged closing device every the example of inaccessible paster, closer in the branch road closing device, heart, part flow arrangement in the closure plate, damaged closed-system and blood vessel.

In can form by a plurality of configurations every inaccessible paster.For example, in described every inaccessible paster can by formed by moulding have at least two spatially at interval coil closed hoop with flexibly at the edge of opening with itself centering.See that for example U.S. Patent number 6,355,052.In can form by delivery rod and paster every inaccessible paster, described paster releasably (releasably) is maintained at configuration and the use configuration that the described thus paster of far-end has contraction state, the configuration of described contraction state is used for by the tube chamber location, and described use configuration is used to pass the septal defect location.See that for example U.S. Patent number 6,346,074.Can form by two flexible membranes every inaccessible paster in described, but thereby described flexible membrane has the framework of the elasticity degeneration of extending along periphery allows that film shrinks passing conduit, and after implantation, recover their predetermined shapes.See that for example U.S. Patent number 6,077,291 and 5,334,217.In can form by obturation bag with two capsules connected to one another and the independently superelastic metal framework with two groups of a plurality of rings every inaccessible paster, described ring is comprised in the inaccessible bag.See that for example U.S. Patent number 5,861,003.In can form by at least two clips and flat fabric closer every inaccessible paster, described clip has the setting tool of the outer peripheral portion of holding opening, described closer be used for closed described every opening.See that for example U.S. Patent number 5,507,811.In can form to be used to allow when closer by two closers that the fastener with pivot connects every inaccessible paster and to rotate during at the configuration of expanding.See that for example U.S. Patent number 5,451,235.In can form by having two folding foamed resins or the polyurethane dish of sewing up wire armature every inaccessible paster, use the fastening technology of passing through heart defect that described dish is fixed to one another thus.See that for example U.S. Patent number 5,433,727; 5,284,488 and 4,917,089.In can be the easy extension fixture of umbrella every inaccessible paster, thereby described device is by making a plurality of pole compositions of movably being settled on central shaft described paster have first punctured position and second expanded position.See that for example U.S. Patent number 4,007,743.Can form by the mechanical expansion instrument every inaccessible paster in described, be placed on the opposite side of shunt damaged (shunt defect) thereby described instrument has two groups of umbrella spline structures that possess central shaft.See that for example U.S. Patent number 3,874,388.

Can also make up with one or more according to fibre modification induced drug of the present invention every inaccessible paster in commercially available.For example, W.L.Gore and Associates, (Newark DE) sells among its HELEX every closer Inc., and described closer is used as the closure of the intrusion degree minimum of atrial septal defect.NMT Medical, (Boston MA) sells their CARDIOSEAL and STARFLEX to Inc., and it is designed to the method for intrusion degree minimum.(Golden Valley MN) sells among their AMPLATZER every closer AGA Medical Corp..

On the one hand, in the invention provides every inaccessible paster, thereby described paster comprises the closure that the fibre modification derivant promotes cicatrization and heart defect.In described every inaccessible paster can be applied with fibrous tissue form agent (with or not with carrier).For example, the fibre modification induced drug can be applied to the surperficial or woven in fabric of paster.Perhaps, or in addition, can be completely or partially fibrotic fibrous in by inducing every inaccessible paster.For example, can with the silk chain or the silk woven in inaccessible paster or in can form by silk fully every inaccessible paster.

On the other hand, the invention provides the sprayable compositions that comprises the fibre modification derivant, thereby described compositions can be used in the closure that promotes cicatrization and heart defect in the transcatheter kposthesis.

The carrier system of above-mentioned many polymer and non-polymer can be used in the practice of the present embodiment.Thereby these compositionss also can comprise the formation that one or more fibre modification derivants promote the fibroid scar tissue.With become fiber composition be attached in every on the inaccessible paster or among method comprise: (a) directly will become fiber composition to be attached to implant (for example, with or not with carrier, by aforesaid spraying process or dip coating); (b) will become fiber composition directly to be attached in the device (for example, with or not with carrier, by aforesaid spraying process or dip coating); (c) by being coated with described device with material such as hydrogel, described hydrogel can absorb into fiber composition again; (d) be woven in the apparatus structure by the line (or polymer itself of formation line) that will become the fiber composition coating; (e) by film or netting knot are incorporated into described in every inaccessible paster, described film or mesh are by becoming fiber composition to form or be coated with; (f) use part into fiber composition construction device itself or described device; And/or (g) fibrous tissue is formed agent directly be covalently bound in every the surface or the joint (micromolecule or polymer) of inaccessible paster, described joint is applied or be attached to described paster surface.For in for the inaccessible paster, can carry out coating process by this way, described mode only is coated with the outer surface of described paster or (b) the described paster inner surface of coating or (c) outer surface of the described paster of coating and inner surface all or part of for (a).

Except inducing compositions to be coated with the described device with fibre modification, can mix and make fibrous tissue form agent with the material that is used for manufacturing installation to be attached to final device thereby fibrous tissue forms agent.

Except (or as alternative) will become fiber agent be administered in every inaccessible paster, the original position that comprises the fibre modification derivant can be formed compositions, gel or hot gel combination are used (as gel, solid implant, liquid or spray) in every the placement site of inaccessible paster, following arbitrary: (a) before placing described paster; (b) after placing described paster; (c) in placing described paster process; Or (d) above-mentioned three arbitrary combination.For hot gel and gel combination that original position forms, fibre modification derivant (for example, silk powder, bleomycin) directly can be attached in the preparation to produce suspension or solution or its and (for example can be incorporated in the secondary carrier, micelle, liposome, microsphere, microgranule, the nanometer spheroid, microparticulates, Emulsion and/or microemulsion), described secondary carrier then is incorporated in the compositions of original position formation.In another embodiment, the fibre modification derivant can be incorporated into statically or covalently original position forms in one or more component of polymer of compositions

In an especially preferred embodiment, described compositions can prepare from 4-arm mercaptan PEG (10K), 4-arm NHS PEG (10K) and methylated collagen protein be such as above-mentioned and comprise the fibre modification derivant, thereby described compositions is sprayed on the surgical sites and will is attached to suitable position and fibre modification is induced in the paster every inaccessible paster in described.

In another embodiment, the fibre modification derivant can be attached in biodegradable or soluble film or the mesh, then implant described in before inaccessible paster, or afterwards described film or mesh are administered to the treatment site.The exemplary material that is used to prepare these films or mesh is hyaluronic acid (crosslinked or noncrosslinking), cellulose derivative (for example, hydroxypropyl cellulose), collagen protein and crosslinked poly-(ethylene glycol).

Tackling in those skilled in the art is to it is evident that potentially, above-mentioned any binding agent or fibre modification derivant can be used alone or in combination in the practice of the present embodiment.The exemplary fibers texturizer that is used in inaccessible paster comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF and above-mentioned analog and derivant.

Because in every inaccessible paster and with in the compositions used every inaccessible paster make with multiple configuration and size, the exact dose of using can be with patch size, surface area and kind of design and change.Yet, some principle can be applied in the application of this area.Can be the function of per unit area (part of applied paster) dosage with medication dose calculation, can measure the total drug dose of using, and can determine the suitable surface concentration of active medicine.No matter medicament administration in every the method for inaccessible paster how, the exemplary fibers texturizer that is used alone or in combination should use under following administration is instructed:

Talcum is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the composition in the polymer of inaccessible paster, or use without polymer support, therefrom send every inaccessible paster or be applied in steatitic accumulated dose every inaccessible paster surface should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the steatitic accumulated dose that discharges from prosthese should be in the scope of 10 μ g-50mg.In implanted every the dosage of the per unit area of inaccessible paster (that is, be applied as medicine and/or bonded in every the steatitic dosage of the function of the surface area of the part of inaccessible paster) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²During the dosage of applied surface area is administered to Talcum every inaccessible paster surface.In one embodiment, thus Talcum therefrom discharges every the surface of inaccessible paster and promotes fibre modification in the tissue in the period of a few hours to several months in the scope.For example, Talcum can discharge the period that reaches 1 week-9 a month scope with valid density.What consider that discussion provided herein it should be obvious that is to be used for purpose of the present invention with having active steatitic analog of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the Talcum effect with half of above-mentioned parameter, use half in chemical compound of Talcum effect etc.) with the twice of above-mentioned parameter.

Silk is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the composition in the polymer of inaccessible paster, or use without polymer support, therefrom send every inaccessible paster or be applied in should be no more than 100mg (scope of 1 μ g-100mg) every the accumulated dose of the lip-deep silk of inaccessible paster.In one embodiment, the total amount of the silk that therefrom discharges every inaccessible paster should be in the scope of 10 μ g-50mg.In implanted every the dosage of the per unit area of inaccessible paster (that is, be applied as medicine and/or bonded in every the dosage of the silk of the function of the surface area of the part of inaccessible paster) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²During the dosage of applied surface area is administered to silk every inaccessible paster surface.Because the drug delivery vehicle of concrete (polymer and non-polymer) with concrete in can discharge silk with different speed every inaccessible paster, thereby above-mentioned administration parameter should therefrom be delivered to described tissue every the silk that the rate of release of inaccessible paster is used in combination the Cmin that makes 0.01nM-1000 μ M with medicine.In one embodiment, thus silk therefrom discharges every the surface of inaccessible paster and promotes fibre modification in the tissue in the period of a few hours to several months in the scope.For example, silk can discharge the period that reaches 1 week-9 a month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active silk of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles an effect with half of above-mentioned parameter, use half in chemical compound of silk effect etc.) with the twice of above-mentioned parameter.

Chitosan is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the composition in the polymer of inaccessible paster, or use without polymer support, therefrom send every inaccessible paster or be applied in should be no more than 100mg (scope of 1 μ g-100mg) every the accumulated dose of the lip-deep chitosan of inaccessible paster.In one embodiment, the total amount of the chitosan that therefrom discharges every inaccessible paster should be in the scope of 10 μ g-50mg.In implanted every the dosage of the per unit area of inaccessible paster (that is, be applied as medicine and/or bonded in every the dosage of the chitosan of the function of the surface area of the part of inaccessible paster) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²During the dosage of applied surface area is administered to chitosan every inaccessible paster surface.Because the drug delivery vehicle of concrete (polymer and non-polymer) with concrete in can discharge chitosan with different speed every inaccessible paster, thereby above-mentioned administration parameter should therefrom be used in combination every the rate of release of inaccessible paster with medicine and makes the chitosan of 0.01nM-1000 μ M Cmin be delivered to described tissue.In one embodiment, thus chitosan therefrom discharges every the surface of inaccessible paster and promotes fibre modification in the tissue in the period of a few hours to several months in the scope.For example, chitosan can discharge the period that reaches 1 week-9 a month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active chitosan of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the chitosan effect with half of above-mentioned parameter, use half in chemical compound of chitosan effect etc.) with the twice of above-mentioned parameter.

Polylysine is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the composition in the polymer of inaccessible paster, or use without polymer support, therefrom send every inaccessible paster or be applied in should be no more than 100mg (scope of 1 μ g-100mg) every the accumulated dose of the lip-deep polylysine of inaccessible paster.In one embodiment, the total amount of the polylysine that therefrom discharges every inaccessible paster should be in the scope of 10 μ g-50mg.In implanted every the dosage of the per unit area of inaccessible paster (that is, be applied as medicine and/or bonded in every the dosage of the polylysine of the function of the surface area of the part of inaccessible paster) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²During the dosage of applied surface area is administered to polylysine every inaccessible paster surface.Because the drug delivery vehicle of concrete (polymer and non-polymer) with concrete in can discharge polylysine with different speed every inaccessible paster, thereby above-mentioned administration parameter should therefrom be used in combination every the rate of release of inaccessible paster with medicine and makes the polylysine of 0.01nM-1000 μ M Cmin be delivered to described tissue.In one embodiment, thus polylysine therefrom discharges every the surface of inaccessible paster and promotes fibre modification in the tissue in the period of a few hours to several months in the scope.For example, polylysine can discharge the period that reaches 1 week-9 a month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active polylysine of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the polylysine effect with half of above-mentioned parameter, use half in chemical compound of polylysine effect etc.) with the twice of above-mentioned parameter.

Fibronectin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the composition in the polymer of inaccessible paster, or use without polymer support, therefrom send every inaccessible paster or be applied in should be no more than 100mg (scope of 1 μ g-100mg) every the accumulated dose of the lip-deep fibronectin of inaccessible paster.In one embodiment, the total amount of the fibronectin that therefrom discharges every inaccessible paster should be in the scope of 10 μ g-50mg.In implanted every the dosage of the per unit area of inaccessible paster (that is, be applied as medicine and/or bonded in every the dosage of the fibronectin of the function of the surface area of the part of inaccessible paster) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²During the dosage of applied surface area is administered to fibronectin every inaccessible paster surface.Because the drug delivery vehicle of concrete (polymer and non-polymer) with concrete in can discharge fibronectin with different speed every inaccessible paster, thereby above-mentioned administration parameter should therefrom be used in combination every the rate of release of inaccessible paster with medicine and makes the fibronectin of 0.01nM-1000 μ M Cmin be delivered to described tissue.In one embodiment, thus fibronectin therefrom discharges every the surface of inaccessible paster and promotes fibre modification in the tissue in the period of a few hours to several months in the scope.For example, fibronectin can discharge the period that reaches 1 week-9 a month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active fibronectin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the fibronectin effect with half of above-mentioned parameter, use half in chemical compound of fibronectin effect etc.) with the twice of above-mentioned parameter.

Bleomycin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the composition in the polymer of inaccessible paster, or use without polymer support, therefrom send every inaccessible paster or be applied in should be no more than 100mg (scope of 0.01 μ g-100mg) every the accumulated dose of the lip-deep bleomycin of inaccessible paster.In one embodiment, the total amount of the bleomycin that therefrom discharges every inaccessible paster should be in the scope of 0.10 μ g-50mg.In implanted every the dosage of the per unit area of inaccessible paster (that is, be applied as medicine and/or bonded in every the dosage of the bleomycin of the function of the surface area of the part of inaccessible paster) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²During the dosage of applied surface area is administered to bleomycin every inaccessible paster surface.Because the drug delivery vehicle of concrete (polymer and non-polymer) with concrete in can discharge bleomycin with different speed every inaccessible paster, thereby above-mentioned administration parameter should therefrom be delivered to described tissue every the bleomycin that the rate of release of inaccessible paster is used in combination the Cmin that makes 0.001nM-1000 μ M with medicine.In one embodiment, thus bleomycin therefrom discharges every the surface of inaccessible paster and promotes fibre modification in the tissue in the period of a few hours to several months in the scope.For example, bleomycin can discharge the period that reaches 1 week-9 a month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active bleomycin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the bleomycin effect with half of above-mentioned parameter, use half in chemical compound of bleomycin effect etc.) with the twice of above-mentioned parameter.

CTGF is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the composition in the polymer of inaccessible paster, or use without polymer support, therefrom send every inaccessible paster or be applied in should be no more than 100mg (scope of 0.01 μ g-100mg) every the accumulated dose of the lip-deep CTGF of inaccessible paster.In one embodiment, the total amount of the CTGF that therefrom discharges every inaccessible paster should be in the scope of 0.10 μ g-50mg.In implanted every the dosage of the per unit area of inaccessible paster (that is, be applied as medicine and/or bonded in every the dosage of the CTGF of the function of the surface area of the part of inaccessible paster) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²During the dosage of applied surface area is administered to CTGF every inaccessible paster surface.Because the drug delivery vehicle of concrete (polymer and non-polymer) with concrete in can discharge CTGF with different speed every inaccessible paster, thereby above-mentioned administration parameter should therefrom be delivered to described tissue every the CTGF that the rate of release of inaccessible paster is used in combination the Cmin that makes 0.001nM-1000 μ M with medicine.In one embodiment, thus CTGF therefrom discharges every the surface of inaccessible paster and promotes fibre modification in the tissue in the period of a few hours to several months in the scope.For example, CTGF can discharge the period that reaches 1 week-9 a month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active CTGF of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the CTGF effect with half of above-mentioned parameter, use half in chemical compound of CTGF effect etc.) with the twice of above-mentioned parameter.

Randomly, described device or compositions can be separately or are comprised inflammatory cytokine (for example, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or its analog or derivant in addition.According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of inflammatory cytokine from 0.0001 μ g/ml to about 20mg/ml is used in the preparation.Preferably, inflammatory cytokine discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 100mg); Preferred 0.001 μ g is to 50mg.When being used as the device coating, dosage is 0.0001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.001 μ g/mm ²-200 μ g/mm ²With 10 ^-10-10 ^-4The Cmin of the inflammatory cytokine of g/ml maintains on the apparatus surface.

In addition, described device or compositions can be separately or are comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA), and analog and derivant.Used dosage is to be proved to be those concentration (seeing that for example, embodiment 16) that stimulate cellular proliferation.According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of multiplication agent from 0.0000001 to 25mg/ml is used in the preparation.Preferably, multiplication agent discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 200mg); Preferred 0.001 μ g is to 100mg.When being used as the device coating, dosage is 0.00001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.0001 μ g/mm ²-200 μ g/mm ²With 10 ^-11-10 ^-6The Cmin of the multiplication agent of M maintains on the apparatus surface.

Should it will be apparent to one skilled in the art that aforementioned fibers degeneration derivant, any of or derivatives thereof and analog can be used to produce the variation of above-mentioned composition under the prerequisite that does not deviate from spirit and scope of the invention.Also should it is evident that described reagent can with or be not used in the compositions and change described carrier and do not depart from scope of the present invention with polymer support.

17. inner chamber fastener (Endoluminal fasteners)

The invention provides the combination of fibre modification derivant and inner chamber fastener.The inner chamber fastener can comprise, but is not limited to, and nail (for example, endostaples), suture, tinsel, filament, rope, bolt, clip and other electrical connector and material.

Thereby the inner chamber fastener is effect be similar to ribet increase impaired or perforation body conduit integrity or the inner chamber graft is fixed in the device of the wall of body conduit (for example, blood vessel).The inner chamber fastener can also be used for multiple inner chamber surgical operation such as, but be not limited to the polypectomy of wall, the excision of pathological changes under the mucosa, intestinal excision; the excision of pathological changes such as ulcer; hemorrhage control, closed perforation, prevention or therapeutic appendectomy; the excision of hemorrhagic diverticulitis or Meckel ' s diverticulum; grappling pipeline or graft (for example, joining artery to graft), fixing long lasting (time-released) medicine; carry out gastroplasty; Unterbindung des Eileiter, the solid organs biopsy, intestinal is arranged (structuring) or partly pneumonectomy.

Can be by the inner chamber fastener being loaded into delivery catheter and then they being introduced in the body cavity through skin and use them.Then, by body conduit described conduit is introduced the site that band is repaired.Thereby described fastener is sent from the tip of delivery catheter and is made it penetrate the wall that required site guarantees the inner chamber fastener is fixed in body conduit thus.The fibre modification derivant is added the inner chamber fastener can promote the development of the strong fibrous tissue around the device neutralization and inwardly growth.Fibrous tissue formed that agent is attached among the inner chamber fastener or on can promote tissue growth, this helps to help device is anchored to the wall of tube chamber.In case the inner chamber fastener is positioned by wall, its part remains in the tube chamber, the component of body contact pipeline.For example, if body conduit is a blood vessel, the inner chamber fastener will contact blood flow, and this can cause the thrombosis incident.Therefore, in another aspect of the present invention,, the inner chamber fastener stops thrombosis thereby can also comprising antithrombotic agent.

The inner chamber fastener can be made up of the metal of biocompatibility, and described metal includes, but not limited to nitinol, and tantalum, rustless steel or metal alloy be such as nickel, gold, silver, titanium nitride and chromium.When they were used in the mode of intrusion degree minimum, the metal fastener had advantage, because metal can develop in the endoscope type delivery process by conduit.Yet, the inner chamber fastener can also by alone or in combination with the polymer of the biocompatibility of metallics and other synthetic or natural materials form.These can comprise the material based on magnesium, plastics, and the inorganic non-metallic resin, based on proteinic material, collagen protein or other similar material.Nonmetal fastener can be preferably in some program, for example, if desired can biological resorbent fastener maybe needs to reduce the scattering of the x-ray that takes place with the metal fastener.The inner chamber fastener can be by rigidity, flexibility, and elasticity, non-resilient, ductility is arranged, there is not ductility, recoverable, thus uncollectible material is made the desirable thrust that fastener applied need being attached to wall of the lumen.

The inner chamber fastener usually can be with " T ", and " H " or " U " shape is carried out configuration.Because they have intensity and ductility, often the metal inner cavity fastener is fixed in correct position by the described fastener structure of curling.The inner chamber fastener of being made by polymer and/or other material does not have the substance characteristics identical with the metal fastener.Therefore, by the fastener that polymer is made, for example, often made by two parts, comprise general U-shaped fastener part, described U-shaped fastener part partly engages its pillar and interlocking with localizer.

On the one hand, the inner chamber fastener can be multiple configuration and material.For example, the inner chamber fastener can be to have the single empiecement device (single-tipped) that possesses most advanced and sophisticated curve modeling.See that for example U.S. Patent number 6,491,707.The inner chamber fastener can have load and extend shape and have a plurality of second load configurations not at the axial coil of spring after discharging from delivery components.See that for example U.S. Patent number 6,113,611.The inner chamber fastener can be to be used to pass and fixing organization suturing nail together, and wherein said nail is positioned between the marginal portion of the lumen device of assisting location, excision and fixing remaining tissue.See that for example U.S. Patent number 6,264,086 and 5,868,760.Thereby the inner chamber fastener can be adapted to make it provide radiation to repair the site to wound in conjunction with radioactive source.See that for example U.S. Patent number 5,906,573.The inner chamber fastener can be made up of fastener and localizer (retainer) assembly, and described localizer assembly is made by hemostatic resinous substances absorbable and that demonstration improves.See that for example U.S. Patent number 4,667,674.The inner chamber fastener can be made up of the surgical staples of shape memory, and based on transition temperature, described nail can form opening shape or close-shaped, and wherein electric current raises the temperature of nail to the heating of nail and makes it closed and therefore connect subjacent tissue.See that for example U.S. Patent number 4,485,816.The inner chamber fastener can be to have the spiral fastener that penetrates terminal and confinement end.See, for example, U.S. Patent number 6,592,593.The inner chamber fastener can be a pin type localizer surgical operation fastener, and it can be made up of the localizer that pin and can being used for is attached to graft artery.See that for example U.S. Patent number 6,074,401.The inner chamber fastener can be general U-shaped, and it has parallel tip and has the localizer part of slit with the point of keeping each tip.See that for example U.S. Patent number 5,292,334.

Commercially available inner chamber fastener can also make up with one or more according to fibre modification induced drug of the present invention.Commercially available inner chamber fastener is often sold together with relevant stapling device or endoscope type equipment.For example, Johnson ﹠amp; (Piscataway NJ) sells their PROXIMATE ILS and the ENDOPATH STEALTHIntraluminal Staplers that anastomose property is repaired that be used for to Johnson Gateway.(Taunton MA) sells their EVSVascular Closure System to Angiolink Corporation.(Norwalk CT) also sells surgical operation stapling and endoscope type equipment to U.S.Surgical.

On the one hand, thus the invention provides the inner chamber fastener that comprises the fibre modification derivant promotes cicatrization between inner chamber fastener and blood vessel wall.The inner chamber fastener can be applied with fibrous tissue form agent (with or not with carrier).For example, the fibre modification induced drug can be applied to the surface of inner chamber fastener.Perhaps, or in addition, the inner chamber fastener can be completely or partially by inducing fibrotic material to form.For example, silk chain or silk can be attached to the inner chamber fastener or the inner chamber fastener can be by becoming fibrous matter (for example, becoming fiber polymer) partly or entirely to form.

On the other hand, the invention provides the sprayable compositions that comprises the fibre modification derivant, thereby it can be used in the fastening method and to promote cicatrization and inner chamber fastener to be attached to blood vessel wall.

The carrier system of above-mentioned many polymer and non-polymer can be used in the practice of the present embodiment.Thereby these compositionss also can comprise the formation that one or more fibre modification derivants promote the fibroid scar tissue.With become fiber composition to be attached on the inner chamber fastener or among method comprise: (a) directly will become fiber composition to be attached to implant (for example, with or not with carrier, by aforesaid spraying process or dip coating); (b) directly will become fiber composition to be attached in the device (for example, with or not with carrier, by aforesaid spraying process or dip coating); (c) by being coated with described device with material such as hydrogel, described hydrogel can absorb into fiber composition again; (d) be woven in the apparatus structure by the line (or polymer itself of formation line) that will become the fiber composition coating; (e) by film or netting knot are incorporated into described inner chamber fastener, described film or mesh are made up of the one-tenth fiber composition or are coated with; (f) use part into fiber composition construction device itself or described device; And/or (g) by fibrous tissue being formed surface or the joint (micromolecule or polymer) that agent directly is covalently bound to the inner chamber fastener, described joint is applied or be attached to described inner chamber fastener surface.

Except inducing compositions to be coated with the described device with fibre modification, can mix and make fibrous tissue form agent with the material that is used for manufacturing installation to be attached to final device thereby fibrous tissue forms agent.

Except forming agent with fibrous tissue, (or as alternative) be administered to the inner chamber fastener, the original position that comprises the fibre modification derivant can be formed compositions, gel or hot gel combination are used (as gel, solid implant, liquid or spray) in the placement site of inner chamber fastener, following arbitrary: (a) before placing described fastener; (b) after placing described fastener; (c) in placing described fastener process; Or (d) above-mentioned three arbitrary combination.Hot gel and gel combination for original position formation, fibre modification derivant (for example, silk powder, bleomycin) directly can be attached in the preparation to produce suspension or solution or its and (for example can be incorporated in the secondary carrier, micelle, liposome, microsphere, microparticulates, the nanometer spheroid, particle, Emulsion and/or microemulsion), described secondary carrier then is incorporated in the compositions of original position formation.In another embodiment, the fibre modification derivant can be incorporated into statically or covalently original position forms in one or more component of polymer of compositions

In an especially preferred embodiment, described compositions can prepare from 4-arm mercaptan PEG (10K), 4-arm NHS PEG (10K) and methylated collagen protein be such as above-mentioned and comprise the fibre modification derivant, thereby described compositions is sprayed on the surgical sites described inner chamber fastener is attached to suitable position and induces fibre modification between fastener and blood vessel wall.

In another embodiment, the fibre modification derivant can be attached in biodegradable or soluble film or the mesh, follow before implanting described inner chamber fastener, or afterwards described film or mesh are administered to the treatment site.The exemplary material that is used to prepare these films or mesh is hyaluronic acid (crosslinked or noncrosslinking), cellulose derivative (for example, hydroxypropyl cellulose), collagen protein and crosslinked poly-(ethylene glycol).

Tackling in those skilled in the art is to it is evident that potentially, above-mentioned any binding agent or fibre modification derivant can be used alone or in combination in the practice of the present embodiment.The exemplary fibers texturizer that uses with the inner chamber fastener comprises Talcum, silk, fine hair, chitosan, polylysine, fibronectin, bleomycin and CTGF and above-mentioned analog and derivant.

Because inner chamber fastener and the compositions of using with the inner chamber fastener are made with multiple configuration and size, the exact dose of using can be with the size of nail, surface area and kind of design and change.Yet, some principle can be applied in the application of this area.Can be the function of per unit area (part of applied paster) dosage with medication dose calculation, can measure the total drug dose of using, and can determine the suitable surface concentration of active medicine.No matter to the method for inner chamber fastener how medicament administration, the exemplary fibers texturizer that is used alone or in combination should use under following administration is instructed:

Talcum is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming endostaples, or use without polymer support, the steatitic accumulated dose of sending from endostaple or be applied to the endostaple surface should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the steatitic total amount that discharges from prosthese should be in the scope of 10 μ g-50mg.The dosage of the per unit area of implanted endostaple (that is, be applied as medicine and/or the steatitic dosage of the function of the surface area of the part of bonded endostaple) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the endostaple surface with Talcum.In one embodiment, thus Talcum discharges from the surface of endostaple and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, Talcum can discharge the period that reaches 1 week-9 a month scope with valid density.What consider that discussion provided herein it should be obvious that is to be used for purpose of the present invention with having active steatitic analog of identity function and derivant (as previously described); Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the Talcum effect with half of above-mentioned parameter, use half in chemical compound of Talcum effect etc.) with the twice of above-mentioned parameter.

Silk is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming endostaple, or use without polymer support, the accumulated dose of sending from endostaple or be applied to the lip-deep silk of endostaple should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the total amount of the silk that discharges from endostaple should be in the scope of 10 μ g-50mg.The dosage of the per unit area of implanted endostaple (that is, be applied as medicine and/or the dosage of the silk of the function of the surface area of the part of bonded endostaple) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the endostaple surface with silk.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge silk with different speed with concrete endostaple, thereby above-mentioned administration parameter should be delivered to described tissue from the silk that the rate of release of endostaple is used in combination the Cmin that makes 0.01nM-1000 μ M with medicine.In one embodiment, thus silk discharges from the surface of endostaple and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, silk can discharge the period that reaches 1 week-9 a month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active silk of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles an effect with half of above-mentioned parameter, use half in chemical compound of silk effect etc.) with the twice of above-mentioned parameter.

Chitosan is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming endostaple, or use without polymer support, the accumulated dose of sending from endostaple or be applied to the lip-deep chitosan of endostaple should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the total amount of the chitosan that discharges from endostaple should be in the scope of 10 μ g-50mg.The dosage of the per unit area of implanted endostaple (that is, be applied as medicine and/or the dosage of the chitosan of the function of the surface area of the part of bonded endostaple) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the endostaple surface with chitosan.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge chitosan with different speed with concrete endostapls, thereby above-mentioned administration parameter should be used in combination from the rate of release of endostaple with medicine and makes the chitosan of 0.01nM-1000 μ M Cmin be delivered to described tissue.In one embodiment, thus chitosan discharges from the surface of endostaple and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, chitosan can discharge the period that reaches 1 week-9 a month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active chitosan of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the chitosan effect with half of above-mentioned parameter, use half in chemical compound of chitosan effect etc.) with the twice of above-mentioned parameter.

Polylysine is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming endostaple, or use without polymer support, the accumulated dose of sending from endostaple or be applied to the lip-deep polylysine of endostaple should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the total amount of the polylysine that discharges from endostaple should be in the scope of 10 μ g-50mg.The dosage of the per unit area of implanted endostaple (that is, be applied as medicine and/or the dosage of the polylysine of the function of the surface area of the part of bonded endostaple) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the endostaple surface with polylysine.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge polylysine with different speed with concrete endostaple, thereby above-mentioned administration parameter should be used in combination from the rate of release of endostaple with medicine and makes the polylysine of 0.01nM-1000 μ M Cmin be delivered to described tissue.In one embodiment, thus polylysine discharges from the surface of endostaple and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, polylysine can discharge the period that reaches 1 week-9 a month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active polylysine of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the polylysine effect with half of above-mentioned parameter, use half in chemical compound of polylysine effect etc.) with the twice of above-mentioned parameter.

Fibronectin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming endostaple, or use without polymer support, the accumulated dose of sending from endostaple or be applied to the lip-deep fibronectin of endostaple should be no more than 100mg (scope of 1 μ g-100mg).In one embodiment, the total amount of the fibronectin that discharges from endostaple should be in the scope of 10 μ g-50mg.The dosage of the per unit area of implanted endostaple (that is, be applied as medicine and/or the dosage of the fibronectin of the function of the surface area of the part of bonded endostaple) should be at 0.05 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.05 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the endostaple surface with fibronectin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge fibronectin with different speed with concrete endostaple, thereby above-mentioned administration parameter should be used in combination from the rate of release of endostaple with medicine the fibronectin of 0.01nM-1000 μ M Cmin is delivered to the described tissue.In one embodiment, thus fibronectin discharges from the surface of endostaple and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, fibronectin can discharge the period that reaches 1 week-9 a month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active fibronectin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the fibronectin effect with half of above-mentioned parameter, use half in chemical compound of fibronectin effect etc.) with the twice of above-mentioned parameter.

Bleomycin is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming endostaple, or use without polymer support, the accumulated dose of sending from endostaple or be applied to the lip-deep bleomycin of endostaple should be no more than 10025mg (scope of 0.01 μ g-10025mg).In one embodiment, the total amount of the bleomycin that discharges from endostaple should be in the scope of 0.10 μ g-5025mg.The dosage of the per unit area of implanted endostaple (that is, be applied as medicine and/or the dosage of the bleomycin of the function of the surface area of the part of bonded paster) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the endostaple surface with bleomycin.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge bleomycin with different speed with concrete endostaple, thereby above-mentioned administration parameter should be delivered to described tissue from the bleomycin that the rate of release of endostaple is used in combination the Cmin that makes 0.001nM-1000 μ M with medicine.In one embodiment, thus bleomycin discharges from the surface of endostaple and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, bleomycin can discharge the period that reaches 1 week-9 a month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active bleomycin of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the bleomycin effect with half of above-mentioned parameter, use half in chemical compound of bleomycin effect etc.) with the twice of above-mentioned parameter.

CTGF is used as exemplary fibers degeneration derivant, no matter it is to use polymer coating to use, be attached in the polymer of forming endostaple, or use without polymer support, the accumulated dose of sending from endostaple or be applied to the lip-deep CTGF of endostaple should be no more than 10025mg (scope of 0.01 μ g-100mg).In one embodiment, the total amount of the CTGF that discharges from endostaple should be in the scope of 0.10 μ g-5025mg.The dosage of the per unit area of implanted endostaple (that is, be applied as medicine and/or the dosage of the CTGF of the function of the surface area of the part of bonded endostaple) should be at 0.005 μ g-10 μ g/mm ²In the applied surface area.In another embodiment, should be with 0.005 μ g/mm ²-10 μ g/mm ²The dosage of applied surface area is administered to the endostaple surface with CTGF.Because the drug delivery vehicle of concrete (polymer and non-polymer) can discharge CTGF with different speed with concrete endostaple, thereby above-mentioned administration parameter should be delivered to described tissue from the CTGF that the rate of release of endostaple is used in combination the Cmin that makes 0.001nM-1000 μ M with medicine.In one embodiment, thus CTGF discharges from the surface of endostaple and promotes fibre modification the tissue in the period of a few hours to several months in the scope.For example, CTGF can discharge the period that reaches 1 week-9 a month scope with valid density.What consider that discussion provided herein it should be obvious that is analog and the derivant (as previously described) with the active CTGF of identity function can be used for purpose of the present invention; Then, (for example adjust above-mentioned administration parameter according to the relative potency of analog of comparing with parent compound or derivant, use the chemical compound that doubles the CTGF effect with half of above-mentioned parameter, use half in chemical compound of CTGF effect etc.) with the twice of above-mentioned parameter.

Randomly, described device or compositions can be separately or are comprised inflammatory cytokine (for example, TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6, and growth hormone) or its analog or derivant in addition.According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of inflammatory cytokine from 0.0001 μ g/ml to about 20mg/ml is used in the preparation.Preferably, inflammatory cytokine discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 100mg); Preferred 0.001 μ g is to 50mg.When being used as the device coating, dosage is 0.0001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.001 μ g/mm ²-200 μ g/mm ²With 10 ^-10-10 ^-4The Cmin of the inflammatory cytokine of g/ml maintains on the apparatus surface.

In addition, described device or compositions can be separately or are comprised the medicament that stimulates cellular proliferation in addition.Example comprises: dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25 dihydroxyvitamin D ₃, diethylstibesterol, Ciclosporin A, L-NAME, complete-trans retinoic acid (ATRA), and analog and derivant.Used dosage is to be proved to be those concentration (seeing that for example, embodiment 16) that stimulate cellular proliferation.According to concrete clinical practice, preparation type (for example, gel, liquid, solid, semisolid), the preparation principles of chemistry, the duration that need use, the type at medical apparatus interface and volumes of formulation and or the surface area that needs cover, the concentration range of multiplication agent from 0.0000001 to 25mg/ml is used in the preparation.Preferably, multiplication agent discharges 1-180 days the scope in period that reaches with valid density.The accumulated dose of single administration typically is no more than 500mg (0.0001 μ g is to the scope of 200mg); Preferred 0.001 μ g is to 100mg.When being used as the device coating, dosage is 0.00001 μ g-500 μ g/mm of per unit area ²Preferred dosage is 0.0001 μ g/mm ²-200 μ g/mm ²With 10 ^-11-10 ^-6The Cmin of the multiplication agent of M maintains on the apparatus surface.

Should it will be apparent to one skilled in the art that aforementioned fibers degeneration derivant, any of or derivatives thereof and analog can be used to produce the variation of above-mentioned composition under the prerequisite that does not deviate from spirit and scope of the invention.Also should it is evident that described reagent can with or be not used in the compositions and change described carrier and do not depart from scope of the present invention with polymer support.

For all previous embodiments, suitable fibre modification derivant comprises tissue stimulating agent such as silk, Silicon stone, and bleomycin, neomycin, Pulvis Talci, metallic beryllium, and copper is particularly suitable for practice of the present invention.Can be incorporated among implant or the device or on or comprise that from other reagent that described implant or device discharge extracellular matrix components such as fibrous structure protein (for example, the fibril collagen protein, non-protofibre collagen protein and elastin laminin), adhesiveness glycoprotein (for example laminin and fibronectin), proteoglycan (for example, heparin sulfate, chondroitin sulfate, dermatan sulfate), hyaluronan (for example hyaluronic acid), be rich in the acidic secretion protein (SPARC) of cysteine, thrombospondin, tenacin, the inhibitor of matrix metalloproteinase, (for example, TIMPs and synthetic property TIMPs are such as marimistat, batimistat, doxycycline, tetracycline, minocycline, TROCADE, Ro-1130830, CGS27023A, and BMS-275291) and polylysine.The somatomedin and the inflammatory cytokine that relate to the synthetic and tissue remodeling of blood vessel generation, fibroblast migration, fibroblast proliferation, ECM are such as epidermal growth factor (EGF) family, transforminggrowthfactor-(TGF-α), transforming growth factor (TGF-9-1, TGF-9-2, TGF-9-3), platelet-derived somatomedin (PDGF), fibroblast growth factor (acidity-aFGF; And alkalescence-bFGF), bone morphogenetic protein, activin, VEGF (comprises VEGF, VEGF-B, VEGF-C, placental growth factor-PIGF), angiogenin, insulin like growth factor (IGF), hepatocyte growth factor (HGF), Connective Tissue Growth Factor (CTGF), bone marrow colony stimulating factor (CSFs), granulocyte-macrophage colony stimutaing factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), M-CSF (M-CSF), erythropoietin, interleukin (IL-1 particularly, IL-8, and IL-6), tumor necrosis factor-alpha (TNF9), nerve growth factor (NGF), interferon-' alpha ', interferon-beta, and growth hormone (GH) also is suitable for discharging from concrete implant and device.Can be applied to that implant or device are gone up or comprise binding agent such as cyanoacrylate or preparation from 4-arm mercaptan PEG (10K) by other reagent of its release, 4-arm NHS PEG (10K) and methylated collagen protein are such as above-mentioned material.

In related fields of the present invention, provide the rectificating surgery implant that comprises implant or device (artificial joint, prosthetic ligament and tendon, screw, plate etc.), dental implant, blood vessel implant (particularly tremulous pulse and venous occlusion, the angiolysis implant), masculinity and femininity contraception or sterillization device and implant are used for incontinence (esophagus, urethra, anus) transplantable tissue filler, the soft palate implant, suppository, lung sealant, the surgical operation mesh (for example, hernia is repaired mesh, organization bracket), and spinal implant is (for example, artificial dish), induce fibrotic reagent in wherein said device or the implant releaser.

On the one hand, provide method to be used to prepare medical apparatus or the implant that discharges the fibre modification agent.In another aspect of this invention, provide method to be used to prepare medical apparatus or implant, it comprises the step of coating (for example, spraying is immersed, and wraps up, or passes through its drug administration) medical apparatus or implant.In addition, thus can make up described implant or medical apparatus and make device itself by in implant or induce fibrotic material to form on every side.Depend on the site and the character of required treatment, the medical apparatus of broad variety and implant can be used in the background of the present invention.

In each embodiment of the present invention, described implant or the device also applied with compositions or chemical compound, described compositions or chemical compound with the active performance of fibre modification derivant prolong to the implantation after a period of time.The representative example of these reagent comprises heparin, PLGA/MePEG, PLA, and Polyethylene Glycol.In other embodiments, fibre modification derivant implant or device before using, be activated in the process or afterwards (for example, the reagent first-selection of the non-activity on the device be activated into induce or acceleration bodies in the reagent of fibre modification reaction).

In various embodiments of the present invention, with the one side that promotes fibrotic compositions apparatus for coating or implant, part or surface, and at the another side that installs, part or surface are with stoping synulotic compositions or chemical compound to be coated with.The representative example that suppresses fibre modification and synulotic reagent comprises paclitaxel, sirolimus, everolimus, and analog and derivant.Other case description is at the same time in the application of pending trial, described application is to submit (U.S.Ser.No.60/523 on November 20th, 2003,908) and (U.S.Ser.No.60/586,861) of submitting on July 9th, 2004 be entitled as the application of " Medical Implants and Anti-Scarring Agents ".

The present invention also provides treatment to undergo a surgical operation, the patient's of the treatment of endoscope or intrusion degree minimum method, and wherein medical apparatus or implant are placed the part as program.When being used for this paper, be to be understood that " inducing fibre modification " refer to the obvious increase on the statistics of variables of scar tissue around the device or will install/implant is attached to the improvement of surrounding tissue rather than refers to any complication of device/implant or the permanent prevention of failure.

The present invention also provides the embodiment of following itemize.

1. method, it comprises that fibrous tissue from the treatment effective dose to its patient's intervertebral disc space of needs that introduce forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification reaction at patient's intervertebral disc space, useful result is provided for thus described patient.

2. the 1st method, wherein useful result is the reparation of spinal disc.

3. the 1st method, wherein said useful result is a fibrous ankylosis.

4. the 1st method, wherein said useful result is a bony ankylosis.

5. the 1st method, wherein said fibrous tissue forms agent and promotes regeneration.

6. the 1st method, wherein said fibrous tissue form agent and promote blood vessel to take place.

7. the 1st method, wherein said fibrous tissue form agent and promote the fibroblast migration.

8. the 1st method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

9. the 1st method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

10. the 1st method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

11. the 1st method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

12. the 1st method, wherein said fibrous tissue formation agent is silk or comprises silk.

13. the 1st method, wherein said fibrous tissue form agent and are silkworm silk or comprise silkworm silk.

14. the 1st method, wherein said fibrous tissue form agent and are spider silks or comprise spider silk.

15. the 1st method, wherein said fibrous tissue formation agent is the reorganization silk or comprises the reorganization silk.

16. the 1st method, wherein said fibrous tissue form agent and are raw silks or comprise raw silk.

17. the 1st method, wherein said fibrous tissue form agent and are hydrolyzed-silks or comprise hydrolyzed-silk.

18. the 1st method, wherein said fibrous tissue formation agent is acid-treated silk or comprises acid-treated silk.

19. it is the silk of acidylate or the silk that comprises acidylate that the 1st method, wherein said fibrous tissue form agent.

20. the 1st method, wherein said fibrous tissue formation agent exists with the form of chain.

21. the 1st method, wherein said fibrous tissue form agent with bunch form exist.

22. the 1st method, wherein said fibrous tissue formation agent exists with the form of microgranule.

23. the 1st method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

24. the 1st method, wherein said fibrous tissue form agent and are Talcums or comprise Talcum.

25. the 1st method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

26. the 1st method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

27. the 1st method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

28. the 1st method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin

29. the 1st method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

30. the 1st method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

31. the 30th method, wherein said fiber is biodegradable.

32. comprising, the 31st method, wherein said biodegradable line be selected from by polyester polyanhydride, poly-(acid anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen protein, chitosan, hyaluronic acid, chromic catgut, alginate, starch, the material in the group that cellulose and cellulose esters are formed.

33. the 30th method, wherein said line are not biodegradable.

34. the 33rd method, wherein said not biodegradable line comprise the material that is selected from the group of being made up of polyester, polyurethanes, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

35. the 30th method is wherein used polymer-coated described line.

36. the 30th method, wherein with medicament is coated with described line, and described medicament is induced the intravital fibre modification reaction of described patient.

37. the 30th method, wherein with medicament is coated with described line, and described medicament is induced the intravital osteogenic response of described patient.

38. the 30th method, wherein said fibrous tissue form agent and exist with particulate form.

39. the 38th method, wherein said microgranule are biodegradable granules.

40. comprising, the 39th method, wherein said biodegradable granule be selected from by polyester polyanhydride, poly-(acid anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen protein, chitosan, hyaluronic acid, chromic catgut, alginate, starch, the material in the group that cellulose and cellulose esters are formed.

41. the 38th method, wherein said granule are not biodegradable.

42. the 41st method, wherein said not biodegradable granule comprise the material that is selected from the group of being made up of polyester, polyurethanes, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

43. the 38th method, wherein said granule are the particulate form that is selected from a member in the group of being made up of silk, Talcum, starch, glass, silicate, silicon dioxide, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral matter, polymethyl methacrylate, silver nitrate, Inorganic Non-metallic Materials (ceramic) and other inorganic particles.

44. the 38th method is wherein used polymer-coated described granule.

45. the 38th method, wherein with medicament is coated with described granule, and described medicament is induced the intravital fibre modification reaction of described patient.

46. the 38th method, wherein said granule are coated with a member that is selected from the group of being made up of silk, Talcum, starch, glass, silicate, silicon dioxide, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral matter, polymethyl methacrylate, silver nitrate, Inorganic Non-metallic Materials and other inorganic particles.

47. the 38th method, wherein said granule is coated with medicament, and described medicament is induced the intravital osteogenic response of described patient.

48. the 1st method, wherein said compositions also comprises the medicament of promote osteogenesis.

49. the 48th method, wherein the fibrous tissue of promote osteogenesis formation agent is a bone morphogenetic protein.

50. the 48th method, wherein the fibrous tissue of promote osteogenesis formation agent is an osteogenic growth factor.

51. the 50th method, wherein said osteogenic growth factor are selected from transforming growth factor, platelet-derived somatomedin, and fibroblast growth factor.

52. also comprising, the 1st method, wherein said compositions induce hardened medicament (sclerosing agent).

53. the 52nd method, wherein said sclerosing agent is selected from the group of being made up of ethanol, dimethyl sulfoxine, sucrose, sodium chloride, glucose, glycerol, minocycline, tetracycline, doxycycline, polidocanol, sodium tetradecyl sulfate, sodium morrhuate and sotradecol.

54. the 52nd method, wherein said sclerosing agent is a surfactant.

55. the 1st method, wherein said compositions also comprises inflammatory cytokine.

56. the 55th method, wherein said inflammatory cytokine are selected from the group of TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-1-β, IL-8, IL-6 and growth hormone composition.

57. the 1st method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

58. the 57th method, the wherein said fibrous tissue that stimulates cellular proliferation forms agent and is selected from by dexamethasone, isotretinoin (13-cis-retinoic acid), 17-, estradiol, 1-α-25-dihydroxyvitamin D ₃, in the group formed of diethylstibesterol, Ciclosporin A, L-NAME, all-trans retinoic acid (ATRA) and analog thereof and derivant.

59. the 1st method, wherein said compositions also comprises filler.

60. the 1st method, wherein said compositions also comprises sealant.

61. the 1st method, wherein said compositions also comprises polymer support.

62. the 61st method, wherein said polymer support provide the lasting release of described compositions active component.

63. the 61st method, wherein said polymer support are not biodegradable materials.

64. the 63rd method, wherein said not biodegradable material is crosslinked.

65. the 64th method, wherein said crosslinked not biodegradable material comprises the cross-linked form of polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide, methyl methacrylate or copolymer of methyl methacrylatestyrene.

66. the 63rd method, wherein said not biodegradable material is hydrogel (hydogel).

67. the 61st method, wherein said polymer support are biodegradable materials.

68. the 67th method, wherein said biodegradable material is crosslinked material, its preparation is from Polyethylene Glycol, gelatin, collagen protein, bone allograft, mescenchymal stem cell, hyaluronic acid, derivatives of hyaluronic acids, polysaccharide, carbohydrate, protein, the bone from body, the bone matrix that demineralizes, cellulose derivative, chitosan, chitosan derivative, and polyester-polyalkylene oxide block copolymer, or introduced its unit.

69. the 61st method, wherein said polymer support preparation is from 4-arm (armed) mercaptan PEG, 4-arm NHS PEG and methylated collagen protein.

70. the 1st method, wherein said compositions also comprise can resorbent Inorganic Non-metallic Materials.

71. the 70th method, wherein said can comprising by resorbent Inorganic Non-metallic Materials, or preparation is selected from by-tricalcium phosphate hydroxyapatite, Ca certainly ₁₀(PO ₄) ₆Material in the group that OH, calcium carbonate, calcium sulfate and calcium phosphate are formed.

72. the 1st method, wherein said compositions also comprises contrast agent.

73. the 72nd method, wherein said contrast agent has response to X ray.

74. the 73rd method, wherein said contrast agent are barium, tantalum, technetium, or gadolinium.

75. the 1st method, wherein said compositions also comprises line.

76. the 75th method, wherein said line is biodegradable.

77. comprising, the 76th method, wherein said biodegradable line be selected from by polyester polyanhydride, poly-(acid anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen protein, chitosan, hyaluronic acid, chromic catgut, alginate, starch, the material in the group that cellulose and cellulose esters are formed.

78. the 75th method, wherein said line are not biodegradable.

79. the 78th method, wherein said not biodegradable line comprise the material that is selected from the group of being made up of polyester, polyurethanes, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

80. the 75th method, wherein said line is coated with polymer.

81. the 75th method, wherein said line is coated with medicament, and described medicament is induced the intravital fibre modification reaction of described patient.

82. the 75th method, wherein said line is coated with medicament, and described medicament is induced the intravital osteogenic response of described patient.

83. the 1st method, wherein said compositions exists with the form of gel.

84. the 1st method, wherein said compositions exists with the form of paste.

85. the 1st method, wherein said compositions exists with the form of spray.

86. the 1st method, wherein said compositions exists with aerocolloidal form.

87. the 1st method, wherein said compositions exists with the form of suspension.

88. the 1st method, wherein said compositions exists with the form of Emulsion or microemulsion.

89. the 1st method, wherein said compositions exists with the form of microsphere.

90. the 1st method, wherein said compositions exists with the form of microgranule.

91. the 1st method, wherein said compositions exists with the form of solid implant.

92. an injectable compositions, it comprises fibrous tissue and forms agent and filler.

93. the 92nd compositions, wherein said fibrous tissue form agent and promote fibre modification and promote regeneration.

94. forming agent, the 92nd compositions, wherein said fibrous tissue promote blood vessel to take place.

95. the 92nd compositions, wherein said fibrous tissue form agent and promote the fibroblast migration.

96. the 92nd compositions, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

97. the 92nd compositions, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

98. the 92nd compositions, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

99. the 92nd compositions, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

100. the 92nd compositions, wherein said fibrous tissue formation agent is silk or comprises silk.

101. the 92nd compositions, wherein said fibrous tissue form agent and are silkworm silk or comprise silkworm silk.

102. the 92nd compositions, wherein said fibrous tissue form agent and are spider silks or comprise spider silk.

103. the 92nd compositions, wherein said fibrous tissue form agent and are the recombinant silks or comprise the recombinant silk.

104. the 92nd compositions, wherein said fibrous tissue form agent and are raw silks or comprise raw silk.

105. the 92nd compositions, wherein said fibrous tissue form agent and are hydrolyzed-silks or comprise hydrolyzed-silk.

106. the 92nd compositions, wherein said fibrous tissue formation agent are with acid-treated silk or comprise with acid-treated silk.

107. the 92nd compositions, wherein said fibrous tissue formation agent is acylated silk or comprises acylated silk.

108. the 92nd compositions, wherein said fibrous tissue formation agent exists with the form of chain.

109. the 92nd compositions, wherein said fibrous tissue form agent with bunch form exist.

110. the 92nd compositions, wherein said fibrous tissue formation agent exists with the form of microgranule.

111. the 92nd compositions, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

112. the 92nd compositions, wherein said fibrous tissue form agent and are Talcums or comprise Talcum.

113. the 92nd compositions, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

114. the 92nd compositions, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

115. the 92nd compositions, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

116. the 92nd compositions, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

117. the 92nd compositions, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

118. the 92nd compositions, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

119. the 118th compositions, wherein said line is biodegradable.

120. comprising, the 119th compositions, wherein said biodegradable line be selected from by polyester polyanhydride, poly-(acid anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen protein, chitosan, hyaluronic acid, chromic catgut, alginate, starch, the material in the group that cellulose and cellulose esters are formed.

121. the 118th compositions, wherein said fiber are not biodegradable.

122. the 121st compositions, wherein said not biodegradable line comprise the material that is selected from the group of being made up of polyester, polyurethanes, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

123. the 118th compositions, wherein said line is coated with polymer.

124. the 118th compositions, wherein said line is coated with medicament, and described medicament is induced the intravital fibre modification reaction of described patient.

125. the 118th compositions, wherein said line is coated with medicament, and described medicament is induced the intravital osteogenic response of described patient.

126. the 92nd compositions, wherein said fibrous tissue form agent and exist with particulate form.

127. the 126th compositions, wherein said microgranule are biodegradable granules.

128. comprising, the 127th compositions, wherein said biodegradable granule be selected from by polyester polyanhydride, poly-(acid anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen protein, chitosan, hyaluronic acid, chromic catgut, alginate, starch, the material in the group that cellulose and cellulose esters are formed.

129. the 126th compositions, wherein said granule are not biodegradable.

130. the 129th compositions, wherein said not biodegradable granule comprise the material that is selected from the group of being made up of polyester, polyurethanes, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

131. the 126th compositions, wherein said granule exists with the particle form that is selected from a member in the group of being made up of silk, Talcum, starch, glass, silicate, silicon dioxide, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral matter, polymethyl methacrylate, silver nitrate, Inorganic Non-metallic Materials and other inorganic particles.

132. the 126th compositions, wherein said granule is coated with polymer.

133. the 126th compositions, wherein said granule is coated with medicament, and described medicament is induced the intravital fibre modification reaction of described patient.

134. the 126th compositions, wherein said granule are coated with a member that is selected from the group of being made up of silk, Talcum, starch, glass, silicate, silicon dioxide, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral matter, polymethyl methacrylate, silver nitrate, Inorganic Non-metallic Materials and other inorganic particles.

135. the 126th compositions, wherein said granule is coated with medicament, and described medicament is induced the intravital osteogenic response of described patient.

136. the 92nd method, wherein said compositions also comprises the medicament of promote osteogenesis.

137. the 136th compositions, wherein the fibrous tissue of promote osteogenesis formation agent is a bone morphogenetic protein.

138. the 136th compositions, wherein the fibrous tissue of promote osteogenesis formation agent is an osteogenic growth factor.

139. the 138th compositions, wherein said osteogenic growth factor are selected from transforming growth factor, platelet-derived somatomedin, and fibroblast growth factor.

140. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, the treatment of capsula articularis humeri damage (shoulder capsule injury) is provided for thus described patient.

141. the 140th method, wherein said fibrous tissue forms agent and promotes regeneration.

142. forming agent, the 140th method, wherein said fibrous tissue promote blood vessel to take place.

143. the 140th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

144. the 140th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

145. the 140th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

146. the 140th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

147. the 140th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

148. the 140th method, wherein said fibrous tissue formation agent is silk or comprises silk.

149. the 140th method, wherein said fibrous tissue form agent with bunch form exist.

150. the 140th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

151. the 140th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

152. the 140th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

153. the 140th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

154. the 140th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

155. the 140th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

156. the 140th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

157. the 140th method, wherein said fibrous tissue form agent and exist with particulate form.

158. the 140th method, wherein said compositions comprises polymer.

159. the 140th method, wherein said compositions comprises polymer, and described polymer is copolymer or comprises copolymer.

160. the 140th method, wherein said compositions comprises polymer, and described polymer is block copolymer or comprises block copolymer.

161. the 140th method, wherein said compositions comprises polymer, and described polymer is random copolymer or comprises random copolymer.

162. the 140th method, wherein said compositions comprises polymer, and described polymer is biodegradable polymer or comprises biodegradable polymer.

163. the 140th method, wherein said compositions comprises polymer, and described polymer is not biodegradable polymer or comprises not biodegradable polymer.

164. the 140th method, wherein said compositions comprises polymer, and described polymer is hydrophilic polymer or comprises hydrophilic polymer.

165. the 140th method, wherein said compositions comprises polymer, and described polymer is hydrophobic polymer or comprises hydrophobic polymer.

166. the 140th method, wherein said compositions comprises polymer, and described polymer is the polymer in possess hydrophilic property zone or the polymer that comprises the possess hydrophilic property zone.

167. the 140th method, wherein said compositions comprises polymer, and described polymer is to have the polymer of water repellent region or comprise the polymer with water repellent region.

168. the 140th method, wherein said compositions comprises polymer, and described polymer is non-conductive polymer or comprises non-conductive polymer.

169. the 140th method, wherein said compositions comprises polymer, and described polymer is elastomer or comprises elastomer.

170. the 140th method, wherein said compositions comprises polymer, and described polymer is hydrogel or comprises hydrogel.

171. the 140th method, wherein said compositions comprises polymer, and described polymer is siloxane polymer or comprises siloxane polymer.

172. the 140th method, wherein said compositions comprises polymer, and described polymer is hydrocarbon polymer or comprises hydrocarbon polymer.

173. the 140th method, wherein said compositions comprises polymer, and described polymer is the styrene derived polymers or comprises the styrene derived polymers.

174. the 140th method, wherein said compositions comprises polymer, and described polymer is the butadiene derived polymers or comprises the butadiene derived polymers.

175. the 140th method, wherein said compositions comprises polymer, and described polymer is macromonomer or comprises macromonomer.

176. the 140th method, wherein said compositions comprises polymer, and described polymer is poly-(ethylene glycol) polymer or comprises poly-(ethylene glycol) polymer.

177. the 140th method, wherein said compositions comprises polymer, and described polymer is amorphous polymer or comprises amorphous polymer.

178. the 140th method, wherein said compositions also comprises second forms of pharmacologically active agents.

179. the 140th method, wherein said compositions also comprises antiinflammatory.

180. the 140th method, wherein said compositions also comprise the medicament that suppresses infection.

181. the 140th method, wherein said compositions also comprises anthracycline.

182. the 140th method, wherein said compositions also comprises doxorubicin.

183. the 140th method, wherein said compositions also comprises mitoxantrone.

184. the 140th method, wherein said compositions also comprises the fluorine pyrimidine.

185. the 140th method, wherein said compositions also comprise 5-fluorouracil (5-FU).

186. the 140th method, wherein said compositions also comprises antifol.

187. the 140th method, wherein said compositions also comprises methotrexate.

188. the 140th method, wherein said compositions also comprises podophyllotoxin.

189. the 140th method, wherein said compositions also comprises etoposide.

190. the 140th method, wherein said compositions also comprises camptothecine.

191. the 140th method, wherein said compositions also comprises hydroxyurea.

192. the 140th method, wherein said compositions also comprises platinum complex.

193. the 140th method, wherein said compositions also comprises cisplatin.

194. the 140th method, wherein said compositions also comprises antithrombotic agent.

195. the 140th method, wherein said compositions also comprises developing agent.

196. the 140th method, wherein said compositions also comprises developing agent, and described developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

197. the 140th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

198. the 140th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises MRI response material.

199. the 140th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

200. the 140th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper, or chromium.

201. the 140th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

202. the 140th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment, or coloring agent.

203. the 140th method wherein forms agent from the compositions that contains fibrous tissue formation agent by the fibrous tissue that diffusion discharges valid density in from time of administration to about 90 days period.

204. the 140th method wherein forms agent from the compositions that contains fibrous tissue formation agent by the fibrous tissue that corrodes said composition release valid density in from time of administration to about 90 days period.

205. the 140th method, wherein said compositions also comprises inflammatory cytokine.

206. the 140th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

207. the 140th method, wherein said compositions also comprises polymer support.

208. the 140th method, wherein said compositions exists with the form of gel, paste or spray.

209. the 140th method is wherein sent described fibrous tissue from a kind of device and is formed agent, and described device is delivered locally to described fibrous tissue formation agent press close in the tissue of described device.

210. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating comprises described fibrous tissue formation agent.

211. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is placed on the surface of described device.

212. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating directly contacts described device.

213. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contacts described device indirectly.

214. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and wherein said coating layer portion ground covers described device.

215. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating fully covers described device.

216. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

217. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

218. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo (echogenic).

219. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo, and the material of wherein said generation echo exists with the form of coating.

220. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device is aseptic.

221. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

222. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

223. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

224. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

225. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

226. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 year period in disposing described device.

227. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 month to 6 months period.

228. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device in 1-90 days period.

229. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device with constant speed.

230. the 140th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

231. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

232. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

233. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10 μ g to about 10mg.

234. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10mg to about 250mg.

235. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 250mg to about 1000mg.

236. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 1000mg to about 2500mg.

237. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, the described fibrous tissue that the surface of wherein said device comprises less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

238. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

239. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

240. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

241. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

242. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

243. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a uniform coating.

244. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a non-uniform coating.

245. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a discontinuous coating.

246. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is to form the coating of pattern.

247. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 100 μ m or littler thickness.

248. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 10 μ m or littler thickness.

249. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is being disposed the surface adhesion that this installs later and this device.

250. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, described coating in room temperature at least 1 year the time interim be stable.

251. the 140th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

252. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

253. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

254. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

255. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contains polymer.

256. the 140th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises first coating with first compositions and second coating with second compositions.

257. the 140th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device comprises first coating with first compositions and second coating with second compositions, and wherein said first compositions is different with second compositions.

258. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, provides ligament repair to the patient thus.

259. the 258th method, wherein said fibrous tissue forms agent and promotes regeneration.

260. forming agent, the 258th method, wherein said fibrous tissue promote blood vessel to take place.

261. the 258th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

262. the 258th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

263. the 258th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

264. the 258th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

265. the 258th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

266. the 258th method, wherein said fibrous tissue formation agent is silk or comprises silk.

267. the 258th method, wherein said fibrous tissue form agent with bunch form exist.

268. the 258th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

269. the 258th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

270. the 258th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

271. the 258th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

272. the 258th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

273. the 258th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

274. the 258th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

275. the 258th method, wherein said fibrous tissue form agent and exist with particulate form.

276. the 258th method, wherein said compositions comprises polymer.

277. the 258th method, wherein said compositions comprises polymer, and described polymer is copolymer or comprises copolymer.

278. the 258th method, wherein said compositions comprises polymer, and described polymer is block copolymer or comprises block copolymer.

279. the 258th method, wherein said compositions comprises polymer, and described polymer is random copolymer or comprises random copolymer.

280. the 258th method, wherein said compositions comprises polymer, and described polymer is biodegradable polymer or comprises biodegradable polymer.

281. the 258th method, wherein said compositions comprises polymer, and described polymer is not biodegradable polymer or comprises not biodegradable polymer.

282. the 258th method, wherein said compositions comprises polymer, and described polymer is hydrophilic polymer or comprises hydrophilic polymer.

283. the 258th method, wherein said compositions comprises polymer, and described polymer is hydrophobic polymer or comprises hydrophobic polymer.

284. the 258th method, wherein said compositions comprises polymer, and described polymer is the polymer in possess hydrophilic property zone or the polymer that comprises the possess hydrophilic property zone.

285. the 258th method, wherein said compositions comprises polymer, and described polymer is to have the polymer of water repellent region or comprise the polymer with water repellent region.

286. the 258th method, wherein said compositions comprises polymer, and described polymer is non-conductive polymer or comprises non-conductive polymer.

287. the 258th method, wherein said compositions comprises polymer, and described polymer is elastomer or comprises elastomer.

288. the 258th method, wherein said compositions comprises polymer, and described polymer is hydrogel or comprises hydrogel.

289. the 258th method, wherein said compositions comprises polymer, and described polymer is siloxane polymer or comprises siloxane polymer.

290. the 258th method, wherein said compositions comprises polymer, and described polymer is hydrocarbon polymer or comprises hydrocarbon polymer.

291. the 258th method, wherein said compositions comprises polymer, and described polymer is the styrene derived polymers or comprises the styrene derived polymers.

292. the 258th method, wherein said compositions comprises polymer, and described polymer is the butadiene derived polymers or comprises the butadiene derived polymers.

293. the 258th method, wherein said compositions comprises polymer, and described polymer is macromonomer or comprises macromonomer.

294. the 258th method, wherein said compositions comprises polymer, and described polymer is poly-(ethylene glycol) polymer or comprises poly-(ethylene glycol) polymer.

295. the 258th method, wherein said compositions comprises polymer, and described polymer is amorphous polymer or comprises amorphous polymer.

296. the 258th method, wherein said compositions also comprises second forms of pharmacologically active agents.

297. the 258th method, wherein said compositions also comprises antiinflammatory.

298. the 258th method, wherein said compositions also comprise the medicament that suppresses infection.

299. the 258th method, wherein said compositions also comprises anthracycline.

300. the 258th method, wherein said compositions also comprises doxorubicin.

301. the 258th method, wherein said compositions also comprises mitoxantrone.

302. the 258th method, wherein said compositions also comprises the fluorine pyrimidine.

303. the 258th method, wherein said compositions also comprise 5-fluorouracil (5-FU).

304. the 258th method, wherein said compositions also comprises antifol.

305. the 258th method, wherein said compositions also comprises methotrexate.

306. the 258th method, wherein said compositions also comprises podophyllotoxin.

307. the 258th method, wherein said compositions also comprises etoposide.

308. the 258th method, wherein said compositions also comprises camptothecine.

309. the 258th method, wherein said compositions also comprises hydroxyurea.

310. the 258th method, wherein said compositions also comprises platinum complex.

311. the 258th method, wherein said compositions also comprises cisplatin.

312. the 258th method, wherein said compositions also comprises antithrombotic agent.

313. the 258th method, wherein said compositions also comprises developing agent.

314. the 258th method, wherein said compositions also comprises developing agent, and described developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

315. the 258th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

316. the 258th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises MRI response material.

317. the 258th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

318. the 258th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper, or chromium.

319. the 258th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

320. the 258th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment, or coloring agent.

321. the 258th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from discharging with valid density to about 90 days period in the administration.

322. the 258th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from discharging with valid density to about 90 days period in the administration.

323. the 258th method, wherein said compositions also comprises inflammatory cytokine.

324. the 258th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

325. the 258th method, wherein said compositions also comprises polymer support.

326. the 258th method, wherein said compositions exists with the form of gel, paste or spray.

327. the 258th method is wherein sent described fibrous tissue from a kind of device and is formed agent, and described device is delivered locally to described fibrous tissue formation agent press close in the tissue of described device.

328. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating comprises described fibrous tissue formation agent.

329. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is placed on the surface of described device.

330. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating directly contacts described device.

331. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contacts described device indirectly.

332. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and wherein said coating layer portion ground covers described device.

333. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating fully covers described device.

334. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

335. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

336. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo.

337. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo, and the material of wherein said generation echo exists with the form of coating.

338. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device is aseptic.

339. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

340. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

341. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

342. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

343. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

344. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 year period in disposing described device.

345. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 month to 6 months period.

346. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device in about 1-90 days period

347. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device with constant speed.

348. the 258th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

349. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

350. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

351. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10 μ g to about 10mg.

352. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10mg to about 250mg.

353. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 250mg to about 1000mg.

354. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 1000mg to about 2500mg.

355. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, the described fibrous tissue that the surface of wherein said device comprises less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

356. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

357. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

358. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

359. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

360. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

361. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a uniform coating.

362. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a non-uniform coating.

363. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a discontinuous coating.

364. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is to form the coating of pattern.

365. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 100 μ m or littler thickness.

366. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 10 μ m or littler thickness.

367. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is being disposed the surface adhesion that this installs later and this device.

368. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, described coating in room temperature at least 1 year the time interim be stable.

369. the 258th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between the approximate weight 1% between about 0.0001 weight %.

370. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

371. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

372. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

373. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contains polymer.

374. the 258th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises first coating with first compositions and second coating with second compositions.

375. the 258th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device comprises first coating with first compositions and second coating with second compositions, and wherein said first compositions is different with second compositions.

376. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, provides the tendon reparation to the patient thus.

377. the 376th method, wherein said fibrous tissue forms agent and promotes regeneration.

378. forming agent, the 376th method, wherein said fibrous tissue promote blood vessel to take place.

379. the 376th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

380. the 376th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

381. the 376th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

382. the 376th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

383. the 376th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

384. the 376th method, wherein said fibrous tissue formation agent is silk or comprises silk.

385. the 376th method, wherein said fibrous tissue form agent with bunch form exist.

386. the 376th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

387. the 376th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

388. the 376th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

389. the 376th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

390. the 376th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

391. the 376th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

392. the 376th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

393. the 376th method, wherein said fibrous tissue form agent and exist with particulate form.

394. the 376th method, wherein said compositions comprises polymer.

395. the 376th method, wherein said compositions comprises polymer, and described polymer is copolymer or comprises copolymer.

396. the 376th method, wherein said compositions comprises polymer, and described polymer is block copolymer or comprises block copolymer.

397. the 376th method, wherein said compositions comprises polymer, and described polymer is random copolymer or comprises random copolymer.

398. the 376th method, wherein said compositions comprises polymer, and described polymer is biodegradable polymer or comprises biodegradable polymer.

399. the 376th method, wherein said compositions comprises polymer, and described polymer is not biodegradable polymer or comprises not biodegradable polymer.

400. the 376th method, wherein said compositions comprises polymer, and described polymer is hydrophilic polymer or comprises hydrophilic polymer.

401. the 376th method, wherein said compositions comprises polymer, and described polymer is hydrophobic polymer or comprises hydrophobic polymer.

402. the 376th method, wherein said compositions comprises polymer, and described polymer is the polymer in possess hydrophilic property zone or the polymer that comprises the possess hydrophilic property zone.

403. the 376th method, wherein said compositions comprises polymer, and described polymer is to have the polymer of water repellent region or comprise the polymer with water repellent region.

404. the 376th method, wherein said compositions comprises polymer, and described polymer is non-conductive polymer or comprises non-conductive polymer.

405. the 376th method, wherein said compositions comprises polymer, and described polymer is elastomer or comprises elastomer.

406. the 376th method, wherein said compositions comprises polymer, and described polymer is hydrogel or comprises hydrogel.

407. the 376th method, wherein said compositions comprises polymer, and described polymer is siloxane polymer or comprises siloxane polymer.

408. the 376th method, wherein said compositions comprises polymer, and described polymer is hydrocarbon polymer or comprises hydrocarbon polymer.

409. the 376th method, wherein said compositions comprises polymer, and described polymer is the styrene derived polymers or comprises the styrene derived polymers.

410. the 376th method, wherein said compositions comprises polymer, and described polymer is the butadiene derived polymers or comprises the butadiene derived polymers.

411. the 376th method, wherein said compositions comprises polymer, and described polymer is macromonomer or comprises macromonomer.

412. the 376th method, wherein said compositions comprises polymer, and described polymer is poly-(ethylene glycol) polymer or comprises poly-(ethylene glycol) polymer.

413. the 376th method, wherein said compositions comprises polymer, and described polymer is amorphous polymer or comprises amorphous polymer.

414. the 376th method, wherein said compositions also comprises second forms of pharmacologically active agents.

415. the 376th method, wherein said compositions also comprises antiinflammatory.

416. the 376th method, wherein said compositions also comprise the medicament that suppresses infection.

417. the 376th method, wherein said compositions also comprises anthracycline.

418. the 376th method, wherein said compositions also comprises doxorubicin.

419. the 376th method, wherein said compositions also comprises mitoxantrone.

420. the 376th method, wherein said compositions also comprises the fluorine pyrimidine.

421. the 376th method, wherein said compositions also comprise 5-fluorouracil (5-FU).

422. the 376th method, wherein said compositions also comprises antifol.

423. the 376th method, wherein said compositions also comprises methotrexate.

424. the 376th method, wherein said compositions also comprises podophyllotoxin.

425. the 376th method, wherein said compositions also comprises etoposide.

426. the 376th method, wherein said compositions also comprises camptothecine.

427. the 376th method, wherein said compositions also comprises hydroxyurea.

428. the 376th method, wherein said compositions also comprises platinum complex.

429. the 376th method, wherein said compositions also comprises cisplatin.

430. the 376th method, wherein said compositions also comprises antithrombotic agent.

431. the 376th method, wherein said compositions also comprises developing agent.

432. the 376th method, wherein said compositions also comprises developing agent, and described developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

433. the 376th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

434. the 376th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises MRI response material.

435. the 376th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

436. the 376th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper, or chromium.

437. the 376th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

438. the 376th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment, or coloring agent.

439. the 376th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

440. the 376th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

441. the 376th method, wherein said compositions also comprises inflammatory cytokine.

442. the 376th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

443. the 376th method, wherein said compositions also comprises polymer support.

444. the 376th method, wherein said compositions exists with the form of gel, paste or spray.

445. the 376th method is wherein sent described fibrous tissue from a kind of device and is formed agent, and described device is delivered locally to described fibrous tissue formation agent press close in the tissue of described device.

446. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating comprises described fibrous tissue formation agent.

447. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is placed on the surface of described device.

448. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating directly contacts described device.

449. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contacts described device indirectly.

450. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and wherein said coating layer portion ground covers described device.

451. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating fully covers described device.

452. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

453. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

454. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo.

455. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo, and the material of wherein said generation echo exists with the form of coating.

456. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device is aseptic.

457. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

458. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

459. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

460. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

461. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

462. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 year period in disposing described device.

463. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 month to 6 months period.

464. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device in about 1-90 days period

465. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device with constant speed.

466. the 376th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

467. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

468. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

469. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10 μ g to about 10mg.

470. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10mg to about 250mg.

471. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 250mg to about 1000mg.

472. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 1000mg to about 2500mg.

473. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, the described fibrous tissue that the surface of wherein said device comprises less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

474. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

475. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

476. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

477. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

478. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

479. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a uniform coating.

480. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a non-uniform coating.

481. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a discontinuous coating.

482. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is to form the coating of pattern.

483. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 100 μ m or littler thickness.

484. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 10 μ m or littler thickness.

485. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is being disposed the surface adhesion that this installs later and this device.

486. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, described coating in room temperature at least 1 year the time interim be stable.

487. the 376th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

488. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

489. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

490. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

491. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contains polymer.

492. the 376th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises first coating with first compositions and second coating with second compositions.

493. the 376th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device comprises first coating with first compositions and second coating with second compositions, and wherein said first compositions is different with second compositions.

494. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, provides the hernia reparation to the patient thus.

495. the 494th method, wherein said fibrous tissue forms agent and promotes regeneration.

496. forming agent, the 494th method, wherein said fibrous tissue promote blood vessel to take place.

497. the 494th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

498. the 494th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

499. the 494th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

500. the 494th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

501. the 494th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

502. the 494th method, wherein said fibrous tissue formation agent is silk or comprises silk.

503. the 494th method, wherein said fibrous tissue form agent with bunch form exist.

504. the 494th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

505. the 494th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

506. the 494th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

507. the 494th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

508. the 494th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

509. the 494th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

510. the 494th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

511. the 494th method, wherein said fibrous tissue form agent and exist with particulate form.

512. the 494th method, wherein said compositions comprises polymer.

513. the 494th method, wherein said compositions comprises polymer, and described polymer is copolymer or comprises copolymer.

514. the 494th method, wherein said compositions comprises polymer, and described polymer is block copolymer or comprises block copolymer.

515. the 494th method, wherein said compositions comprises polymer, and described polymer is random copolymer or comprises random copolymer.

516. the 494th method, wherein said compositions comprises polymer, and described polymer is biodegradable polymer or comprises biodegradable polymer.

517. the 494th method, wherein said compositions comprises polymer, and described polymer is not biodegradable polymer or comprises not biodegradable polymer.

518. the 494th method, wherein said compositions comprises polymer, and described polymer is hydrophilic polymer or comprises hydrophilic polymer.

519. the 494th method, wherein said compositions comprises polymer, and described polymer is hydrophobic polymer or comprises hydrophobic polymer.

520. the 494th method, wherein said compositions comprises polymer, and described polymer is the polymer in possess hydrophilic property zone or the polymer that comprises the possess hydrophilic property zone.

521. the 494th method, wherein said compositions comprises polymer, and described polymer is to have the polymer of water repellent region or comprise the polymer with water repellent region.

522. the 494th method, wherein said compositions comprises polymer, and described polymer is non-conductive polymer or comprises non-conductive polymer.

523. the 494th method, wherein said compositions comprises polymer, and described polymer is elastomer or comprises elastomer.

524. the 494th method, wherein said compositions comprises polymer, and described polymer is hydrogel or comprises hydrogel.

525. the 494th method, wherein said compositions comprises polymer, and described polymer is siloxane polymer or comprises siloxane polymer.

526. the 494th method, wherein said compositions comprises polymer, and described polymer is hydrocarbon polymer or comprises hydrocarbon polymer.

527. the 494th method, wherein said compositions comprises polymer, and described polymer is the styrene derived polymers or comprises the styrene derived polymers.

528. the 494th method, wherein said compositions comprises polymer, and described polymer is the butadiene derived polymers or comprises the butadiene derived polymers.

529. the 494th method, wherein said compositions comprises polymer, and described polymer is macromonomer or comprises macromonomer.

530. the 494th method, wherein said compositions comprises polymer, and described polymer is poly-(ethylene glycol) polymer or comprises poly-(ethylene glycol) polymer.

531. the 494th method, wherein said compositions comprises polymer, and described polymer is amorphous polymer or comprises amorphous polymer.

532. the 494th method, wherein said compositions also comprises second forms of pharmacologically active agents.

533. the 494th method, wherein said compositions also comprises antiinflammatory.

534. the 494th method, wherein said compositions also comprise the medicament that suppresses infection.

535. the 494th method, wherein said compositions also comprises anthracycline.

536. the 494th method, wherein said compositions also comprises doxorubicin.

537. the 494th method, wherein said compositions also comprises mitoxantrone.

538. the 494th method, wherein said compositions also comprises the fluorine pyrimidine.

539. the 494th method, wherein said compositions also comprise 5-fluorouracil (5-FU).

540. the 494th method, wherein said compositions also comprises antifol.

541. the 494th method, wherein said compositions also comprises methotrexate.

542. the 494th method, wherein said compositions also comprises podophyllotoxin.

543. the 494th method, wherein said compositions also comprises etoposide.

544. the 494th method, wherein said compositions also comprises camptothecine.

545. the 494th method, wherein said compositions also comprises hydroxyurea.

546. the 494th method, wherein said compositions also comprises platinum complex.

547. the 494th method, wherein said compositions also comprises cisplatin.

548. the 494th method, wherein said compositions also comprises antithrombotic agent.

549. the 494th method, wherein said compositions also comprises developing agent.

550. the 494th method, wherein said compositions also comprises developing agent, and described developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

551. the 494th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

552. the 494th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises MRI response material.

553. the 494th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

554. the 494th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper, or chromium.

555. the 494th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

556. the 494th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment, or coloring agent.

557. the 494th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

558. the 494th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

559. the 494th method, wherein said compositions also comprises inflammatory cytokine.

560. the 494th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

561. the 494th method, wherein said compositions also comprises polymer support.

562. the 494th method, wherein said compositions exists with the form of gel, paste or spray.

563. the 494th method is wherein sent described fibrous tissue from a kind of device and is formed agent, and described device is delivered locally to described fibrous tissue formation agent press close in the tissue of described device.

564. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating comprises described fibrous tissue formation agent.

565. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is placed on the surface of described device.

566. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating directly contacts described device.

567. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contacts described device indirectly.

568. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and wherein said coating layer portion ground covers described device.

569. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating fully covers described device.

570. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

571. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

572. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo.

573. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo, and the material of wherein said generation echo exists with the form of coating.

574. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device is aseptic.

575. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

576. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

577. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

578. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

579. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

580. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 year period in disposing described device.

581. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 month to 6 months period.

582. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device in about 1-90 days period

583. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device with constant speed.

584. the 494th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

585. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

586. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

587. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10 μ g to about 10mg.

588. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10mg to about 250mg.

589. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 250mg to about 1000mg.

590. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 1000mg to about 2500mg.

591. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, the described fibrous tissue that the surface of wherein said device comprises less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

592. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

593. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

594. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

595. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

596. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

597. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a uniform coating.

598. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a non-uniform coating.

599. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a discontinuous coating.

600. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is to form the coating of pattern.

601. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 100 μ m or littler thickness.

602. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 10 μ m or littler thickness.

603. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is being disposed the surface adhesion that this installs later and this device.

604. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, described coating in room temperature at least 1 year the time interim be stable.

605. the 494th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

606. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

607. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

608. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

609. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contains polymer.

610. the 494th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises first coating with first compositions and second coating with second compositions.

611. the 494th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device comprises first coating with first compositions and second coating with second compositions, and wherein said first compositions is different with second compositions.

612. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, and the sealing of lung is provided to the patient thus.

613. the 612nd method, wherein said fibrous tissue forms agent and promotes regeneration.

614. forming agent, the 612nd method, wherein said fibrous tissue promote blood vessel to take place.

615. the 612nd method, wherein said fibrous tissue form agent and promote the fibroblast migration.

616. the 612nd method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

617. the 612nd method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

618. the 612nd method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

619. the 612nd method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

620. the 612nd method, wherein said fibrous tissue formation agent is silk or comprises silk.

621. the 612nd method, wherein said fibrous tissue form agent with bunch form exist.

622. the 612nd method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

623. the 612nd method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

624. the 612nd method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

625. the 612nd method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

626. the 612nd method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

627. the 612nd method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

628. the 612nd method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

629. the 612nd method, wherein said fibrous tissue form agent and exist with particulate form.

630. the 612nd method, wherein said compositions comprises polymer.

631. the 612nd method, wherein said compositions comprises polymer, and described polymer is copolymer or comprises copolymer.

632. the 612nd method, wherein said compositions comprises polymer, and described polymer is block copolymer or comprises block copolymer.

633. the 612nd method, wherein said compositions comprises polymer, and described polymer is random copolymer or comprises random copolymer.

634. the 612nd method, wherein said compositions comprises polymer, and described polymer is biodegradable polymer or comprises biodegradable polymer.

635. the 612nd method, wherein said compositions comprises polymer, and described polymer is not biodegradable polymer or comprises not biodegradable polymer.

636. the 612nd method, wherein said compositions comprises polymer, and described polymer is hydrophilic polymer or comprises hydrophilic polymer.

637. the 612nd method, wherein said compositions comprises polymer, and described polymer is hydrophobic polymer or comprises hydrophobic polymer.

638. the 612nd method, wherein said compositions comprises polymer, and described polymer is the polymer in possess hydrophilic property zone or the polymer that comprises the possess hydrophilic property zone.

639. the 612nd method, wherein said compositions comprises polymer, and described polymer is to have the polymer of water repellent region or comprise the polymer with water repellent region.

640. the 612nd method, wherein said compositions comprises polymer, and described polymer is non-conductive polymer or comprises non-conductive polymer.

641. the 612nd method, wherein said compositions comprises polymer, and described polymer is elastomer or comprises elastomer.

642. the 612nd method, wherein said compositions comprises polymer, and described polymer is hydrogel or comprises hydrogel.

643. the 612nd method, wherein said compositions comprises polymer, and described polymer is siloxane polymer or comprises siloxane polymer.

644. the 612nd method, wherein said compositions comprises polymer, and described polymer is hydrocarbon polymer or comprises hydrocarbon polymer.

645. the 612nd method, wherein said compositions comprises polymer, and described polymer is the styrene derived polymers or comprises the styrene derived polymers.

646. the 612nd method, wherein said compositions comprises polymer, and described polymer is the butadiene derived polymers or comprises the butadiene derived polymers.

647. the 612nd method, wherein said compositions comprises polymer, and described polymer is macromonomer or comprises macromonomer.

648. the 612nd method, wherein said compositions comprises polymer, and described polymer is poly-(ethylene glycol) polymer or comprises poly-(ethylene glycol) polymer.

649. the 612nd method, wherein said compositions comprises polymer, and described polymer is amorphous polymer or comprises amorphous polymer.

650. the 612nd method, wherein said compositions also comprises second forms of pharmacologically active agents.

651. the 612nd method, wherein said compositions also comprises antiinflammatory.

652. the 612nd method, wherein said compositions also comprise the medicament that suppresses infection.

653. the 612nd method, wherein said compositions also comprises anthracycline.

654. the 612nd method, wherein said compositions also comprises doxorubicin.

655. the 612nd method, wherein said compositions also comprises mitoxantrone.

656. the 612nd method, wherein said compositions also comprises the fluorine pyrimidine.

657. the 612nd method, wherein said compositions also comprise 5-fluorouracil (5-FU).

658. the 612nd method, wherein said compositions also comprises antifol.

659. the 612nd method, wherein said compositions also comprises methotrexate.

660. the 612nd method, wherein said compositions also comprises podophyllotoxin.

661. the 612nd method, wherein said compositions also comprises etoposide.

662. the 612nd method, wherein said compositions also comprises camptothecine.

663. the 612nd method, wherein said compositions also comprises hydroxyurea.

664. the 612nd method, wherein said compositions also comprises platinum complex.

665. the 612nd method, wherein said compositions also comprises cisplatin.

666. the 612nd method, wherein said compositions also comprises antithrombotic agent.

667. the 612nd method, wherein said compositions also comprises developing agent.

668. the 612nd method, wherein said compositions also comprises developing agent, and described developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

669. the 612nd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

670. the 612nd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises MRI response material.

671. the 612nd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

672. the 612nd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper, or chromium.

673. the 612nd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

674. the 612nd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment, or coloring agent.

675. the 612nd method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

676. the 612nd method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

677. the 612nd method, wherein said compositions also comprises inflammatory cytokine.

678. the 612nd method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

679. the 612nd method, wherein said compositions also comprises polymer support.

680. the 612nd method, wherein said compositions exists with the form of gel, paste or spray.

681. the 612nd method is wherein sent described fibrous tissue from a kind of device and is formed agent, and described device is delivered locally to described fibrous tissue formation agent press close in the tissue of described device.

682. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating comprises described fibrous tissue formation agent.

683. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is placed on the surface of described device.

684. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating directly contacts described device.

685. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contacts described device indirectly.

686. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and wherein said coating layer portion ground covers described device.

687. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating fully covers described device.

688. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

689. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

690. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo.

691. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo, and the material of wherein said generation echo exists with the form of coating.

692. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device is aseptic.

693. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

694. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

695. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

696. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

697. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

698. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 year period in disposing described device.

699. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 month to 6 months period.

700. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device in about 1-90 days period.

701. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device with constant speed.

702. the 612nd method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

703. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

704. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

705. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10 μ g to about 10mg.

706. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10mg to about 250mg.

707. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 250mg to about 1000mg.

708. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 1000mg to about 2500mg.

709. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, the described fibrous tissue that the surface of wherein said device comprises less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

710. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

711. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

712. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

713. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

714. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

715. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a uniform coating.

716. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a non-uniform coating.

717. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a discontinuous coating.

718. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is to form the coating of pattern.

719. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 100 μ m or littler thickness.

720. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 10 μ m or littler thickness.

721. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is being disposed the surface adhesion that this installs later and this device.

722. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, described coating in room temperature at least 1 year the time interim be stable.

723. the 612nd method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

724. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

725. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

726. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

727. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contains polymer.

728. the 612nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises first coating with first compositions and second coating with second compositions.

729. the 612nd method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device comprises first coating with first compositions and second coating with second compositions, and wherein said first compositions is different with second compositions.

730. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, provides aneurysmal treatment or prevention to the patient thus.

731. the 730th method, wherein said fibrous tissue forms agent and promotes regeneration.

732. forming agent, the 730th method, wherein said fibrous tissue promote blood vessel to take place.

733. the 730th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

734. the 730th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

735. the 730th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

736. the 730th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

737. the 730th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

738. the 730th method, wherein said fibrous tissue formation agent is silk or comprises silk.

739. the 730th method, wherein said fibrous tissue form agent with bunch form exist.

740. the 730th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

741. the 730th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

742. the 730th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

743. the 730th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

744. the 730th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

745. the 730th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

746. the 730th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

747. the 730th method, wherein said fibrous tissue form agent and exist with particulate form.

748. the 730th method, wherein said compositions comprises polymer.

749. the 730th method, wherein said compositions comprises polymer, and described polymer is copolymer or comprises copolymer.

750. the 730th method, wherein said compositions comprises polymer, and described polymer is block copolymer or comprises block copolymer.

751. the 730th method, wherein said compositions comprises polymer, and described polymer is random copolymer or comprises random copolymer.

752. the 730th method, wherein said compositions comprises polymer, and described polymer is biodegradable polymer or comprises biodegradable polymer.

753. the 730th method, wherein said compositions comprises polymer, and described polymer is not biodegradable polymer or comprises not biodegradable polymer.

754. the 730th method, wherein said compositions comprises polymer, and described polymer is hydrophilic polymer or comprises hydrophilic polymer.

755. the 730th method, wherein said compositions comprises polymer, and described polymer is hydrophobic polymer or comprises hydrophobic polymer.

756. the 730th method, wherein said compositions comprises polymer, and described polymer is the polymer in possess hydrophilic property zone or the polymer that comprises the possess hydrophilic property zone.

757. the 730th method, wherein said compositions comprises polymer, and described polymer is to have the polymer of water repellent region or comprise the polymer with water repellent region.

758. the 730th method, wherein said compositions comprises polymer, and described polymer is non-conductive polymer or comprises non-conductive polymer.

759. the 730th method, wherein said compositions comprises polymer, and described polymer is elastomer or comprises elastomer.

760. the 730th method, wherein said compositions comprises polymer, and described polymer is hydrogel or comprises hydrogel.

761. the 730th method, wherein said compositions comprises polymer, and described polymer is siloxane polymer or comprises siloxane polymer.

762. the 730th method, wherein said compositions comprises polymer, and described polymer is hydrocarbon polymer or comprises hydrocarbon polymer.

763. the 730th method, wherein said compositions comprises polymer, and described polymer is the styrene derived polymers or comprises the styrene derived polymers.

764. the 730th method, wherein said compositions comprises polymer, and described polymer is the butadiene derived polymers or comprises the butadiene derived polymers.

765. the 730th method, wherein said compositions comprises polymer, and described polymer is macromonomer or comprises macromonomer.

766. the 730th method, wherein said compositions comprises polymer, and described polymer is poly-(ethylene glycol) polymer or comprises poly-(ethylene glycol) polymer.

767. the 730th method, wherein said compositions comprises polymer, and described polymer is amorphous polymer or comprises amorphous polymer.

768. the 730th method, wherein said compositions also comprises second forms of pharmacologically active agents.

769. the 730th method, wherein said compositions also comprises antiinflammatory.

770. the 730th method, wherein said compositions also comprise the medicament that suppresses infection.

771. the 730th method, wherein said compositions also comprises anthracycline.

772. the 730th method, wherein said compositions also comprises doxorubicin.

773. the 730th method, wherein said compositions also comprises mitoxantrone.

774. the 730th method, wherein said compositions also comprises the fluorine pyrimidine.

775. the 730th method, wherein said compositions also comprise 5-fluorouracil (5-FU).

776. the 730th method, wherein said compositions also comprises antifol.

777. the 730th method, wherein said compositions also comprises methotrexate.

778. the 730th method, wherein said compositions also comprises podophyllotoxin.

779. the 730th method, wherein said compositions also comprises etoposide.

780. the 730th method, wherein said compositions also comprises camptothecine.

781. the 730th method, wherein said compositions also comprises hydroxyurea.

782. the 730th method, wherein said compositions also comprises platinum complex.

783. the 730th method, wherein said compositions also comprises cisplatin.

784. the 730th method, wherein said compositions also comprises antithrombotic agent.

785. the 730th method, wherein said compositions also comprises developing agent.

786. the 730th method, wherein said compositions also comprises developing agent, and described developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

787. the 730th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

788. the 730th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises MRI response material.

789. the 730th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

790. the 730th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper, or chromium.

791. the 730th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

792. the 730th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment, or coloring agent.

793. the 730th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

794. the 730th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

795. the 730th method, wherein said compositions also comprises inflammatory cytokine.

796. the 730th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

797. the 730th method, wherein said compositions also comprises polymer support.

798. the 730th method, wherein said compositions exists with the form of gel, paste or spray.

799. the 730th method is wherein sent described fibrous tissue from a kind of device and is formed agent, and described device is delivered locally to described fibrous tissue formation agent press close in the tissue of described device.

800. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating comprises described fibrous tissue formation agent.

801. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is placed on the surface of described device.

802. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating directly contacts described device.

803. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contacts described device indirectly.

804. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and wherein said coating layer portion ground covers described device.

805. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating fully covers described device.

806. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

807. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

808. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo.

809. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo, and the material of wherein said generation echo exists with the form of coating.

810. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device is aseptic.

811. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

812. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

813. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

814. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

815. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

816. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 year period in disposing described device.

817. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 month to 6 months period.

818. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device in about 1-90 days period.

819. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device with constant speed.

820. the 730th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

821. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

822. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

823. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10 μ g to about 10mg.

824. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10mg to about 250mg.

825. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 250mg to about 1000mg.

826. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 1000mg to about 2500mg.

827. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, the described fibrous tissue that the surface of wherein said device comprises less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

828. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

829. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

830. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

831. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

832. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

833. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a uniform coating.

834. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a non-uniform coating.

835. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a discontinuous coating.

836. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is to form the coating of pattern.

837. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 100 μ m or littler thickness.

838. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 10 μ m or littler thickness.

839. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is being disposed the surface adhesion that this installs later and this device.

840. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, described coating in room temperature at least 1 year the time interim be stable.

841. the 730th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

842. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

843. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

844. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

845. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contains polymer.

846. the 730th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises first coating with first compositions and second coating with second compositions.

847. the 730th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device comprises first coating with first compositions and second coating with second compositions, and wherein said first compositions is different with second compositions.

848. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, provides suberification to the patient thus.

849. the 848th method, wherein said fibrous tissue forms agent and promotes regeneration.

850. forming agent, the 848th method, wherein said fibrous tissue promote blood vessel to take place.

851. the 848th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

852. the 848th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

853. the 848th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

854. the 848th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

855. the 848th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

856. the 848th method, wherein said fibrous tissue formation agent is silk or comprises silk.

857. the 848th method, wherein said fibrous tissue form agent with bunch form exist.

858. the 848th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

859. the 848th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

860. the 848th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

861. the 848th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

862. the 848th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

863. the 848th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

864. the 848th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

865. the 848th method, wherein said fibrous tissue form agent and exist with particulate form.

866. the 848th method, wherein said compositions comprises polymer.

867. the 848th method, wherein said compositions comprises polymer, and described polymer is copolymer or comprises copolymer.

868. the 848th method, wherein said compositions comprises polymer, and described polymer is block copolymer or comprises block copolymer.

869. the 848th method, wherein said compositions comprises polymer, and described polymer is random copolymer or comprises random copolymer.

870. the 848th method, wherein said compositions comprises polymer, and described polymer is biodegradable polymer or comprises biodegradable polymer.

871. the 848th method, wherein said compositions comprises polymer, and described polymer is not biodegradable polymer or comprises not biodegradable polymer.

872. the 848th method, wherein said compositions comprises polymer, and described polymer is hydrophilic polymer or comprises hydrophilic polymer.

873. the 848th method, wherein said compositions comprises polymer, and described polymer is hydrophobic polymer or comprises hydrophobic polymer.

874. the 848th method, wherein said compositions comprises polymer, and described polymer is the polymer in possess hydrophilic property zone or the polymer that comprises the possess hydrophilic property zone.

875. the 848th method, wherein said compositions comprises polymer, and described polymer is to have the polymer of water repellent region or comprise the polymer with water repellent region.

876. the 848th method, wherein said compositions comprises polymer, and described polymer is non-conductive polymer or comprises non-conductive polymer.

877. the 848th method, wherein said compositions comprises polymer, and described polymer is elastomer or comprises elastomer.

878. the 848th method, wherein said compositions comprises polymer, and described polymer is hydrogel or comprises hydrogel.

879. the 848th method, wherein said compositions comprises polymer, and described polymer is siloxane polymer or comprises siloxane polymer.

880. the 848th method, wherein said compositions comprises polymer, and described polymer is hydrocarbon polymer or comprises hydrocarbon polymer.

881. the 848th method, wherein said compositions comprises polymer, and described polymer is the styrene derived polymers or comprises the styrene derived polymers.

882. the 848th method, wherein said compositions comprises polymer, and described polymer is the butadiene derived polymers or comprises the butadiene derived polymers.

883. the 848th method, wherein said compositions comprises polymer, and described polymer is macromonomer or comprises macromonomer.

884. the 848th method, wherein said compositions comprises polymer, and described polymer is poly-(ethylene glycol) polymer or comprises poly-(ethylene glycol) polymer.

885. the 848th method, wherein said compositions comprises polymer, and described polymer is amorphous polymer or comprises amorphous polymer.

886. the 848th method, wherein said compositions also comprises second forms of pharmacologically active agents.

887. the 848th method, wherein said compositions also comprises antiinflammatory.

888. the 848th method, wherein said compositions also comprise the medicament that suppresses infection.

889. the 848th method, wherein said compositions also comprises anthracycline.

890. the 848th method, wherein said compositions also comprises doxorubicin.

891. the 848th method, wherein said compositions also comprises mitoxantrone.

892. the 848th method, wherein said compositions also comprises the fluorine pyrimidine.

893. the 848th method, wherein said compositions also comprise 5-fluorouracil (5-FU).

894. the 848th method, wherein said compositions also comprises antifol.

895. the 848th method, wherein said compositions also comprises methotrexate.

896. the 848th method, wherein said compositions also comprises podophyllotoxin.

897. the 848th method, wherein said compositions also comprises etoposide.

898. the 848th method, wherein said compositions also comprises camptothecine.

899. the 848th method, wherein said compositions also comprises hydroxyurea.

900. the 848th method, wherein said compositions also comprises platinum complex.

901. the 848th method, wherein said compositions also comprises cisplatin.

902. the 848th method, wherein said compositions also comprises antithrombotic agent.

903. the 848th method, wherein said compositions also comprises developing agent.

904. the 848th method, wherein said compositions also comprises developing agent, and described developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

905. the 848th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

906. the 848th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises MRI response material.

907. the 848th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

908. the 848th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper, or chromium.

909. the 848th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

910. the 848th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment, or coloring agent.

911. the 848th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

912. the 848th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

913. the 848th method, wherein said compositions also comprises inflammatory cytokine.

914. the 848th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

915. the 848th method, wherein said compositions also comprises polymer support.

916. the 848th method, wherein said compositions exists with the form of gel, paste or spray.

917. the 848th method is wherein sent described fibrous tissue from a kind of device and is formed agent, and described device is delivered locally to described fibrous tissue formation agent press close in the tissue of described device.

918. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating comprises described fibrous tissue formation agent.

919. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is placed on the surface of described device.

920. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating directly contacts described device.

921. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contacts described device indirectly.

922. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and wherein said coating layer portion ground covers described device.

923. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating fully covers described device.

924. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

925. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

926. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo.

927. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo, and the material of wherein said generation echo exists with the form of coating.

928. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device is aseptic.

929. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

930. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

931. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

932. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

933. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

934. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 year period in disposing described device.

935. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 month to 6 months period.

936. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device in about 1-90 days period.

937. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device with constant speed.

938. the 848th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

939. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

940. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

941. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10 μ g to about 10mg.

942. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10mg to about 250mg.

943. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 250mg to about 1000mg.

944. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 1000mg to about 2500mg.

945. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, the described fibrous tissue that the surface of wherein said device comprises less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

946. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

947. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

948. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

949. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

950. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

951. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a uniform coating.

952. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a non-uniform coating.

953. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a discontinuous coating.

954. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is to form the coating of pattern.

955. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 100 μ m or littler thickness.

956. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 10 μ m or littler thickness.

957. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is being disposed the surface adhesion that this installs later and this device.

958. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, described coating in room temperature at least 1 year the time interim be stable.

959. the 848th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

960. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

961. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

962. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

963. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contains polymer.

964. the 848th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises first coating with first compositions and second coating with second compositions.

965. the 848th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device comprises first coating with first compositions and second coating with second compositions, and wherein said first compositions is different with second compositions.

966. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, provides the reaction of the fibre modification between patient and the soft palate implant to the patient thus.

967. the 966th method, wherein said fibrous tissue forms agent and promotes regeneration.

968. forming agent, the 966th method, wherein said fibrous tissue promote blood vessel to take place.

969. the 966th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

970. the 966th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

971. the 966th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

972. the 966th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

973. the 966th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

974. the 966th method, wherein said fibrous tissue formation agent is silk or comprises silk.

975. the 966th method, wherein said fibrous tissue form agent with bunch form exist.

976. the 966th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

977. the 966th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

978. the 966th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

979. the 966th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

980. the 966th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

981. the 966th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

982. the 966th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

983. the 966th method, wherein said fibrous tissue form agent and exist with particulate form.

984. the 966th method, wherein said compositions comprises polymer.

985. the 966th method, wherein said compositions comprises polymer, and described polymer is copolymer or comprises copolymer.

986. the 966th method, wherein said compositions comprises polymer, and described polymer is block copolymer or comprises block copolymer.

987. the 966th method, wherein said compositions comprises polymer, and described polymer is random copolymer or comprises random copolymer.

988. the 966th method, wherein said compositions comprises polymer, and described polymer is biodegradable polymer or comprises biodegradable polymer.

989. the 966th method, wherein said compositions comprises polymer, and described polymer is not biodegradable polymer or comprises not biodegradable polymer.

990. the 966th method, wherein said compositions comprises polymer, and described polymer is hydrophilic polymer or comprises hydrophilic polymer.

991. the 966th method, wherein said compositions comprises polymer, and described polymer is hydrophobic polymer or comprises hydrophobic polymer.

992. the 966th method, wherein said compositions comprises polymer, and described polymer is the polymer in possess hydrophilic property zone or the polymer that comprises the possess hydrophilic property zone.

993. the 966th method, wherein said compositions comprises polymer, and described polymer is to have the polymer of water repellent region or comprise the polymer with water repellent region.

994. the 966th method, wherein said compositions comprises polymer, and described polymer is non-conductive polymer or comprises non-conductive polymer.

995. the 966th method, wherein said compositions comprises polymer, and described polymer is elastomer or comprises elastomer.

996. the 966th method, wherein said compositions comprises polymer, and described polymer is hydrogel or comprises hydrogel.

997. the 966th method, wherein said compositions comprises polymer, and described polymer is siloxane polymer or comprises siloxane polymer.

998. the 966th method, wherein said compositions comprises polymer, and described polymer is hydrocarbon polymer or comprises hydrocarbon polymer.

999. the 966th method, wherein said compositions comprises polymer, and described polymer is the styrene derived polymers or comprises the styrene derived polymers.

1000. the 966th method, wherein said compositions comprises polymer, and described polymer is the butadiene derived polymers or comprises the butadiene derived polymers.

1001. the 966th method, wherein said compositions comprises polymer, and described polymer is macromonomer or comprises macromonomer.

1002. the 966th method, wherein said compositions comprises polymer, and described polymer is poly-(ethylene glycol) polymer or comprises poly-(ethylene glycol) polymer.

1003. the 966th method, wherein said compositions comprises polymer, and described polymer is amorphous polymer or comprises amorphous polymer.

1004. the 966th method, wherein said compositions also comprises second forms of pharmacologically active agents.

1005. the 966th method, wherein said compositions also comprises antiinflammatory.

1006. the 966th method, wherein said compositions also comprise the medicament that suppresses infection.

1007. the 966th method, wherein said compositions also comprises anthracycline.

1008. the 966th method, wherein said compositions also comprises doxorubicin.

1009. the 966th method, wherein said compositions also comprises mitoxantrone.

1010. the 966th method, wherein said compositions also comprises the fluorine pyrimidine.

1011. the 966th method, wherein said compositions also comprise 5-fluorouracil (5-FU).

1012. the 966th method, wherein said compositions also comprises antifol.

1013. the 966th method, wherein said compositions also comprises methotrexate.

1014. the 966th method, wherein said compositions also comprises podophyllotoxin.

1015. the 966th method, wherein said compositions also comprises etoposide.

1016. the 966th method, wherein said compositions also comprises camptothecine.

1017. the 966th method, wherein said compositions also comprises hydroxyurea.

1018. the 966th method, wherein said compositions also comprises platinum complex.

1019. the 966th method, wherein said compositions also comprises cisplatin.

1020. the 966th method, wherein said compositions also comprises antithrombotic agent.

1021. the 966th method, wherein said compositions also comprises developing agent.

1022. the 966th method, wherein said compositions also comprises developing agent, and described developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

1023. the 966th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

1024. the 966th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises MRI response material.

1025. the 966th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

1026. the 966th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper, or chromium.

1027. the 966th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

1028. the 966th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment, or coloring agent.

1029. the 966th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

1030. the 966th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

1031. the 966th method, wherein said compositions also comprises inflammatory cytokine.

1032. the 966th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

1033. the 966th method, wherein said compositions also comprises polymer support.

1034. the 966th method, wherein said compositions exists with the form of gel, paste or spray.

1035. the 966th method is wherein sent described fibrous tissue from a kind of device and is formed agent, and described device is delivered locally to described fibrous tissue formation agent press close in the tissue of described device.

1036. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating comprises described fibrous tissue formation agent.

1037. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is placed on the surface of described device.

1038. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating directly contacts described device.

1039. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contacts described device indirectly.

1040. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and wherein said coating layer portion ground covers described device.

1041. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating fully covers described device.

1042. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

1043. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

1044. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo.

1045. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo, and the material of wherein said generation echo exists with the form of coating.

1046. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device is aseptic.

1047. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

1048. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

1049. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

1050. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

1051. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

1052. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 year period in disposing described device.

1053. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 month to 6 months period.

1054. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device in about 1-90 days period.

1055. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device with constant speed.

1056. the 966th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

1057. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

1058. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

1059. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10 μ g to about 10mg.

1060. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10mg to about 250mg.

1061. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 250mg to about 1000mg.

1062. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 1000mg to about 2500mg.

1063. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, the described fibrous tissue that the surface of wherein said device comprises less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

1064. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1065. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1066. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1067. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1068. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1069. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a uniform coating.

1070. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a non-uniform coating.

1071. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a discontinuous coating.

1072. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is to form the coating of pattern.

1073. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 100 μ m or littler thickness.

1074. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 10 μ m or littler thickness.

1075. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is being disposed the surface adhesion that this installs later and this device.

1076. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, described coating in room temperature at least 1 year the time interim be stable.

1077. the 966th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

1078. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

1079. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

1080. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

1081. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contains polymer.

1082. the 966th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises first coating with first compositions and second coating with second compositions.

1083. the 966th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device comprises first coating with first compositions and second coating with second compositions, and wherein said first compositions is different with second compositions.

1084. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, and the treatment of obesity is provided to the patient thus.

1085. the 1084th method, wherein said fibrous tissue forms agent and promotes regeneration.

1086. forming agent, the 1084th method, wherein said fibrous tissue promote blood vessel to take place.

1087. the 1084th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

1088. the 1084th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

1089. the 1084th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

1090. the 1084th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

1091. the 1084th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

1092. the 1084th method, wherein said fibrous tissue formation agent is silk or comprises silk.

1093. the 1084th method, wherein said fibrous tissue form agent with bunch form exist.

1094. the 1084th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

1095. the 1084th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

1096. the 1084th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

1097. the 1084th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

1098. the 1084th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

1099. the 1084th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

1100. the 1084th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

1101. the 1084th method, wherein said fibrous tissue form agent and exist with particulate form.

1102. the 1084th method, wherein said compositions comprises polymer.

1103. the 1084th method, wherein said compositions comprises polymer, and described polymer is copolymer or comprises copolymer.

1104. the 1084th method, wherein said compositions comprises polymer, and described polymer is block copolymer or comprises block copolymer.

1105. the 1084th method, wherein said compositions comprises polymer, and described polymer is random copolymer or comprises random copolymer.

1106. the 1084th method, wherein said compositions comprises polymer, and described polymer is biodegradable polymer or comprises biodegradable polymer.

1107. the 1084th method, wherein said compositions comprises polymer, and described polymer is not biodegradable polymer or comprises not biodegradable polymer.

1108. the 1084th method, wherein said compositions comprises polymer, and described polymer is hydrophilic polymer or comprises hydrophilic polymer.

1109. the 1084th method, wherein said compositions comprises polymer, and described polymer is hydrophobic polymer or comprises hydrophobic polymer.

1110. the 1084th method, wherein said compositions comprises polymer, and described polymer is the polymer in possess hydrophilic property zone or the polymer that comprises the possess hydrophilic property zone.

1111. the 1084th method, wherein said compositions comprises polymer, and described polymer is to have the polymer of water repellent region or comprise the polymer with water repellent region.

1112. the 1084th method, wherein said compositions comprises polymer, and described polymer is non-conductive polymer or comprises non-conductive polymer.

1113. the 1084th method, wherein said compositions comprises polymer, and described polymer is elastomer or comprises elastomer.

1114. the 1084th method, wherein said compositions comprises polymer, and described polymer is hydrogel or comprises hydrogel.

1115. the 1084th method, wherein said compositions comprises polymer, and described polymer is siloxane polymer or comprises siloxane polymer.

1116. the 1084th method, wherein said compositions comprises polymer, and described polymer is hydrocarbon polymer or comprises hydrocarbon polymer.

1117. the 1084th method, wherein said compositions comprises polymer, and described polymer is the styrene derived polymers or comprises the styrene derived polymers.

1118. the 1084th method, wherein said compositions comprises polymer, and described polymer is the butadiene derived polymers or comprises the butadiene derived polymers.

1119. the 1084th method, wherein said compositions comprises polymer, and described polymer is macromonomer or comprises macromonomer.

1120. the 1084th method, wherein said compositions comprises polymer, and described polymer is poly-(ethylene glycol) polymer or comprises poly-(ethylene glycol) polymer.

1121. the 1084th method, wherein said compositions comprises polymer, and described polymer is amorphous polymer or comprises amorphous polymer.

1122. the 1084th method, wherein said compositions also comprises second forms of pharmacologically active agents.

1123. the 1084th method, wherein said compositions also comprises antiinflammatory.

1124. the 1084th method, wherein said compositions also comprise the medicament that suppresses infection.

1125. the 1084th method, wherein said compositions also comprises anthracycline.

1126. the 1084th method, wherein said compositions also comprises doxorubicin.

1127. the 1084th method, wherein said compositions also comprises mitoxantrone.

1128. the 1084th method, wherein said compositions also comprises the fluorine pyrimidine.

1129. the 1084th method, wherein said compositions also comprise 5-fluorouracil (5-FU).

1130. the 1084th method, wherein said compositions also comprises antifol.

1131. the 1084th method, wherein said compositions also comprises methotrexate.

1132. the 1084th method, wherein said compositions also comprises podophyllotoxin.

1133. the 1084th method, wherein said compositions also comprises etoposide.

1134. the 1084th method, wherein said compositions also comprises camptothecine.

1135. the 1084th method, wherein said compositions also comprises hydroxyurea.

1136. the 1084th method, wherein said compositions also comprises platinum complex.

1137. the 1084th method, wherein said compositions also comprises cisplatin.

1138. the 1084th method, wherein said compositions also comprises antithrombotic agent.

1139. the 1084th method, wherein said compositions also comprises developing agent.

1140. the 1084th method, wherein said compositions also comprises developing agent, and described developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

1141. the 1084th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

1142. the 1084th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises MRI response material.

1143. the 1084th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

1144. the 1084th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper, or chromium.

1145. the 1084th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

1146. the 1084th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment, or coloring agent.

1147. the 1084th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

1148. the 1084th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

1149. the 1084th method, wherein said compositions also comprises inflammatory cytokine.

1150. the 1084th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

1151. the 1084th method, wherein said compositions also comprises polymer support.

1152. the 1084th method, wherein said compositions exists with the form of gel, paste or spray.

1153. the 1084th method is wherein sent described fibrous tissue from a kind of device and is formed agent, and described device is delivered locally to described fibrous tissue formation agent press close in the tissue of described device.

1154. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating comprises described fibrous tissue formation agent.

1155. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is placed on the surface of described device.

1156. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating directly contacts described device.

1157. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contacts described device indirectly.

1158. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and wherein said coating layer portion ground covers described device.

1159. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating fully covers described device.

1160. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

1161. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

1162. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo.

1163. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo, and the material of wherein said generation echo exists with the form of coating.

1164. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device is aseptic.

1165. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

1166. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

1167. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

1168. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

1169. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

1170. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 year period in disposing described device.

1171. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 month to 6 months period.

1172. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device in about 1-90 days period.

1173. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device with constant speed.

1174. the 1084th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

1175. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

1176. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

1177. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10 μ g to about 10mg.

1178. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10mg to about 250mg.

1179. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 250mg to about 1000mg.

1180. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 1000mg to about 2500mg.

1181. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, the described fibrous tissue that the surface of wherein said device comprises less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

1182. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1183. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1184. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1185. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1186. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1187. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a uniform coating.

1188. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a non-uniform coating.

1189. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a discontinuous coating.

1190. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is to form the coating of pattern.

1191. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 100 μ m or littler thickness.

1192. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 10 μ m or littler thickness.

1193. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is being disposed the surface adhesion that this installs later and this device.

1194. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, described coating in room temperature at least 1 year the time interim be stable.

1195. the 1084th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

1196. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

1197. the 1084th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

1198. the 1084th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

1199. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contains polymer.

1200. the 1084th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises first coating with first compositions and second coating with second compositions.

1201. the 1084th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device comprises first coating with first compositions and second coating with second compositions, and wherein said first compositions is different with second compositions.

1202. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, and the treatment of GERD is provided to the patient thus.

1203. the 1202nd method, wherein said fibrous tissue forms agent and promotes regeneration.

1204. forming agent, the 1202nd method, wherein said fibrous tissue promote blood vessel to take place.

1205. the 1202nd method, wherein said fibrous tissue form agent and promote the fibroblast migration.

1206. the 1202nd method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

1207. the 1202nd method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

1208. the 1202nd method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

1209. the 1202nd method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

1210. the 1202nd method, wherein said fibrous tissue formation agent is silk or comprises silk.

1211. the 1202nd method, wherein said fibrous tissue form agent with bunch form exist.

1212. the 1202nd method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

1213. the 1202nd method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

1214. the 1202nd method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

1215. the 1202nd method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

1216. the 1202nd method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

1217. the 1202nd method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

1218. the 1202nd method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

1219. the 1202nd method, wherein said fibrous tissue form agent and exist with particulate form.

1220. the 1202nd method, wherein said compositions comprises polymer.

1221. the 1202nd method, wherein said compositions comprises polymer, and described polymer is copolymer or comprises copolymer.

1222. the 1202nd method, wherein said compositions comprises polymer, and described polymer is block copolymer or comprises block copolymer.

1223. the 1202nd method, wherein said compositions comprises polymer, and described polymer is random copolymer or comprises random copolymer.

1224. the 1202nd method, wherein said compositions comprises polymer, and described polymer is biodegradable polymer or comprises biodegradable polymer.

1225. the 1202nd method, wherein said compositions comprises polymer, and described polymer is not biodegradable polymer or comprises not biodegradable polymer.

1226. the 1202nd method, wherein said compositions comprises polymer, and described polymer is hydrophilic polymer or comprises hydrophilic polymer.

1227. the 1202nd method, wherein said compositions comprises polymer, and described polymer is hydrophobic polymer or comprises hydrophobic polymer.

1228. the 1202nd method, wherein said compositions comprises polymer, and described polymer is the polymer in possess hydrophilic property zone or the polymer that comprises the possess hydrophilic property zone.

1229. the 1202nd method, wherein said compositions comprises polymer, and described polymer is to have the polymer of water repellent region or comprise the polymer with water repellent region.

1230. the 1202nd method, wherein said compositions comprises polymer, and described polymer is non-conductive polymer or comprises non-conductive polymer.

1231. the 1202nd method, wherein said compositions comprises polymer, and described polymer is elastomer or comprises elastomer.

1232. the 1202nd method, wherein said compositions comprises polymer, and described polymer is hydrogel or comprises hydrogel.

1233. the 1202nd method, wherein said compositions comprises polymer, and described polymer is siloxane polymer or comprises siloxane polymer.

1234. the 1202nd method, wherein said compositions comprises polymer, and described polymer is hydrocarbon polymer or comprises hydrocarbon polymer.

1235. the 1202nd method, wherein said compositions comprises polymer, and described polymer is the styrene derived polymers or comprises the styrene derived polymers.

1236. the 1202nd method, wherein said compositions comprises polymer, and described polymer is the butadiene derived polymers or comprises the butadiene derived polymers.

1237. the 1202nd method, wherein said compositions comprises polymer, and described polymer is macromonomer or comprises macromonomer.

1238. the 1202nd method, wherein said compositions comprises polymer, and described polymer is poly-(ethylene glycol) polymer or comprises poly-(ethylene glycol) polymer.

1239. the 1202nd method, wherein said compositions comprises polymer, and described polymer is amorphous polymer or comprises amorphous polymer.

1240. the 1202nd method, wherein said compositions also comprises second forms of pharmacologically active agents.

1241. the 1202nd method, wherein said compositions also comprises antiinflammatory.

1242. the 1202nd method, wherein said compositions also comprise the medicament that suppresses infection.

1243. the 1202nd method, wherein said compositions also comprises anthracycline.

1244. the 1202nd method, wherein said compositions also comprises doxorubicin.

1245. the 1202nd method, wherein said compositions also comprises mitoxantrone.

1246. the 1202nd method, wherein said compositions also comprises the fluorine pyrimidine.

1247. the 1202nd method, wherein said compositions also comprise 5-fluorouracil (5-FU).

1248. the 1202nd method, wherein said compositions also comprises antifol.

1249. the 1202nd method, wherein said compositions also comprises methotrexate.

1250. the 1202nd method, wherein said compositions also comprises podophyllotoxin.

1251. the 1202nd method, wherein said compositions also comprises etoposide.

1252. the 1202nd method, wherein said compositions also comprises camptothecine.

1253. the 1202nd method, wherein said compositions also comprises hydroxyurea.

1254. the 1202nd method, wherein said compositions also comprises platinum complex.

1255. the 1202nd method, wherein said compositions also comprises cisplatin.

1256. the 1202nd method, wherein said compositions also comprises antithrombotic agent.

1257. the 1202nd method, wherein said compositions also comprises developing agent.

1258. the 1202nd method, wherein said compositions also comprises developing agent, and described developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

1259. the 1202nd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

1260. the 1202nd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises MRI response material.

1261. the 1202nd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

1262. the 1202nd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper, or chromium.

1263. the 1202nd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

1264. the 1202nd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment, or coloring agent.

1265. the 1202nd method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

1266. the 1202nd method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

1267. the 1202nd method, wherein said compositions also comprises inflammatory cytokine.

1268. the 1202nd method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

1269. the 1202nd method, wherein said compositions also comprises polymer support.

1270. the 1202nd method, wherein said compositions exists with the form of gel, paste or spray.

1271. the 1202nd method is wherein sent described fibrous tissue from a kind of device and is formed agent, and described device is delivered locally to described fibrous tissue formation agent press close in the tissue of described device.

1272. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating comprises described fibrous tissue formation agent.

1273. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is placed on the surface of described device.

1274. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating directly contacts described device.

1275. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contacts described device indirectly.

1276. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and wherein said coating layer portion ground covers described device.

1277. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating fully covers described device.

1278. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

1279. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

1280. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo.

1281. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo, and the material of wherein said generation echo exists with the form of coating.

1282. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device is aseptic.

1283. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

1284. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

1285. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

1286. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

1287. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

1288. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 year period in disposing described device.

1289. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 month to 6 months period.

1290. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device in about 1-90 days period.

1291. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device with constant speed.

1292. the 1202nd method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

1293. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

1294. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

1295. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10 μ g to about 10mg.

1296. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10mg to about 250mg.

1297. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 250mg to about 1000mg.

1298. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 1000mg to about 2500mg.

1299. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, the described fibrous tissue that the surface of wherein said device comprises less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

1300. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1301. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1302. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1303. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1304. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1305. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a uniform coating.

1306. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a non-uniform coating.

1307. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a discontinuous coating.

1308. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is to form the coating of pattern.

1309. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 100 μ m or littler thickness.

1310. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 10 μ m or littler thickness.

1311. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is being disposed the surface adhesion that this installs later and this device.

1312. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, described coating in room temperature at least 1 year the time interim be stable.

1313. the 1202nd method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

1314. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

1315. the 1202nd method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

1316. the 1202nd method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

1317. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contains polymer.

1318. the 1202nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises first coating with first compositions and second coating with second compositions.

1319. the 1202nd method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device comprises first coating with first compositions and second coating with second compositions, and wherein said first compositions is different with second compositions.

1320. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, and the treatment or the prevention of fecal incontinence are provided to the patient thus.

1321. the 1320th method, wherein said fibrous tissue forms agent and promotes regeneration.

1322. forming agent, the 1320th method, wherein said fibrous tissue promote blood vessel to take place.

1323. the 1320th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

1324. the 1320th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

1325. the 1320th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

1326. the 1320th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

1327. the 1320th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

1328. the 1320th method, wherein said fibrous tissue formation agent is silk or comprises silk.

1329. the 1320th method, wherein said fibrous tissue form agent with bunch form exist.

1330. the 1320th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

1331. the 1320th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

1332. the 1320th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

1333. the 1320th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

1334. the 1320th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

1335. the 1320th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

1336. the 1320th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

1337. the 1320th method, wherein said fibrous tissue form agent and exist with particulate form.

1338. the 1320th method, wherein said compositions comprises polymer.

1339. the 1320th method, wherein said compositions comprises polymer, and described polymer is copolymer or comprises copolymer.

1340. the 1320th method, wherein said compositions comprises polymer, and described polymer is block copolymer or comprises block copolymer.

1341. the 1320th method, wherein said compositions comprises polymer, and described polymer is random copolymer or comprises random copolymer.

1342. the 1320th method, wherein said compositions comprises polymer, and described polymer is biodegradable polymer or comprises biodegradable polymer.

1343. the 1320th method, wherein said compositions comprises polymer, and described polymer is not biodegradable polymer or comprises not biodegradable polymer.

1344. the 1320th method, wherein said compositions comprises polymer, and described polymer is hydrophilic polymer or comprises hydrophilic polymer.

1345. the 1320th method, wherein said compositions comprises polymer, and described polymer is hydrophobic polymer or comprises hydrophobic polymer.

1346. the 1320th method, wherein said compositions comprises polymer, and described polymer is the polymer in possess hydrophilic property zone or the polymer that comprises the possess hydrophilic property zone.

1347. the 1320th method, wherein said compositions comprises polymer, and described polymer is to have the polymer of water repellent region or comprise the polymer with water repellent region.

1348. the 1320th method, wherein said compositions comprises polymer, and described polymer is non-conductive polymer or comprises non-conductive polymer.

1349. the 1320th method, wherein said compositions comprises polymer, and described polymer is elastomer or comprises elastomer.

1350. the 1320th method, wherein said compositions comprises polymer, and described polymer is hydrogel or comprises hydrogel.

1351. the 1320th method, wherein said compositions comprises polymer, and described polymer is siloxane polymer or comprises siloxane polymer.

1352. the 1320th method, wherein said compositions comprises polymer, and described polymer is hydrocarbon polymer or comprises hydrocarbon polymer.

1353. the 1320th method, wherein said compositions comprises polymer, and described polymer is the styrene derived polymers or comprises the styrene derived polymers.

1354. the 1320th method, wherein said compositions comprises polymer, and described polymer is the butadiene derived polymers or comprises the butadiene derived polymers.

1355. the 1320th method, wherein said compositions comprises polymer, and described polymer is macromonomer or comprises macromonomer.

1356. the 1320th method, wherein said compositions comprises polymer, and described polymer is poly-(ethylene glycol) polymer or comprises poly-(ethylene glycol) polymer.

1357. the 1320th method, wherein said compositions comprises polymer, and described polymer is amorphous polymer or comprises amorphous polymer.

1358. the 1320th method, wherein said compositions also comprises second forms of pharmacologically active agents.

1359. the 1320th method, wherein said compositions also comprises antiinflammatory.

1360. the 1320th method, wherein said compositions also comprise the medicament that suppresses infection.

1361. the 1320th method, wherein said compositions also comprises anthracycline.

1362. the 1320th method, wherein said compositions also comprises doxorubicin.

1363. the 1320th method, wherein said compositions also comprises mitoxantrone.

1364. the 1320th method, wherein said compositions also comprises the fluorine pyrimidine.

1365. the 1320th method, wherein said compositions also comprise 5-fluorouracil (5-FU).

1366. the 1320th method, wherein said compositions also comprises antifol.

1367. the 1320th method, wherein said compositions also comprises methotrexate.

1368. the 1320th method, wherein said compositions also comprises podophyllotoxin.

1369. the 1320th method, wherein said compositions also comprises etoposide.

1370. the 1320th method, wherein said compositions also comprises camptothecine.

1371. the 1320th method, wherein said compositions also comprises hydroxyurea.

1372. the 1320th method, wherein said compositions also comprises platinum complex.

1373. the 1320th method, wherein said compositions also comprises cisplatin.

1374. the 1320th method, wherein said compositions also comprises antithrombotic agent.

1375. the 1320th method, wherein said compositions also comprises developing agent.

1376. the 1320th method, wherein said compositions also comprises developing agent, and described developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

1377. the 1320th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

1378. the 1320th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises MRI response material.

1379. the 1320th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

1380. the 1320th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper, or chromium.

1381. the 1320th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

1382. the 1320th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment, or coloring agent.

1383. the 1320th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

1384. the 1320th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

1385. the 1320th method, wherein said compositions also comprises inflammatory cytokine.

1386. the 1320th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

1387. the 1320th method, wherein said compositions also comprises polymer support.

1388. the 1320th method, wherein said compositions exists with the form of gel, paste or spray.

1389. the 1320th method is wherein sent described fibrous tissue from a kind of device and is formed agent, and described device is delivered locally to described fibrous tissue formation agent press close in the tissue of described device.

1390. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating comprises described fibrous tissue formation agent.

1391. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is placed on the surface of described device.

1392. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating directly contacts described device.

1393. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contacts described device indirectly.

1394. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and wherein said coating layer portion ground covers described device.

1395. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating fully covers described device.

1396. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

1397. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

1398. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo.

1399. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo, and the material of wherein said generation echo exists with the form of coating.

1400. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device is aseptic.

1401. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

1402. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

1403. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

1404. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

1405. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

1406. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 year period in disposing described device.

1407. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 month to 6 months period.

1408. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device in about 1-90 days period.

1409. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device with constant speed.

1410. the 1320th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

1411. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

1412. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

1413. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10 μ g to about 10mg.

1414. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10mg to about 250mg.

1415. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 250mg to about 1000mg.

1416. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 1000mg to about 2500mg.

1417. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, the described fibrous tissue that the surface of wherein said device comprises less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

1418. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1419. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1420. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1421. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1422. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1423. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a uniform coating.

1424. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a non-uniform coating.

1425. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a discontinuous coating.

1426. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is to form the coating of pattern.

1427. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 100 μ m or littler thickness.

1428. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 10 μ m or littler thickness.

1429. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is being disposed the surface adhesion that this installs later and this device.

1430. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, described coating in room temperature at least 1 year the time interim be stable.

1431. the 1320th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

1432. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

1433. the 1320th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

1434. the 1320th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

1435. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contains polymer.

1436. the 1320th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises first coating with first compositions and second coating with second compositions.

1437. the 1320th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device comprises first coating with first compositions and second coating with second compositions, and wherein said first compositions is different with second compositions.

1438. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, and the venous treatment or the prevention of varicose are provided to the patient thus.

1439. the 1438th method, wherein said fibrous tissue forms agent and promotes regeneration.

1440. forming agent, the 1438th method, wherein said fibrous tissue promote blood vessel to take place.

1441. the 1438th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

1442. the 1438th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

1443. the 1438th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

1444. the 1438th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

1445. the 1438th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

1446. the 1438th method, wherein said fibrous tissue formation agent is silk or comprises silk.

1447. the 1438th method, wherein said fibrous tissue form agent with bunch form exist.

1448. the 1438th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

1449. the 1438th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

1450. the 1438th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

1451. the 1438th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

1452. the 1438th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

1453. the 1438th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

1454. the 1438th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

1455. the 1438th method, wherein said fibrous tissue form agent and exist with particulate form.

1456. the 1438th method, wherein said compositions comprises polymer.

1457. the 1438th method, wherein said compositions comprises polymer, and described polymer is copolymer or comprises copolymer.

1458. the 1438th method, wherein said compositions comprises polymer, and described polymer is block copolymer or comprises block copolymer.

1459. the 1438th method, wherein said compositions comprises polymer, and described polymer is random copolymer or comprises random copolymer.

1460. the 1438th method, wherein said compositions comprises polymer, and described polymer is biodegradable polymer or comprises biodegradable polymer.

1461. the 1438th method, wherein said compositions comprises polymer, and described polymer is not biodegradable polymer or comprises not biodegradable polymer.

1462. the 1438th method, wherein said compositions comprises polymer, and described polymer is hydrophilic polymer or comprises hydrophilic polymer.

1463. the 1438th method, wherein said compositions comprises polymer, and described polymer is hydrophobic polymer or comprises hydrophobic polymer.

1464. the 1438th method, wherein said compositions comprises polymer, and described polymer is the polymer in possess hydrophilic property zone or the polymer that comprises the possess hydrophilic property zone.

1465. the 1438th method, wherein said compositions comprises polymer, and described polymer is to have the polymer of water repellent region or comprise the polymer with water repellent region.

1466. the 1438th method, wherein said compositions comprises polymer, and described polymer is non-conductive polymer or comprises non-conductive polymer.

1467. the 1438th method, wherein said compositions comprises polymer, and described polymer is elastomer or comprises elastomer.

1468. the 1438th method, wherein said compositions comprises polymer, and described polymer is hydrogel or comprises hydrogel.

1469. the 1438th method, wherein said compositions comprises polymer, and described polymer is siloxane polymer or comprises siloxane polymer.

1470. the 1438th method, wherein said compositions comprises polymer, and described polymer is hydrocarbon polymer or comprises hydrocarbon polymer.

1471. the 1438th method, wherein said compositions comprises polymer, and described polymer is the styrene derived polymers or comprises the styrene derived polymers.

1472. the 1438th method, wherein said compositions comprises polymer, and described polymer is the butadiene derived polymers or comprises the butadiene derived polymers.

1473. the 1438th method, wherein said compositions comprises polymer, and described polymer is macromonomer or comprises macromonomer.

1474. the 1438th method, wherein said compositions comprises polymer, and described polymer is poly-(ethylene glycol) polymer or comprises poly-(ethylene glycol) polymer.

1475. the 1438th method, wherein said compositions comprises polymer, and described polymer is amorphous polymer or comprises amorphous polymer.

1476. the 1438th method, wherein said compositions also comprises second forms of pharmacologically active agents.

1477. the 1438th method, wherein said compositions also comprises antiinflammatory.

1478. the 1438th method, wherein said compositions also comprise the medicament that suppresses infection.

1479. the 1438th method, wherein said compositions also comprises anthracycline.

1480. the 1438th method, wherein said compositions also comprises doxorubicin.

1481. the 1438th method, wherein said compositions also comprises mitoxantrone.

1482. the 1438th method, wherein said compositions also comprises the fluorine pyrimidine.

1483. the 1438th method, wherein said compositions also comprise 5-fluorouracil (5-FU).

1484. the 1438th method, wherein said compositions also comprises antifol.

1485. the 1438th method, wherein said compositions also comprises methotrexate.

1486. the 1438th method, wherein said compositions also comprises podophyllotoxin.

1487. the 1438th method, wherein said compositions also comprises etoposide.

1488. the 1438th method, wherein said compositions also comprises camptothecine.

1489. the 1438th method, wherein said compositions also comprises hydroxyurea.

1490. the 1438th method, wherein said compositions also comprises platinum complex.

1491. the 1438th method, wherein said compositions also comprises cisplatin.

1492. the 1438th method, wherein said compositions also comprises antithrombotic agent.

1493. the 1438th method, wherein said compositions also comprises developing agent.

1494. the 1438th method, wherein said compositions also comprises developing agent, and described developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

1495. the 1438th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

1496. the 1438th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises MRI response material.

1497. the 1438th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

1498. the 1438th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper, or chromium.

1499. the 1438th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

1500. the 1438th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment, or coloring agent.

1501. the 1438th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

1502. the 1438th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

1503. the 1438th method, wherein said compositions also comprises inflammatory cytokine.

1504. the 1438th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

1505. the 1438th method, wherein said compositions also comprises polymer support.

1506. the 1438th method, wherein said compositions exists with the form of gel, paste or spray.

1507. the 1438th method is wherein sent described fibrous tissue from a kind of device and is formed agent, and described device is delivered locally to described fibrous tissue formation agent press close in the tissue of described device.

1508. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating comprises described fibrous tissue formation agent.

1509. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is placed on the surface of described device.

1510. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating directly contacts described device.

1511. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contacts described device indirectly.

1512. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and wherein said coating layer portion ground covers described device.

1513. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating fully covers described device.

1514. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

1515. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

1516. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo.

1517. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo, and the material of wherein said generation echo exists with the form of coating.

1518. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device is aseptic.

1519. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

1520. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

1521. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

1522. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

1523. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

1524. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 year period in disposing described device.

1525. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 month to 6 months period.

1526. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device in about 1-90 days period.

1527. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device with constant speed.

1528. the 1438th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

1529. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

1530. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

1531. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10 μ g to about 10mg.

1532. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10mg to about 250mg.

1533. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 250mg to about 1000mg.

1534. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 1000mg to about 2500mg.

1535. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, the described fibrous tissue that the surface of wherein said device comprises less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

1536. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1537. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1538. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1539. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1540. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1541. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a uniform coating.

1542. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a non-uniform coating.

1543. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a discontinuous coating.

1544. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is to form the coating of pattern.

1545. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 100 μ m or littler thickness.

1546. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 10 μ m or littler thickness.

1547. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is being disposed the surface adhesion that this installs later and this device.

1548. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, described coating in room temperature at least 1 year the time interim be stable.

1549. the 1438th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

1550. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

1551. the 1438th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

1552. the 1438th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

1553. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contains polymer.

1554. the 1438th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises first coating with first compositions and second coating with second compositions.

1555. the 1438th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device comprises first coating with first compositions and second coating with second compositions, and wherein said first compositions is different with second compositions.

1556. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, and the treatment of urinary incontinence is provided to the patient thus.

1557. the 1556th method, wherein said fibrous tissue forms agent and promotes regeneration.

1558. forming agent, the 1556th method, wherein said fibrous tissue promote blood vessel to take place.

1559. the 1556th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

1560. the 1556th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

1561. the 1556th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

1562. the 1556th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

1563. the 1556th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

1564. the 1556th method, wherein said fibrous tissue formation agent is silk or comprises silk.

1565. the 1556th method, wherein said fibrous tissue form agent with bunch form exist.

1566. the 1556th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

1567. the 1556th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

1568. the 1556th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

1569. the 1556th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

1570. the 1556th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

1571. the 1556th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

1572. the 1556th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

1573. the 1556th method, wherein said fibrous tissue form agent and exist with particulate form.

1574. the 1556th method, wherein said compositions comprises polymer.

1575. the 1556th method, wherein said compositions comprises polymer, and described polymer is copolymer or comprises copolymer.

1576. the 1556th method, wherein said compositions comprises polymer, and described polymer is block copolymer or comprises block copolymer.

1577. the 1556th method, wherein said compositions comprises polymer, and described polymer is random copolymer or comprises random copolymer.

1578. the 1556th method, wherein said compositions comprises polymer, and described polymer is biodegradable polymer or comprises biodegradable polymer.

1579. the 1556th method, wherein said compositions comprises polymer, and described polymer is not biodegradable polymer or comprises not biodegradable polymer.

1580. the 1556th method, wherein said compositions comprises polymer, and described polymer is hydrophilic polymer or comprises hydrophilic polymer.

1581. the 1556th method, wherein said compositions comprises polymer, and described polymer is hydrophobic polymer or comprises hydrophobic polymer.

1582. the 1556th method, wherein said compositions comprises polymer, and described polymer is the polymer in possess hydrophilic property zone or the polymer that comprises the possess hydrophilic property zone.

1583. the 1556th method, wherein said compositions comprises polymer, and described polymer is to have the polymer of water repellent region or comprise the polymer with water repellent region.

1584. the 1556th method, wherein said compositions comprises polymer, and described polymer is non-conductive polymer or comprises non-conductive polymer.

1585. the 1556th method, wherein said compositions comprises polymer, and described polymer is elastomer or comprises elastomer.

1586. the 1556th method, wherein said compositions comprises polymer, and described polymer is hydrogel or comprises hydrogel.

1587. the 1556th method, wherein said compositions comprises polymer, and described polymer is siloxane polymer or comprises siloxane polymer.

1588. the 1556th method, wherein said compositions comprises polymer, and described polymer is hydrocarbon polymer or comprises hydrocarbon polymer.

1589. the 1556th method, wherein said compositions comprises polymer, and described polymer is the styrene derived polymers or comprises the styrene derived polymers.

1590. the 1556th method, wherein said compositions comprises polymer, and described polymer is the butadiene derived polymers or comprises the butadiene derived polymers.

1591. the 1556th method, wherein said compositions comprises polymer, and described polymer is macromonomer or comprises macromonomer.

1592. the 1556th method, wherein said compositions comprises polymer, and described polymer is poly-(ethylene glycol) polymer or comprises poly-(ethylene glycol) polymer.

1593. the 1556th method, wherein said compositions comprises polymer, and described polymer is amorphous polymer or comprises amorphous polymer.

1594. the 1556th method, wherein said compositions also comprises second forms of pharmacologically active agents.

1595. the 1556th method, wherein said compositions also comprises antiinflammatory.

1596. the 1556th method, wherein said compositions also comprise the medicament that suppresses infection.

1597. the 1556th method, wherein said compositions also comprises anthracycline.

1598. the 1556th method, wherein said compositions also comprises doxorubicin.

1599. the 1556th method, wherein said compositions also comprises mitoxantrone.

1600. the 1556th method, wherein said compositions also comprises the fluorine pyrimidine.

1601. the 1556th method, wherein said compositions also comprise 5-fluorouracil (5-FU).

1602. the 1556th method, wherein said compositions also comprises antifol.

1603. the 1556th method, wherein said compositions also comprises methotrexate.

1604. the 1556th method, wherein said compositions also comprises podophyllotoxin.

1605. the 1556th method, wherein said compositions also comprises etoposide.

1606. the 1556th method, wherein said compositions also comprises camptothecine.

1607. the 1556th method, wherein said compositions also comprises hydroxyurea.

1608. the 1556th method, wherein said compositions also comprises platinum complex.

1609. the 1556th method, wherein said compositions also comprises cisplatin.

1610. the 1556th method, wherein said compositions also comprises antithrombotic agent.

1611. the 1556th method, wherein said compositions also comprises developing agent.

1612. the 1556th method, wherein said compositions also comprises developing agent, and described developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

1613. the 1556th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

1614. the 1556th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises MRI response material.

1615. the 1556th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

1616. the 1556th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper, or chromium.

1617. the 1556th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

1618. the 1556th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment, or coloring agent.

1619. the 1556th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

1620. the 1556th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

1621. the 1556th method, wherein said compositions also comprises inflammatory cytokine.

1622. the 1556th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

1623. the 1556th method, wherein said compositions also comprises polymer support.

1624. the 1556th method, wherein said compositions exists with the form of gel, paste or spray.

1625. the 1556th method is wherein sent described fibrous tissue from a kind of device and is formed agent, and described device is delivered locally to described fibrous tissue formation agent press close in the tissue of described device.

1626. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating comprises described fibrous tissue formation agent.

1627. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is placed on the surface of described device.

1628. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating directly contacts described device.

1629. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contacts described device indirectly.

1630. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and wherein said coating layer portion ground covers described device.

1631. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating fully covers described device.

1632. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

1633. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

1634. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo.

1635. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo, and the material of wherein said generation echo exists with the form of coating.

1636. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device is aseptic.

1637. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

1638. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

1639. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

1640. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

1641. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

1642. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 year period in disposing described device.

1643. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 month to 6 months period.

1644. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device in about 1-90 days period.

1645. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device with constant speed.

1646. the 1556th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

1647. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

1648. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

1649. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10 μ g to about 10mg.

1650. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10mg to about 250mg.

1651. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 250mg to about 1000mg.

1652. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 1000mg to about 2500mg.

1653. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, the described fibrous tissue that the surface of wherein said device comprises less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

1654. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1655. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1656. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1657. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1658. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1659. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a uniform coating.

1660. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a non-uniform coating.

1661. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a discontinuous coating.

1662. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is to form the coating of pattern.

1663. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 100 μ m or littler thickness.

1664. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 10 μ m or littler thickness.

1665. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is being disposed the surface adhesion that this installs later and this device.

1666. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, described coating in room temperature at least 1 year the time interim be stable.

1667. the 1556th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

1668. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

1669. the 1556th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

1670. the 1556th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

1671. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contains polymer.

1672. the 1556th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises first coating with first compositions and second coating with second compositions.

1673. the 1556th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device comprises first coating with first compositions and second coating with second compositions, and wherein said first compositions is different with second compositions.

1674. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, provides contraception to the patient thus.

1675. the 1674th method, wherein said fibrous tissue forms agent and promotes regeneration.

1676. forming agent, the 1674th method, wherein said fibrous tissue promote blood vessel to take place.

1677. the 1674th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

1678. the 1674th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

1679. the 1674th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

1680. the 1674th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

1681. the 1674th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

1682. the 1674th method, wherein said fibrous tissue formation agent is silk or comprises silk.

1683. the 1674th method, wherein said fibrous tissue form agent with bunch form exist.

1684. the 1674th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

1685. the 1674th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

1686. the 1674th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

1687. the 1674th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

1688. the 1674th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

1689. the 1674th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

1690. the 1674th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

1691. the 1674th method, wherein said fibrous tissue form agent and exist with particulate form.

1692. the 1674th method, wherein said compositions comprises polymer.

1693. the 1674th method, wherein said compositions comprises polymer, and described polymer is copolymer or comprises copolymer.

1694. the 1674th method, wherein said compositions comprises polymer, and described polymer is block copolymer or comprises block copolymer.

1695. the 1674th method, wherein said compositions comprises polymer, and described polymer is random copolymer or comprises random copolymer.

1696. the 1674th method, wherein said compositions comprises polymer, and described polymer is biodegradable polymer or comprises biodegradable polymer.

1697. the 1674th method, wherein said compositions comprises polymer, and described polymer is not biodegradable polymer or comprises not biodegradable polymer.

1698. the 1674th method, wherein said compositions comprises polymer, and described polymer is hydrophilic polymer or comprises hydrophilic polymer.

1699. the 1674th method, wherein said compositions comprises polymer, and described polymer is hydrophobic polymer or comprises hydrophobic polymer.

1700. the 1674th method, wherein said compositions comprises polymer, and described polymer is the polymer in possess hydrophilic property zone or the polymer that comprises the possess hydrophilic property zone.

1701. the 1674th method, wherein said compositions comprises polymer, and described polymer is to have the polymer of water repellent region or comprise the polymer with water repellent region.

1702. the 1674th method, wherein said compositions comprises polymer, and described polymer is non-conductive polymer or comprises non-conductive polymer.

1703. the 1674th method, wherein said compositions comprises polymer, and described polymer is elastomer or comprises elastomer.

1704. the 1674th method, wherein said compositions comprises polymer, and described polymer is hydrogel or comprises hydrogel.

1705. the 1674th method, wherein said compositions comprises polymer, and described polymer is siloxane polymer or comprises siloxane polymer.

1706. the 1674th method, wherein said compositions comprises polymer, and described polymer is hydrocarbon polymer or comprises hydrocarbon polymer.

1707. the 1674th method, wherein said compositions comprises polymer, and described polymer is the styrene derived polymers or comprises the styrene derived polymers.

1708. the 1674th method, wherein said compositions comprises polymer, and described polymer is the butadiene derived polymers or comprises the butadiene derived polymers.

1709. the 1674th method, wherein said compositions comprises polymer, and described polymer is macromonomer or comprises macromonomer.

1710. the 1674th method, wherein said compositions comprises polymer, and described polymer is poly-(ethylene glycol) polymer or comprises poly-(ethylene glycol) polymer.

1711. the 1674th method, wherein said compositions comprises polymer, and described polymer is amorphous polymer or comprises amorphous polymer.

1712. the 1674th method, wherein said compositions also comprises second forms of pharmacologically active agents.

1713. the 1674th method, wherein said compositions also comprises antiinflammatory.

1714. the 1674th method, wherein said compositions also comprise the medicament that suppresses infection.

1715. the 1674th method, wherein said compositions also comprises anthracycline.

1716. the 1674th method, wherein said compositions also comprises doxorubicin.

1717. the 1674th method, wherein said compositions also comprises mitoxantrone.

1718. the 1674th method, wherein said compositions also comprises the fluorine pyrimidine.

1719. the 1674th method, wherein said compositions also comprise 5-fluorouracil (5-FU).

1720. the 1674th method, wherein said compositions also comprises antifol.

1721. the 1674th method, wherein said compositions also comprises methotrexate.

1722. the 1674th method, wherein said compositions also comprises podophyllotoxin.

1723. the 1674th method, wherein said compositions also comprises etoposide.

1724. the 1674th method, wherein said compositions also comprises camptothecine.

1725. the 1674th method, wherein said compositions also comprises hydroxyurea.

1726. the 1674th method, wherein said compositions also comprises platinum complex.

1727. the 1674th method, wherein said compositions also comprises cisplatin.

1728. the 1674th method, wherein said compositions also comprises antithrombotic agent.

1729. the 1674th method, wherein said compositions also comprises developing agent.

1730. the 1674th method, wherein said compositions also comprises developing agent, and described developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

1731. the 1674th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

1732. the 1674th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises MRI response material.

1733. the 1674th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

1734. the 1674th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper, or chromium.

1735. the 1674th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

1736. the 1674th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment, or coloring agent.

1737. the 1674th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

1738. the 1674th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

1739. the 1674th method, wherein said compositions also comprises inflammatory cytokine.

1740. the 1674th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

1741. the 1674th method, wherein said compositions also comprises polymer support.

1742. the 1674th method, wherein said compositions exists with the form of gel, paste or spray.

1743. the 1674th method is wherein sent described fibrous tissue from a kind of device and is formed agent, and described device is delivered locally to described fibrous tissue formation agent press close in the tissue of described device.

1744. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating comprises described fibrous tissue formation agent.

1745. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is placed on the surface of described device.

1746. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating directly contacts described device.

1747. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contacts described device indirectly.

1748. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and wherein said coating layer portion ground covers described device.

1749. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating fully covers described device.

1750. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

1751. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

1752. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo.

1753. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo, and the material of wherein said generation echo exists with the form of coating.

1754. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device is aseptic.

1755. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

1756. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

1757. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

1758. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

1759. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

1760. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 year period in disposing described device.

1761. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 month to 6 months period.

1762. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device in about 1-90 days period.

1763. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device with constant speed.

1764. the 1674th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

1765. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

1766. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

1767. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10 μ g to about 10mg.

1768. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10mg to about 250mg.

1769. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 250mg to about 1000mg.

1770. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 1000mg to about 2500mg.

1771. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, the described fibrous tissue that the surface of wherein said device comprises less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

1772. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1773. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1774. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1775. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1776. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1777. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a uniform coating.

1778. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a non-uniform coating.

1779. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a discontinuous coating.

1780. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is to form the coating of pattern.

1781. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 100 μ m or littler thickness.

1782. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 10 μ m or littler thickness.

1783. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is being disposed the surface adhesion that this installs later and this device.

1784. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, described coating in room temperature at least 1 year the time interim be stable.

1785. the 1674th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

1786. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

1787. the 1674th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

1788. the 1674th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

1789. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contains polymer.

1790. the 1674th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises first coating with first compositions and second coating with second compositions.

1791. the 1674th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device comprises first coating with first compositions and second coating with second compositions, and wherein said first compositions is different with second compositions.

1792. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, provides orthopedics's treatment of diseases to the patient thus.

1793. the 1792nd method, wherein said fibrous tissue forms agent and promotes regeneration.

1794. forming agent, the 1792nd method, wherein said fibrous tissue promote blood vessel to take place.

1795. the 1792nd method, wherein said fibrous tissue form agent and promote the fibroblast migration.

1796. the 1792nd method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

1797. the 1792nd method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

1798. the 1792nd method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

1799. the 1792nd method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

1800. the 1792nd method, wherein said fibrous tissue formation agent is silk or comprises silk.

1801. the 1792nd method, wherein said fibrous tissue form agent with bunch form exist.

1802. the 1792nd method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

1803. the 1792nd method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

1804. the 1792nd method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

1805. the 1792nd method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

1806. the 1792nd method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

1807. the 1792nd method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

1808. the 1792nd method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

1809. the 1792nd method, wherein said fibrous tissue form agent and exist with particulate form.

1810. the 1792nd method, wherein said compositions comprises polymer.

1811. the 1792nd method, wherein said compositions comprises polymer, and described polymer is copolymer or comprises copolymer.

1812. the 1792nd method, wherein said compositions comprises polymer, and described polymer is block copolymer or comprises block copolymer.

1813. the 1792nd method, wherein said compositions comprises polymer, and described polymer is random copolymer or comprises random copolymer.

1814. the 1792nd method, wherein said compositions comprises polymer, and described polymer is biodegradable polymer or comprises biodegradable polymer.

1815. the 1792nd method, wherein said compositions comprises polymer, and described polymer is not biodegradable polymer or comprises not biodegradable polymer.

1816. the 1792nd method, wherein said compositions comprises polymer, and described polymer is hydrophilic polymer or comprises hydrophilic polymer.

1817. the 1792nd method, wherein said compositions comprises polymer, and described polymer is hydrophobic polymer or comprises hydrophobic polymer.

1818. the 1792nd method, wherein said compositions comprises polymer, and described polymer is the polymer in possess hydrophilic property zone or the polymer that comprises the possess hydrophilic property zone.

1819. the 1792nd method, wherein said compositions comprises polymer, and described polymer is to have the polymer of water repellent region or comprise the polymer with water repellent region.

1820. the 1792nd method, wherein said compositions comprises polymer, and described polymer is non-conductive polymer or comprises non-conductive polymer.

1821. the 1792nd method, wherein said compositions comprises polymer, and described polymer is elastomer or comprises elastomer.

1822. the 1792nd method, wherein said compositions comprises polymer, and described polymer is hydrogel or comprises hydrogel.

1823. the 1792nd method, wherein said compositions comprises polymer, and described polymer is siloxane polymer or comprises siloxane polymer.

1824. the 1792nd method, wherein said compositions comprises polymer, and described polymer is hydrocarbon polymer or comprises hydrocarbon polymer.

1825. the 1792nd method, wherein said compositions comprises polymer, and described polymer is the styrene derived polymers or comprises the styrene derived polymers.

1826. the 1792nd method, wherein said compositions comprises polymer, and described polymer is the butadiene derived polymers or comprises the butadiene derived polymers.

1827. the 1792nd method, wherein said compositions comprises polymer, and described polymer is macromonomer or comprises macromonomer.

1828. the 1792nd method, wherein said compositions comprises polymer, and described polymer is poly-(ethylene glycol) polymer or comprises poly-(ethylene glycol) polymer.

1829. the 1792nd method, wherein said compositions comprises polymer, and described polymer is amorphous polymer or comprises amorphous polymer.

1830. the 1792nd method, wherein said compositions also comprises second forms of pharmacologically active agents.

1831. the 1792nd method, wherein said compositions also comprises antiinflammatory.

1832. the 1792nd method, wherein said compositions also comprise the medicament that suppresses infection.

1833. the 1792nd method, wherein said compositions also comprises anthracycline.

1834. the 1792nd method, wherein said compositions also comprises doxorubicin.

1835. the 1792nd method, wherein said compositions also comprises mitoxantrone.

1836. the 1792nd method, wherein said compositions also comprises the fluorine pyrimidine.

1837. the 1792nd method, wherein said compositions also comprise 5-fluorouracil (5-FU).

1838. the 1792nd method, wherein said compositions also comprises antifol.

1839. the 1792nd method, wherein said compositions also comprises methotrexate.

1840. the 1792nd method, wherein said compositions also comprises podophyllotoxin.

1841. the 1792nd method, wherein said compositions also comprises etoposide.

1842. the 1792nd method, wherein said compositions also comprises camptothecine.

1843. the 1792nd method, wherein said compositions also comprises hydroxyurea.

1844. the 1792nd method, wherein said compositions also comprises platinum complex.

1845. the 1792nd method, wherein said compositions also comprises cisplatin.

1846. the 1792nd method, wherein said compositions also comprises antithrombotic agent.

1847. the 1792nd method, wherein said compositions also comprises developing agent.

1848. the 1792nd method, wherein said compositions also comprises developing agent, and described developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

1849. the 1792nd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

1850. the 1792nd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises MRI response material.

1851. the 1792nd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

1852. the 1792nd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper, or chromium.

1853. the 1792nd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

1854. the 1792nd method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment, or coloring agent.

1855. the 1792nd method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

1856. the 1792nd method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

1857. the 1792nd method, wherein said compositions also comprises inflammatory cytokine.

1858. the 1792nd method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

1859. the 1792nd method, wherein said compositions also comprises polymer support.

1860. the 1792nd method, wherein said compositions exists with the form of gel, paste or spray.

1861. the 1792nd method is wherein sent described fibrous tissue from a kind of device and is formed agent, and described device is delivered locally to described fibrous tissue formation agent press close in the tissue of described device.

1862. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating comprises described fibrous tissue formation agent.

1863. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is placed on the surface of described device.

1864. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating directly contacts described device.

1865. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contacts described device indirectly.

1866. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and wherein said coating layer portion ground covers described device.

1867. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating fully covers described device.

1868. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

1869. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

1870. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo.

1871. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo, and the material of wherein said generation echo exists with the form of coating.

1872. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device is aseptic.

1873. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

1874. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

1875. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

1876. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

1877. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

1878. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 year period in disposing described device.

1879. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 month to 6 months period.

1880. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device in about 1-90 days period.

1881. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device with constant speed.

1882. the 1792nd method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

1883. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

1884. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

1885. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10 μ g to about 10mg.

1886. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10mg to about 250mg.

1887. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 250mg to about 1000mg.

1888. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 1000mg to about 2500mg.

1889. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, the described fibrous tissue that the surface of wherein said device comprises less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

1890. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1891. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1892. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1893. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1894. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

1895. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a uniform coating.

1896. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a non-uniform coating.

1897. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a discontinuous coating.

1898. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is to form the coating of pattern.

1899. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 100 μ m or littler thickness.

1900. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 10 μ m or littler thickness.

1901. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is being disposed the surface adhesion that this installs later and this device.

1902. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, described coating in room temperature at least 1 year the time interim be stable.

1903. the 1792nd method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

1904. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

1905. the 1792nd method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

1906. the 1792nd method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

1907. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contains polymer.

1908. the 1792nd method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises first coating with first compositions and second coating with second compositions.

1909. the 1792nd method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device comprises first coating with first compositions and second coating with second compositions, and wherein said first compositions is different with second compositions.

1910. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, and odontopathy's treatment is provided to the patient thus.

1911. the 1910th method, wherein said fibrous tissue forms agent and promotes regeneration.

1912. forming agent, the 1910th method, wherein said fibrous tissue promote blood vessel to take place.

1913. the 1910th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

1914. the 1910th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

1915. the 1910th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

1916. the 1910th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

1917. the 1910th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

1918. the 1910th method, wherein said fibrous tissue formation agent is silk or comprises silk.

1919. the 1910th method, wherein said fibrous tissue form agent with bunch form exist.

1920. the 1910th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

1921. the 1910th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

1922. the 1910th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

1923. the 1910th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

1924. the 1910th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

1925. the 1910th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

1926. the 1910th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

1927. the 1910th method, wherein said fibrous tissue form agent and exist with particulate form.

1928. the 1910th method, wherein said compositions comprises polymer.

1929. the 1910th method, wherein said compositions comprises polymer, and described polymer is copolymer or comprises copolymer.

1930. the 1910th method, wherein said compositions comprises polymer, and described polymer is block copolymer or comprises block copolymer.

1931. the 1910th method, wherein said compositions comprises polymer, and described polymer is random copolymer or comprises random copolymer.

1932. the 1910th method, wherein said compositions comprises polymer, and described polymer is biodegradable polymer or comprises biodegradable polymer.

1933. the 1910th method, wherein said compositions comprises polymer, and described polymer is not biodegradable polymer or comprises not biodegradable polymer.

1934. the 1910th method, wherein said compositions comprises polymer, and described polymer is hydrophilic polymer or comprises hydrophilic polymer.

1935. the 1910th method, wherein said compositions comprises polymer, and described polymer is hydrophobic polymer or comprises hydrophobic polymer.

1936. the 1910th method, wherein said compositions comprises polymer, and described polymer is the polymer in possess hydrophilic property zone or the polymer that comprises the possess hydrophilic property zone.

1937. the 1910th method, wherein said compositions comprises polymer, and described polymer is to have the polymer of water repellent region or comprise the polymer with water repellent region.

1938. the 1910th method, wherein said compositions comprises polymer, and described polymer is non-conductive polymer or comprises non-conductive polymer.

1939. the 1910th method, wherein said compositions comprises polymer, and described polymer is elastomer or comprises elastomer.

1940. the 1910th method, wherein said compositions comprises polymer, and described polymer is hydrogel or comprises hydrogel.

1941. the 1910th method, wherein said compositions comprises polymer, and described polymer is siloxane polymer or comprises siloxane polymer.

1942. the 1910th method, wherein said compositions comprises polymer, and described polymer is hydrocarbon polymer or comprises hydrocarbon polymer.

1943. the 1910th method, wherein said compositions comprises polymer, and described polymer is the styrene derived polymers or comprises the styrene derived polymers.

1944. the 1910th method, wherein said compositions comprises polymer, and described polymer is the butadiene derived polymers or comprises the butadiene derived polymers.

1945. the 1910th method, wherein said compositions comprises polymer, and described polymer is macromonomer or comprises macromonomer.

1946. the 1910th method, wherein said compositions comprises polymer, and described polymer is poly-(ethylene glycol) polymer or comprises poly-(ethylene glycol) polymer.

1947. the 1910th method, wherein said compositions comprises polymer, and described polymer is amorphous polymer or comprises amorphous polymer.

1948. the 1910th method, wherein said compositions also comprises second forms of pharmacologically active agents.

1949. the 1910th method, wherein said compositions also comprises antiinflammatory.

1950. the 1910th method, wherein said compositions also comprise the medicament that suppresses infection.

1951. the 1910th method, wherein said compositions also comprises anthracycline.

1952. the 1910th method, wherein said compositions also comprises doxorubicin.

1953. the 1910th method, wherein said compositions also comprises mitoxantrone.

1954. the 1910th method, wherein said compositions also comprises the fluorine pyrimidine.

1955. the 1910th method, wherein said compositions also comprise 5-fluorouracil (5-FU).

1956. the 1910th method, wherein said compositions also comprises antifol.

1957. the 1910th method, wherein said compositions also comprises methotrexate.

1958. the 1910th method, wherein said compositions also comprises podophyllotoxin.

1959. the 1910th method, wherein said compositions also comprises etoposide.

1960. the 1910th method, wherein said compositions also comprises camptothecine.

1961. the 1910th method, wherein said compositions also comprises hydroxyurea.

1962. the 1910th method, wherein said compositions also comprises platinum complex.

1963. the 1910th method, wherein said compositions also comprises cisplatin.

1964. the 1910th method, wherein said compositions also comprises antithrombotic agent.

1965. the 1910th method, wherein said compositions also comprises developing agent.

1966. the 1910th method, wherein said compositions also comprises developing agent, and described developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

1967. the 1910th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises barium, tantalum or technetium.

1968. the 1910th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises MRI response material.

1969. the 1910th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises gadolinium chelate compound.

1970. the 1910th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises ferrum, magnesium, manganese, copper, or chromium.

1971. the 1910th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises iron oxide compound.

1972. the 1910th method, wherein said compositions also comprises developing agent, and described developing agent is, or comprises dyestuff, pigment, or coloring agent.

1973. the 1910th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

1974. the 1910th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

1975. the 1910th method, wherein said compositions also comprises inflammatory cytokine.

1976. the 1910th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

1977. the 1910th method, wherein said compositions also comprises polymer support.

1978. the 1910th method, wherein said compositions exists with the form of gel, paste or spray.

1979. the 1910th method is wherein sent described fibrous tissue from a kind of device and is formed agent, and described device is delivered locally to described fibrous tissue formation agent press close in the tissue of described device.

1980. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating comprises described fibrous tissue formation agent.

1981. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is placed on the surface of described device.

1982. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating directly contacts described device.

1983. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contacts described device indirectly.

1984. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and wherein said coating layer portion ground covers described device.

1985. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating fully covers described device.

1986. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

1987. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

1988. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo.

1989. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises the material that produces echo, and the material of wherein said generation echo exists with the form of coating.

1990. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device is aseptic.

1991. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

1992. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

1993. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

1994. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

1995. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

1996. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 year period in disposing described device.

1997. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and is discharging with valid density from described device in about 1 month to 6 months period.

1998. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device in about 1-90 days period.

1999. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue forms agent and discharges with valid density from described device with constant speed.

2000. the 1910th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

2001. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

2002. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

2003. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10 μ g to about 10mg.

2004. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 10mg to about 250mg.

2005. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 250mg to about 1000mg.

2006. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises the described fibrous tissue formation agent of about 1000mg to about 2500mg.

2007. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, the described fibrous tissue that the surface of wherein said device comprises less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

2008. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2009. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2010. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2011. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2012. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, the surface of wherein said device comprises the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2013. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a uniform coating.

2014. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a non-uniform coating.

2015. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is a discontinuous coating.

2016. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is to form the coating of pattern.

2017. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 100 μ m or littler thickness.

2018. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating has 10 μ m or littler thickness.

2019. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating is being disposed the surface adhesion that this installs later and this device.

2020. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, described coating in room temperature at least 1 year the time interim be stable.

2021. the 1910th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

2022. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

2023. the 1910th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

2024. the 1910th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device also comprises coating, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

2025. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device also comprises coating, and described coating contains polymer.

2026. the 1910th method is wherein sent described fibrous tissue from a kind of device and formed agent, wherein said device comprises first coating with first compositions and second coating with second compositions.

2027. the 1910th method, wherein send described fibrous tissue and form agent from a kind of device, wherein said device comprises first coating with first compositions and second coating with second compositions, and wherein said first compositions is different with second compositions.

2028. a medical apparatus that comprises rectificating surgery implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

2029. the 2028th device, wherein said fibrous tissue forms agent and promotes regeneration.

2030. forming agent, the 2028th device, wherein said fibrous tissue promote blood vessel to take place.

2031. the 2028th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

2032. the 2028th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

2033. the 2028th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

2034. the 2028th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

2035. the 2028th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

2036. the 2028th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

2037. the 2028th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

2038. the 2028th device, wherein said fibrous tissue formation agent is silk or comprises silk.

2039. the 2028th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

2040. the 2028th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

2041. the 2028th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

2042. the 2028th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

2043. the 2028th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

2044. the 2028th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

2045. the 2028th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

2046. the 2028th device, wherein said fibrous tissue form agent and exist with particulate form.

2047. the 2028th device, wherein said compositions also comprises inflammatory cytokine.

2048. the 2028th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

2049. the 2028th device, wherein said compositions exists with the form of gel, paste or spray.

2050. the 2028th device, wherein said fibrous tissue form the form that agent is bunch.

2051. the 2028th device also comprises polymer.

2052. the 2028th device also comprises polymer support.

2053. the 2028th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

2054. the 2028th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

2055. the 2028th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

2056. the 2028th device also comprises coating, wherein said coating is placed on the surface of described device.

2057. the 2028th device also comprises coating, wherein said coating directly contacts described device.

2058. the 2028th device also comprises coating, wherein said coating contacts described device indirectly.

2059. the 2028th device also comprises coating, wherein said coating layer portion ground covers described device.

2060. the 2028th device also comprises coating, wherein said coating fully covers described device.

2061. the 2028th device also comprises coating, wherein said coating is uniform coating.

2062. the 2028th device also comprises coating, wherein said coating is uneven coating.

2063. the 2028th device also comprises coating, wherein said coating is a discontinuous coating.

2064. the 2028th device also comprises coating, wherein said coating is to form the coating of pattern.

2065. the 2028th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

2066. the 2028th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

2067. the 2028th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

2068. the 2028th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

2069. the 2028th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

2070. the 2028th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

2071. the 2028th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

2072. the 2028th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

2073. the 2028th device also comprises coating, wherein said coating also contains polymer.

2074. the 2028th device also comprises first coating with first compositions and second coating with second compositions.

2075. the 2028th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

2076. the 2028th device also comprises polymer.

2077. the 2028th device also comprises polymer support.

2078. the 2028th device also comprises polymer support, wherein said polymer support comprises copolymer.

2079. the 2028th device also comprises polymer support, wherein said polymer support comprises block copolymer.

2080. the 2028th device also comprises polymer support, wherein said polymer support comprises random copolymer.

2081. the 2028th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

2082. the 2028th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

2083. the 2028th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

2084. the 2028th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

2085. the 2028th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

2086. the 2028th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

2087. the 2028th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

2088. the 2028th device also comprises polymer support, wherein said polymer support comprises elastomer.

2089. the 2028th device also comprises polymer support, wherein said polymer support comprises hydrogel.

2090. the 2028th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

2091. the 2028th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

2092. the 2028th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

2093. the 2028th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

2094. the 2028th device also comprises polymer support, wherein said polymer support comprises macromonomer.

2095. the 2028th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

2096. the 2028th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

2097. the 2028th device also comprises lubricant coating.

2098. the 2028th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

2099. the 2028th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

2100. the 2028th device also comprises second forms of pharmacologically active agents.

2101. the 2028th device also comprises antiinflammatory.

2102. the 2028th device also comprises the medicament that suppresses infection.

2103. the 2028th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

2104. the 2028th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

2105. the 2028th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

2106. the 2028th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

2107. the 2028th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

2108. the 2028th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

2109. the 2028th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

2110. the 2028th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

2111. the 2028th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

2112. the 2028th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

2113. the 2028th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

2114. the 2028th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

2115. the 2028th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

2116. the 2028th device also comprises antithrombotic agent.

2117. the 2028th device also comprises developing agent.

2118. the 2028th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

2119. the 2028th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

2120. the 2028th device also comprises developing agent, wherein said developing agent comprises MRI response material.

2121. the 2028th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

2122. the 2028th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

2123. the 2028th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

2124. the 2028th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

2125. the 2028th device also comprises the material that produces echo.

2126. the 2028th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

2127. the 2028th device, wherein said device is aseptic.

2128. the 2028th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

2129. the 2028th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

2130. the 2028th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

2131. the 2028th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

2132. the 2028th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

2133. the 2028th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

2134. the 2028th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

2135. the 2028th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

2136. the 2028th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

2137. the 2028th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

2138. the 2028th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

2139. the 2028th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

2140. the 2028th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

2141. the 2028th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

2142. the 2028th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

2143. the 2028th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

2144. the 2028th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

2145. the 2028th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

2146. the described fibrous tissue that the 2028th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

2147. the 2028th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2148. the 2028th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2149. the 2028th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2150. the 2028th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2151. the 2028th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2152. the 2028th device, wherein said rectificating surgery implant is used as the substitute of bone graft.

2153. the 2028th device, wherein said rectificating surgery implant are orthopedics's pin (pin) implants.

2154. the 2028th device, wherein said rectificating surgery implant are orthopedics's nail (nail) implants.

2155. a medical apparatus that comprises orthopedics's prosthese and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

2156. the 2155th device, wherein said fibrous tissue forms agent and promotes regeneration.

2157. forming agent, the 2155th device, wherein said fibrous tissue promote blood vessel to take place.

2158. the 2155th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

2159. the 2155th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

2160. the 2155th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

2161. the 2155th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

2162. the 2155th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

2163. the 2155th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

2164. the 2155th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

2165. the 2155th device, wherein said fibrous tissue formation agent is silk or comprises silk.

2166. the 2155th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

2167. the 2155th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

2168. the 2155th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

2169. the 2155th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

2170. the 2155th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

2171. the 2155th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

2172. the 2155th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

2173. the 2155th device, wherein said fibrous tissue form agent and exist with particulate form.

2174. the 2155th device, wherein said compositions also comprises inflammatory cytokine.

2175. the 2155th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

2176. the 2155th device, wherein said compositions exists with the form of gel, paste or spray.

2177. the 2155th device, wherein said fibrous tissue form agent with bunch form exist.

2178. the 2155th device, it also comprises polymer.

2179. the 2155th device, it also comprises polymer support.

2180. the 2155th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

2181. the 2155th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

2182. the 2155th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

2183. the 2155th device also comprises coating, wherein said coating is placed on the surface of described device.

2184. the 2155th device also comprises coating, wherein said coating directly contacts described device.

2185. the 2155th device also comprises coating, wherein said coating contacts described device indirectly.

2186. the 2155th device also comprises coating, wherein said coating layer portion ground covers described device.

2187. the 2155th device also comprises coating, wherein said coating fully covers described device.

2188. the 2155th device also comprises coating, wherein said coating is uniform coating.

2189. the 2155th device also comprises coating, wherein said coating is uneven coating.

2190. the 2155th device also comprises coating, wherein said coating is a discontinuous coating.

2191. the 2155th device also comprises coating, wherein said coating is to form the coating of pattern.

2192. the 2155th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

2193. the 2155th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

2194. the 2155th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

2195. the 2155th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

2196. the 2155th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

2197. the 2155th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

2198. the 2155th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

2199. the 2155th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

2200. the 2155th device also comprises coating, wherein said coating also contains polymer.

2201. the 2155th device also comprises first coating with first compositions and second coating with second compositions.

2202. the 2155th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

2203. the 2155th device also comprises polymer.

2204. the 2155th device also comprises polymer support.

2205. the 2155th device also comprises polymer support, wherein said polymer support comprises copolymer.

2206. the 2155th device also comprises polymer support, wherein said polymer support comprises block copolymer.

2207. the 2155th device also comprises polymer support, wherein said polymer support comprises random copolymer.

2208. the 2155th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

2209. the 2155th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

2210. the 2155th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

2211. the 2155th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

2212. the 2155th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

2213. the 2155th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

2214. the 2155th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

2215. the 2155th device also comprises polymer support, wherein said polymer support comprises elastomer.

2216. the 2155th device also comprises polymer support, wherein said polymer support comprises hydrogel.

2217. the 2155th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

2218. the 2155th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

2219. the 2155th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

2220. the 2155th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

2221. the 2155th device also comprises polymer support, wherein said polymer support comprises macromonomer.

2222. the 2155th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

2223. the 2155th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

2224. the 2155th device also comprises lubricant coating.

2225. the 2155th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

2226. the 2155th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

2227. the 2155th device also comprises second forms of pharmacologically active agents.

2228. the 2155th device also comprises antiinflammatory.

2229. the 2155th device also comprises the medicament that suppresses infection.

2230. the 2155th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

2231. the 2155th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

2232. the 2155th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

2233. the 2155th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

2234. the 2155th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

2235. the 2155th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

2236. the 2155th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

2237. the 2155th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

2238. the 2155th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

2239. the 2155th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

2240. the 2155th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

2241. the 2155th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

2242. the 2155th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

2243. the 2155th device also comprises antithrombotic agent.

2244. the 2155th device also comprises developing agent.

2245. the 2155th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

2246. the 2155th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

2247. the 2155th device also comprises developing agent, wherein said developing agent comprises MRI response material.

2248. the 2155th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

2249. the 2155th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

2250. the 2155th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

2251. the 2155th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

2252. the 2155th device also comprises the material that produces echo.

2253. the 2155th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

2254. the 2155th device, wherein said device is aseptic.

2255. the 2155th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

2256. the 2155th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

2257. the 2155th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

2258. the 2155th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

2259. the 2155th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

2260. the 2155th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

2261. the 2155th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

2262. the 2155th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

2263. the 2155th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

2264. the 2155th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

2265. the 2155th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

2266. the 2155th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

2267. the 2155th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

2268. the 2155th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

2269. the 2155th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

2270. the 2155th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

2271. the 2155th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

2272. the 2155th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

2273. the described fibrous tissue that the 2155th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

2274. the 2155th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2275. the 2155th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2276. the 2155th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2277. the 2155th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2278. the 2155th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2279. a medical apparatus that comprises modular implant (modular implant) and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

2280. the 2279th device, wherein said fibrous tissue forms agent and promotes regeneration.

2281. forming agent, the 2279th device, wherein said fibrous tissue promote blood vessel to take place.

2282. the 2279th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

2283. the 2279th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

2284. the 2279th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

2285. the 2279th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

2286. the 2279th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

2287. the 2279th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

2288. the 2279th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

2289. the 2279th device, wherein said fibrous tissue formation agent is silk or comprises silk.

2290. the 2279th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

2291. the 2279th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

2292. the 2279th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

2293. the 2279th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

2294. the 2279th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

2295. the 2279th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

2296. the 2279th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

2297. the 2279th device, wherein said fibrous tissue form agent and exist with particulate form.

2298. the 2279th device, wherein said compositions also comprises inflammatory cytokine.

2299. the 2279th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

2300. the 2279th device, wherein said compositions exists with the form of gel, paste or spray.

2301. the 2279th device, wherein said fibrous tissue form the form that agent is bunch.

2302. the 2279th device also comprises polymer.

2303. the 2279th device also comprises polymer support.

2304. the 2279th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

2305. the 2279th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

2306. the 2279th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

2307. the 2279th device also comprises coating, wherein said coating is placed on the surface of described device.

2308. the 2279th device also comprises coating, wherein said coating directly contacts described device.

2309. the 2279th device also comprises coating, wherein said coating contacts described device indirectly.

2310. the 2279th device also comprises coating, wherein said coating layer portion ground covers described device.

2311. the 2279th device also comprises coating, wherein said coating fully covers described device.

2312. the 2279th device also comprises coating, wherein said coating is uniform coating.

2313. the 2279th device also comprises coating, wherein said coating is uneven coating.

2314. the 2279th device also comprises coating, wherein said coating is a discontinuous coating.

2315. the 2279th device also comprises coating, wherein said coating is to form the coating of pattern.

2316. the 2279th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

2317. the 2279th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

2318. the 2279th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

2319. the 2279th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

2320. the 2279th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

2321. the 2279th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

2322. the 2279th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

2323. the 2279th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

2324. the 2279th device also comprises coating, wherein said coating also contains polymer.

2325. the 2279th device also comprises first coating with first compositions and second coating with second compositions.

2326. the 2279th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

2327. the 2279th device also comprises polymer.

2328. the 2279th device also comprises polymer support.

2329. the 2279th device also comprises polymer support, wherein said polymer support comprises copolymer.

2330. the 2279th device also comprises polymer support, wherein said polymer support comprises block copolymer.

2331. the 2279th device also comprises polymer support, wherein said polymer support comprises random copolymer.

2332. the 2279th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

2333. the 2279th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

2334. the 2279th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

2335. the 2279th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

2336. the 2279th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

2337. the 2279th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

2338. the 2279th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

2339. the 2279th device also comprises polymer support, wherein said polymer support comprises elastomer.

2340. the 2279th device also comprises polymer support, wherein said polymer support comprises hydrogel.

2341. the 2279th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

2342. the 2279th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

2343. the 2279th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

2344. the 2279th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

2345. the 2279th device also comprises polymer support, wherein said polymer support comprises macromonomer.

2346. the 2279th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

2347. the 2279th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

2348. the 2279th device also comprises lubricant coating.

2349. the 2279th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

2350. the 2279th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

2351. the 2279th device also comprises second forms of pharmacologically active agents.

2352. the 2279th device also comprises antiinflammatory.

2353. the 2279th device also comprises the medicament that suppresses infection.

2354. the 2279th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

2355. the 2279th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

2356. the 2279th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

2357. the 2279th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

2358. the 2279th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

2359. the 2279th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

2360. the 2279th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

2361. the 2279th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

2362. the 2279th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

2363. the 2279th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

2364. the 2279th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

2365. the 2279th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

2366. the 2279th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

2367. the 2279th device also comprises antithrombotic agent.

2368. the 2279th device also comprises developing agent.

2369. the 2279th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

2370. the 2279th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

2371. the 2279th device also comprises developing agent, wherein said developing agent comprises MRI response material.

2372. the 2279th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

2373. the 2279th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

2374. the 2279th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

2375. the 2279th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

2376. the 2279th device also comprises the material that produces echo.

2377. the 2279th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

2378. the 2279th device, wherein said device is aseptic.

2379. the 2279th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

2380. the 2279th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

2381. the 2279th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

2382. the 2279th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

2383. the 2279th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

2384. the 2279th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

2385. the 2279th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

2386. the 2279th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

2387. the 2279th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

2388. the 2279th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

2389. the 2279th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

2390. the 2279th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

2391. the 2279th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

2392. the 2279th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

2393. the 2279th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

2394. the 2279th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

2395. the 2279th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

2396. the 2279th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

2397. the described fibrous tissue that the 2279th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

2398. the 2279th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2399. the 2279th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2400. the 2279th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2401. the 2279th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2402. the 2279th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2403. a medical apparatus that comprises urine sling and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

2404. the 2403rd device, wherein said fibrous tissue forms agent and promotes regeneration.

2405. forming agent, the 2403rd device, wherein said fibrous tissue promote blood vessel to take place.

2406. the 2403rd device, wherein said fibrous tissue form agent and promote the fibroblast migration.

2407. the 2403rd device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

2408. the 2403rd device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

2409. the 2403rd device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

2410. the 2403rd device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

2411. the 2403rd device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

2412. the 2403rd device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

2413. the 2403rd device, wherein said fibrous tissue formation agent is silk or comprises silk.

2414. the 2403rd device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

2415. the 2403rd device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

2416. the 2403rd device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

2417. the 2403rd device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

2418. the 2403rd device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

2419. the 2403rd device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

2420. the 2403rd device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

2421. the 2403rd device, wherein said fibrous tissue form agent and exist with particulate form.

2422. the 2403rd device, wherein said compositions also comprises inflammatory cytokine.

2423. the 2403rd device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

2424. the 2403rd device, wherein said compositions exists with the form of gel, paste or spray.

2425. the 2403rd device, wherein said fibrous tissue form the form that agent is bunch.

2426. the 2403rd device also comprises polymer.

2427. the 2403rd device also comprises polymer support.

2428. the 2403rd device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

2429. the 2403rd device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

2430. the 2403rd device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

2431. the 2403rd device also comprises coating, wherein said coating is placed on the surface of described device.

2432. the 2403rd device also comprises coating, wherein said coating directly contacts described device.

2433. the 2403rd device also comprises coating, wherein said coating contacts described device indirectly.

2434. the 2403rd device also comprises coating, wherein said coating layer portion ground covers described device.

2435. the 2403rd device also comprises coating, wherein said coating fully covers described device.

2436. the 2403rd device also comprises coating, wherein said coating is uniform coating.

2437. the 2403rd device also comprises coating, wherein said coating is uneven coating.

2438. the 2403rd device also comprises coating, wherein said coating is a discontinuous coating.

2439. the 2403rd device also comprises coating, wherein said coating is to form the coating of pattern.

2440. the 2403rd device also comprises coating, wherein said coating has 100 μ m or littler thickness.

2441. the 2403rd device also comprises coating, wherein said coating has 10 μ m or littler thickness.

2442. the 2403rd device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

2443. the 2403rd device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

2444. the 2403rd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

2445. the 2403rd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

2446. the 2403rd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

2447. the 2403rd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

2448. the 2403rd device also comprises coating, wherein said coating also contains polymer.

2449. the 2403rd device also comprises first coating with first compositions and second coating with second compositions.

2450. the 2403rd device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

2451. the 2403rd device also comprises polymer.

2452. the 2403rd device also comprises polymer support.

2453. the 2403rd device also comprises polymer support, wherein said polymer support comprises copolymer.

2454. the 2403rd device also comprises polymer support, wherein said polymer support comprises block copolymer.

2455. the 2403rd device also comprises polymer support, wherein said polymer support comprises random copolymer.

2456. the 2403rd device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

2457. the 2403rd device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

2458. the 2403rd device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

2459. the 2403rd device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

2460. the 2403rd device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

2461. the 2403rd device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

2462. the 2403rd device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

2463. the 2403rd device also comprises polymer support, wherein said polymer support comprises elastomer.

2464. the 2403rd device also comprises polymer support, wherein said polymer support comprises hydrogel.

2465. the 2403rd device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

2466. the 2403rd device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

2467. the 2403rd device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

2468. the 2403rd device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

2469. the 2403rd device also comprises polymer support, wherein said polymer support comprises macromonomer.

2470. the 2403rd device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

2471. the 2403rd device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

2472. the 2403rd device also comprises lubricant coating.

2473. the 2403rd device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

2474. the 2403rd device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

2475. the 2403rd device also comprises second forms of pharmacologically active agents.

2476. the 2403rd device also comprises antiinflammatory.

2477. the 2403rd device also comprises the medicament that suppresses infection.

2478. the 2403rd device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

2479. the 2403rd device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

2480. the 2403rd device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

2481. the 2403rd device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

2482. the 2403rd device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

2483. the 2403rd device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

2484. the 2403rd device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

2485. the 2403rd device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

2486. the 2403rd device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

2487. the 2403rd device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

2488. the 2403rd device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

2489. the 2403rd device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

2490. the 2403rd device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

2491. the 2403rd device also comprises antithrombotic agent.

2492. the 2403rd device also comprises developing agent.

2493. the 2403rd device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

2494. the 2403rd device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

2495. the 2403rd device also comprises developing agent, wherein said developing agent comprises MRI response material.

2496. the 2403rd device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

2497. the 2403rd device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

2498. the 2403rd device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

2499. the 2403rd device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

2500. the 2403rd device also comprises the material that produces echo.

2501. the 2403rd device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

2502. the 2403rd device, wherein said device is aseptic.

2503. the 2403rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

2504. the 2403rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

2505. the 2403rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

2506. the 2403rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

2507. the 2403rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

2508. the 2403rd device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

2509. the 2403rd device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

2510. the 2403rd device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

2511. the 2403rd device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

2512. the 2403rd device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

2513. the 2403rd device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

2514. the 2403rd device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

2515. the 2403rd device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

2516. the 2403rd device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

2517. the 2403rd device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

2518. the 2403rd device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

2519. the 2403rd device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

2520. the 2403rd device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

2521. the described fibrous tissue that the 2403rd device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

2522. the 2403rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2523. the 2403rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2524. the 2403rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2525. the 2403rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2526. the 2403rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2527. a medical apparatus that comprises prosthetic joint and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

2528. the 2527th device, wherein said fibrous tissue forms agent and promotes regeneration.

2529. forming agent, the 2527th device, wherein said fibrous tissue promote blood vessel to take place.

2530. the 2527th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

2531. the 2527th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

2532. the 2527th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

2533. the 2527th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

2534. the 2527th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

2535. the 2527th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

2536. the 2527th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

2537. the 2527th device, wherein said fibrous tissue formation agent is silk or comprises silk.

2538. the 2527th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

2539. the 2527th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

2540. the 2527th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

2541. the 2527th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

2542. the 2527th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

2543. the 2527th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

2544. the 2527th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

2545. the 2527th device, wherein said fibrous tissue form agent and exist with particulate form.

2546. the 2527th device, wherein said compositions also comprises inflammatory cytokine.

2547. the 2527th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

2548. the 2527th device, wherein said compositions exists with the form of gel, paste or spray.

2549. the 2527th device, wherein said fibrous tissue form the form that agent is bunch.

2550. the 2527th device also comprises polymer.

2551. the 2527th device also comprises polymer support.

2552. the 2527th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

2553. the 2527th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

2554. the 2527th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

2555. the 2527th device also comprises coating, wherein said coating is placed on the surface of described device.

2556. the 2527th device also comprises coating, wherein said coating directly contacts described device.

2557. the 2527th device also comprises coating, wherein said coating contacts described device indirectly.

2558. the 2527th device also comprises coating, wherein said coating layer portion ground covers described device.

2559. the 2527th device also comprises coating, wherein said coating fully covers described device.

2560. the 2527th device also comprises coating, wherein said coating is uniform coating.

2561. the 2527th device also comprises coating, wherein said coating is uneven coating.

2562. the 2527th device also comprises coating, wherein said coating is a discontinuous coating.

2563. the 2527th device also comprises coating, wherein said coating is to form the coating of pattern.

2564. the 2527th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

2565. the 2527th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

2566. the 2527th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

2567. the 2527th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

2568. the 2527th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

2569. the 2527th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

2570. the 2527th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

2571. the 2527th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

2572. the 2527th device also comprises coating, wherein said coating also contains polymer.

2573. the 2527th device also comprises first coating with first compositions and second coating with second compositions.

2574. the 2527th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

2575. the 2527th device also comprises polymer.

2576. the 2527th device also comprises polymer support.

2577. the 2527th device also comprises polymer support, wherein said polymer support comprises copolymer.

2578. the 2527th device also comprises polymer support, wherein said polymer support comprises block copolymer.

2579. the 2527th device also comprises polymer support, wherein said polymer support comprises random copolymer.

2580. the 2527th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

2581. the 2527th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

2582. the 2527th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

2583. the 2527th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

2584. the 2527th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

2585. the 2527th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

2586. the 2527th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

2587. the 2527th device also comprises polymer support, wherein said polymer support comprises elastomer.

2588. the 2527th device also comprises polymer support, wherein said polymer support comprises hydrogel.

2589. the 2527th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

2590. the 2527th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

2591. the 2527th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

2592. the 2527th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

2593. the 2527th device also comprises polymer support, wherein said polymer support comprises macromonomer.

2594. the 2527th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

2595. the 2527th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

2596. the 2527th device also comprises lubricant coating.

2597. the 2527th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

2598. the 2527th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

2599. the 2527th device also comprises second forms of pharmacologically active agents.

2600. the 2527th device also comprises antiinflammatory.

2601. the 2527th device also comprises the medicament that suppresses infection.

2602. the 2527th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

2603. the 2527th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

2604. the 2527th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

2605. the 2527th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

2606. the 2527th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

2607. the 2527th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

2608. the 2527th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

2609. the 2527th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

2610. the 2527th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

2611. the 2527th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

2612. the 2527th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

2613. the 2527th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

2614. the 2527th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

2615. the 2527th device also comprises antithrombotic agent.

2616. the 2527th device also comprises developing agent.

2617. the 2527th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

2618. the 2527th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

2619. the 2527th device also comprises developing agent, wherein said developing agent comprises MRI response material.

2620. the 2527th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

2621. the 2527th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

2622. the 2527th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

2623. the 2527th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

2624. the 2527th device also comprises the material that produces echo.

2625. the 2527th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

2626. the 2527th device, wherein said device is aseptic.

2627. the 2527th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

2628. the 2527th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

2629. the 2527th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

2630. the 2527th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

2631. the 2527th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

2632. the 2527th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

2633. the 2527th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

2634. the 2527th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

2635. the 2527th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

2636. the 2527th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

2637. the 2527th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

2638. the 2527th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

2639. the 2527th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

2640. the 2527th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

2641. the 2527th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

2642. the 2527th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

2643. the 2527th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

2644. the 2527th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

2645. the described fibrous tissue that the 2527th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

2646. the 2527th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2647. the 2527th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2648. the 2527th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2649. the 2527th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2650. the 2527th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2651. a medical apparatus that comprises modular prosthese and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

2652. the 2651st device, wherein said fibrous tissue forms agent and promotes regeneration.

2653. forming agent, the 2651st device, wherein said fibrous tissue promote blood vessel to take place.

2654. the 2651st device, wherein said fibrous tissue form agent and promote the fibroblast migration.

2655. the 2651st device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

2656. the 2651st device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

2657. the 2651st device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

2658. the 2651st device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

2659. the 2651st device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

2660. the 2651st device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

2661. the 2651st device, wherein said fibrous tissue formation agent is silk or comprises silk.

2662. the 2651st device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

2663. the 2651st device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

2664. the 2651st device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

2665. the 2651st device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

2666. the 2651st device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

2667. the 2651st device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

2668. the 2651st device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

2669. the 2651st device, wherein said fibrous tissue form agent and exist with particulate form.

2670. the 2651st device, wherein said compositions also comprises inflammatory cytokine.

2671. the 2651st device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

2672. the 2651st device, wherein said compositions exists with the form of gel, paste or spray.

2673. the 2651st device, wherein said fibrous tissue form agent with bunch form exist.

2674. the 2651st device also comprises polymer.

2675. the 2651st device also comprises polymer support.

2676. the 2651st device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

2677. the 2651st device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

2678. the 2651st device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

2679. the 2651st device also comprises coating, wherein said coating is placed on the surface of described device.

2680. the 2651st device also comprises coating, wherein said coating directly contacts described device.

2681. the 2651st device also comprises coating, wherein said coating contacts described device indirectly.

2682. the 2651st device also comprises coating, wherein said coating layer portion ground covers described device.

2683. the 2651st device also comprises coating, wherein said coating fully covers described device.

2684. the 2651st device also comprises coating, wherein said coating is uniform coating.

2685. the 2651st device also comprises coating, wherein said coating is uneven coating.

2686. the 2651st device also comprises coating, wherein said coating is a discontinuous coating.

2687. the 2651st device also comprises coating, wherein said coating is to form the coating of pattern.

2688. the 2651st device also comprises coating, wherein said coating has 100 μ m or littler thickness.

2689. the 2651st device also comprises coating, wherein said coating has 10 μ m or littler thickness.

2690. the 2651st device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

2691. the 2651st device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

2692. the 2651st device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

2693. the 2651st device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

2694. the 2651st device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

2695. the 2651st device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

2696. the 2651st device also comprises coating, wherein said coating also contains polymer.

2697. the 2651st device also comprises first coating with first compositions and second coating with second compositions.

2698. the 2651st device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

2699. the 2651st device also comprises polymer.

2700. the 2651st device also comprises polymer support.

2701. the 2651st device also comprises polymer support, wherein said polymer support comprises copolymer.

2702. the 2651st device also comprises polymer support, wherein said polymer support comprises block copolymer.

2703. the 2651st device also comprises polymer support, wherein said polymer support comprises random copolymer.

2704. the 2651st device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

2705. the 2651st device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

2706. the 2651st device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

2707. the 2651st device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

2708. the 2651st device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

2709. the 2651st device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

2710. the 2651st device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

2711. the 2651st device also comprises polymer support, wherein said polymer support comprises elastomer.

2712. the 2651st device also comprises polymer support, wherein said polymer support comprises hydrogel.

2713. the 2651st device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

2714. the 2651st device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

2715. the 2651st device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

2716. the 2651st device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

2717. the 2651st device also comprises polymer support, wherein said polymer support comprises macromonomer.

2718. the 2651st device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

2719. the 2651st device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

2720. the 2651st device also comprises lubricant coating.

2721. the 2651st device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

2722. the 2651st device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

2723. the 2651st device also comprises second forms of pharmacologically active agents.

2724. the 2651st device also comprises antiinflammatory.

2725. the 2651st device also comprises the medicament that suppresses infection.

2726. the 2651st device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

2727. the 2651st device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

2728. the 2651st device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

2729. the 2651st device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

2730. the 2651st device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

2731. the 2651st device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

2732. the 2651st device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

2733. the 2651st device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

2734. the 2651st device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

2735. the 2651st device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

2736. the 2651st device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

2737. the 2651st device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

2738. the 2651st device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

2739. the 2651st device also comprises antithrombotic agent.

2740. the 2651st device also comprises developing agent.

2741. the 2651st device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

2742. the 2651st device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

2743. the 2651st device also comprises developing agent, wherein said developing agent comprises MRI response material.

2744. the 2651st device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

2745. the 2651st device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

2746. the 2651st device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

2747. the 2651st device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

2748. the 2651st device also comprises the material that produces echo.

2749. the 2651st device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

2750. the 2651st device, wherein said device is aseptic.

2751. the 2651st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

2752. the 2651st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

2753. the 2651st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

2754. the 2651st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

2755. the 2651st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

2756. the 2651st device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

2757. the 2651st device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

2758. the 2651st device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

2759. the 2651st device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

2760. the 2651st device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

2761. the 2651st device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

2762. the 2651st device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

2763. the 2651st device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

2764. the 2651st device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

2765. the 2651st device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

2766. the 2651st device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

2767. the 2651st device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

2768. the 2651st device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

2769. the described fibrous tissue that the 2651st device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

2770. the 2651st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2771. the 2651st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2772. the 2651st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2773. the 2651st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2774. the 2651st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2775. a medical apparatus that comprises articular prosthesis and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

2776. the 2775th device, wherein said fibrous tissue forms agent and promotes regeneration.

2777. forming agent, the 2775th device, wherein said fibrous tissue promote blood vessel to take place.

2778. the 2775th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

2779. the 2775th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

2780. the 2775th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

2781. the 2775th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

2782. the 2775th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

2783. the 2775th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

2784. the 2775th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

2785. the 2775th device, wherein said fibrous tissue formation agent is silk or comprises silk.

2786. the 2775th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

2787. the 2775th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

2788. the 2775th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

2789. the 2775th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

2790. the 2775th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

2791. the 2775th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

2792. the 2775th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

2793. the 2775th device, wherein said fibrous tissue form agent and exist with particulate form.

2794. the 2775th device, wherein said compositions also comprises inflammatory cytokine.

2795. the 2775th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

2796. the 2775th device, wherein said compositions exists with the form of gel, paste or spray.

2797. the 2775th device, wherein said fibrous tissue form the form that agent is bunch.

2798. the 2775th device also comprises polymer.

2799. the 2775th device also comprises polymer support.

2800. the 2775th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

2801. the 2775th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

2802. the 2775th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

2803. the 2775th device also comprises coating, wherein said coating is placed on the surface of described device.

2804. the 2775th device also comprises coating, wherein said coating directly contacts described device.

2805. the 2775th device also comprises coating, wherein said coating contacts described device indirectly.

2806. the 2775th device also comprises coating, wherein said coating layer portion ground covers described device.

2807. the 2775th device also comprises coating, wherein said coating fully covers described device.

2808. the 2775th device also comprises coating, wherein said coating is uniform coating.

2809. the 2775th device also comprises coating, wherein said coating is uneven coating.

2810. the 2775th device also comprises coating, wherein said coating is a discontinuous coating.

2811. the 2775th device also comprises coating, wherein said coating is to form the coating of pattern.

2812. the 2775th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

2813. the 2775th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

2814. the 2775th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

2815. the 2775th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

2816. the 2775th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

2817. the 2775th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

2818. the 2775th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

2819. the 2775th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

2820. the 2775th device also comprises coating, wherein said coating also contains polymer.

2821. the 2775th device also comprises first coating with first compositions and second coating with second compositions.

2822. the 2775th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

2823. the 2775th device also comprises polymer.

2824. the 2775th device also comprises polymer support.

2825. the 2775th device also comprises polymer support, wherein said polymer support comprises copolymer.

2826. the 2775th device also comprises polymer support, wherein said polymer support comprises block copolymer.

2827. the 2775th device also comprises polymer support, wherein said polymer support comprises random copolymer.

2828. the 2775th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

2829. the 2775th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

2830. the 2775th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

2831. the 2775th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

2832. the 2775th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

2833. the 2775th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

2834. the 2775th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

2835. the 2775th device also comprises polymer support, wherein said polymer support comprises elastomer.

2836. the 2775th device also comprises polymer support, wherein said polymer support comprises hydrogel.

2837. the 2775th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

2838. the 2775th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

2839. the 2775th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

2840. the 2775th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

2841. the 2775th device also comprises polymer support, wherein said polymer support comprises macromonomer.

2842. the 2775th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

2843. the 2775th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

2844. the 2775th device also comprises lubricant coating.

2845. the 2775th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

2846. the 2775th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

2847. the 2775th device also comprises second forms of pharmacologically active agents.

2848. the 2775th device also comprises antiinflammatory.

2849. the 2775th device also comprises the medicament that suppresses infection.

2850. the 2775th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

2851. the 2775th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

2852. the 2775th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

2853. the 2775th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

2854. the 2775th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

2855. the 2775th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

2856. the 2775th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

2857. the 2775th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

2858. the 2775th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

2859. the 2775th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

2860. the 2775th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

2861. the 2775th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

2862. the 2775th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

2863. the 2775th device also comprises antithrombotic agent.

2864. the 2775th device also comprises developing agent.

2865. the 2775th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

2866. the 2775th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

2867. the 2775th device also comprises developing agent, wherein said developing agent comprises MRI response material.

2868. the 2775th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

2869. the 2775th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

2870. the 2775th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

2871. the 2775th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

2872. the 2775th device also comprises the material that produces echo.

2873. the 2775th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

2874. the 2775th device, wherein said device is aseptic.

2875. the 2775th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

2876. the 2775th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

2877. the 2775th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

2878. the 2775th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

2879. the 2775th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

2880. the 2775th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

2881. the 2775th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

2882. the 2775th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

2883. the 2775th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

2884. the 2775th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

2885. the 2775th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

2886. the 2775th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

2887. the 2775th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

2888. the 2775th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

2889. the 2775th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

2890. the 2775th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

2891. the 2775th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

2892. the 2775th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

2893. the described fibrous tissue that the 2775th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

2894. the 2775th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2895. the 2775th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2896. the 2775th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2897. the 2775th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2898. the 2775th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

2899. a medical apparatus that comprises part prosthese and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

2900. the 2899th device, wherein said fibrous tissue forms agent and promotes regeneration.

2901. forming agent, the 2899th device, wherein said fibrous tissue promote blood vessel to take place.

2902. the 2899th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

2903. the 2899th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

2904. the 2899th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

2905. the 2899th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

2906. the 2899th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

2907. the 2899th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

2908. the 2899th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

2909. the 2899th device, wherein said fibrous tissue formation agent is silk or comprises silk.

2910. the 2899th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

2911. the 2899th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

2912. the 2899th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

2913. the 2899th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

2914. the 2899th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

2915. the 2899th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

2916. the 2899th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

2917. the 2899th device, wherein said fibrous tissue form agent and exist with particulate form.

2918. the 2899th device, wherein said compositions also comprises inflammatory cytokine.

2919. the 2899th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

2920. the 2899th device, wherein said compositions exists with the form of gel, paste or spray.

2921. the 2899th device, wherein said fibrous tissue form agent with bunch form exist.

2922. the 2899th device also comprises polymer.

2923. the 2899th device also comprises polymer support.

2924. the 2899th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

2925. the 2899th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

2926. the 2899th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

2927. the 2899th device also comprises coating, wherein said coating is placed on the surface of described device.

2928. the 2899th device also comprises coating, wherein said coating directly contacts described device.

2929. the 2899th device also comprises coating, wherein said coating contacts described device indirectly.

2930. the 2899th device also comprises coating, wherein said coating layer portion ground covers described device.

2931. the 2899th device also comprises coating, wherein said coating fully covers described device.

2932. the 2899th device also comprises coating, wherein said coating is uniform coating.

2933. the 2899th device also comprises coating, wherein said coating is uneven coating.

2934. the 2899th device also comprises coating, wherein said coating is a discontinuous coating.

2935. the 2899th device also comprises coating, wherein said coating is to form the coating of pattern.

2936. the 2899th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

2937. the 2899th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

2938. the 2899th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

2939. the 2899th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

2940. the 2899th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

2941. the 2899th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

2942. the 2899th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

2943. the 2899th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

2944. the 2899th device also comprises coating, wherein said coating also contains polymer.

2945. the 2899th device also comprises first coating with first compositions and second coating with second compositions.

2946. the 2899th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

2947. the 2899th device also comprises polymer.

2948. the 2899th device also comprises polymer support.

2949. the 2899th device also comprises polymer support, wherein said polymer support comprises copolymer.

2950. the 2899th device also comprises polymer support, wherein said polymer support comprises block copolymer.

2951. the 2899th device also comprises polymer support, wherein said polymer support comprises random copolymer.

2952. the 2899th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

2953. the 2899th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

2954. the 2899th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

2955. the 2899th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

2956. the 2899th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

2957. the 2899th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

2958. the 2899th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

2959. the 2899th device also comprises polymer support, wherein said polymer support comprises elastomer.

2960. the 2899th device also comprises polymer support, wherein said polymer support comprises hydrogel.

2961. the 2899th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

2962. the 2899th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

2963. the 2899th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

2964. the 2899th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

2965. the 2899th device also comprises polymer support, wherein said polymer support comprises macromonomer.

2966. the 2899th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

2967. the 2899th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

2968. the 2899th device also comprises lubricant coating.

2969. the 2899th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

2970. the 2899th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

2971. the 2899th device also comprises second forms of pharmacologically active agents.

2972. the 2899th device also comprises antiinflammatory.

2973. the 2899th device also comprises the medicament that suppresses infection.

2974. the 2899th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

2975. the 2899th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

2976. the 2899th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

2977. the 2899th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

2978. the 2899th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

2979. the 2899th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

2980. the 2899th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

2981. the 2899th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

2982. the 2899th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

2983. the 2899th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

2984. the 2899th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

2985. the 2899th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

2986. the 2899th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

2987. the 2899th device also comprises antithrombotic agent.

2988. the 2899th device also comprises developing agent.

2989. the 2899th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

2990. the 2899th device also comprises developing agent, wherein said developing agent comprises, barium, tantalum or technetium.

2991. the 2899th device also comprises developing agent, wherein said developing agent comprises MRI response material.

2992. the 2899th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

2993. the 2899th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

2994. the 2899th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

2995. the 2899th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

2996. the 2899th device also comprises the material that produces echo.

2997. the 2899th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

2998. the 2899th device, wherein said device is aseptic.

2999. the 2899th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

3000. the 2899th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

3001. the 2899th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

3002. the 2899th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

3003. the 2899th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

3004. the 2899th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

3005. the 2899th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

3006. the 2899th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

3007. the 2899th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

3008. the 2899th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

3009. the 2899th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

3010. the 2899th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

3011. the 2899th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

3012. the 2899th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

3013. the 2899th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

3014. the 2899th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

3015. the 2899th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

3016. the 2899th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

3017. the described fibrous tissue that the 2899th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

3018. the 2899th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3019. the 2899th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3020. the 2899th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3021. the 2899th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3022. the 2899th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3023. a medical apparatus that comprises hip implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

3024. the 3023rd device, wherein said fibrous tissue forms agent and promotes regeneration.

3025. forming agent, the 3023rd device, wherein said fibrous tissue promote blood vessel to take place.

3026. the 3023rd device, wherein said fibrous tissue form agent and promote the fibroblast migration.

3027. the 3023rd device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

3028. the 3023rd device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

3029. the 3023rd device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

3030. the 3023rd device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

3031. the 3023rd device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

3032. the 3023rd device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

3033. the 3023rd device, wherein said fibrous tissue formation agent is silk or comprises silk.

3034. the 3023rd device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

3035. the 3023rd device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

3036. the 3023rd device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

3037. the 3023rd device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

3038. the 3023rd device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

3039. the 3023rd device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

3040. the 3023rd device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

3041. the 3023rd device, wherein said fibrous tissue form agent and exist with particulate form.

3042. the 3023rd device, wherein said compositions also comprises inflammatory cytokine.

3043. the 3023rd device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

3044. the 3023rd device, wherein said compositions exists with the form of gel, paste or spray.

3045. the 3023rd device, wherein said fibrous tissue form agent with bunch form exist.

3046. the 3023rd device also comprises polymer.

3047. the 3023rd device also comprises polymer support.

3048. the 3023rd device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

3049. the 3023rd device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

3050. the 3023rd device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

3051. the 3023rd device also comprises coating, wherein said coating is placed on the surface of described device.

3052. the 3023rd device also comprises coating, wherein said coating directly contacts described device.

3053. the 3023rd device also comprises coating, wherein said coating contacts described device indirectly.

3054. the 3023rd device also comprises coating, wherein said coating layer portion ground covers described device.

3055. the 3023rd device also comprises coating, wherein said coating fully covers described device.

3056. the 3023rd device also comprises coating, wherein said coating is uniform coating.

3057. the 3023rd device also comprises coating, wherein said coating is uneven coating.

3058. the 3023rd device also comprises coating, wherein said coating is a discontinuous coating.

3059. the 3023rd device also comprises coating, wherein said coating is to form the coating of pattern.

3060. the 3023rd device also comprises coating, wherein said coating has 100 μ m or littler thickness.

3061. the 3023rd device also comprises coating, wherein said coating has 10 μ m or littler thickness.

3062. the 3023rd device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

3063. the 3023rd device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

3064. the 3023rd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

3065. the 3023rd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

3066. the 3023rd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

3067. the 3023rd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

3068. the 3023rd device also comprises coating, wherein said coating also contains polymer.

3069. the 3023rd device also comprises first coating with first compositions and second coating with second compositions.

3070. the 3023rd device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

3071. the 3023rd device also comprises polymer.

3072. the 3023rd device also comprises polymer support.

3073. the 3023rd device also comprises polymer support, wherein said polymer support comprises copolymer.

3074. the 3023rd device also comprises polymer support, wherein said polymer support comprises block copolymer.

3075. the 3023rd device also comprises polymer support, wherein said polymer support comprises random copolymer.

3076. the 3023rd device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

3077. the 3023rd device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

3078. the 3023rd device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

3079. the 3023rd device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

3080. the 3023rd device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

3081. the 3023rd device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

3082. the 3023rd device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

3083. the 3023rd device also comprises polymer support, wherein said polymer support comprises elastomer.

3084. the 3023rd device also comprises polymer support, wherein said polymer support comprises hydrogel.

3085. the 3023rd device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

3086. the 3023rd device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

3087. the 3023rd device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

3088. the 3023rd device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

3089. the 3023rd device also comprises polymer support, wherein said polymer support comprises macromonomer.

3090. the 3023rd device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

3091. the 3023rd device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

3092. the 3023rd device also comprises lubricant coating.

3093. the 3023rd device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

3094. the 3023rd device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

3095. the 3023rd device also comprises second forms of pharmacologically active agents.

3096. the 3023rd device also comprises antiinflammatory.

3097. the 3023rd device also comprises the medicament that suppresses infection.

3098. the 3023rd device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

3099. the 3023rd device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

3100. the 3023rd device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

3101. the 3023rd device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

3102. the 3023rd device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

3103. the 3023rd device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

3104. the 3023rd device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

3105. the 3023rd device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

3106. the 3023rd device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

3107. the 3023rd device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

3108. the 3023rd device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

3109. the 3023rd device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

3110. the 3023rd device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

3111. the 3023rd device also comprises antithrombotic agent.

3112. the 3023rd device also comprises developing agent.

3113. the 3023rd device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

3114. the 3023rd device also comprises developing agent, wherein said developing agent comprises, barium, tantalum or technetium.

3115. the 3023rd device also comprises developing agent, wherein said developing agent comprises MRI response material.

3116. the 3023rd device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

3117. the 3023rd device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

3118. the 3023rd device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

3119. the 3023rd device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

3120. the 3023rd device also comprises the material that produces echo.

3121. the 3023rd device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

3122. the 3023rd device, wherein said device is aseptic.

3123. the 3023rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

3124. the 3023rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

3125. the 3023rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

3126. the 3023rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

3127. the 3023rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

3128. the 3023rd device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

3129. the 3023rd device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

3130. the 3023rd device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

3131. the 3023rd device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

3132. the 3023rd device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

3133. the 3023rd device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

3134. the 3023rd device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

3135. the 3023rd device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

3136. the 3023rd device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

3137. the 3023rd device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

3138. the 3023rd device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

3139. the 3023rd device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

3140. the 3023rd device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

3141. the described fibrous tissue that the 3023rd device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

3142. the 3023rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3143. the 3023rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3144. the 3023rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3145. the 3023rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3146. the 3023rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3147. the 3023rd device, wherein said hip implant are whole hip substitutes.

3148. the 3023rd device, wherein said hip implant are part hip substitutes.

3149. the 3023rd device, wherein said hip implant is a modular.

3150. a medical apparatus that comprises knee joint implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

3151. the 3150th device, wherein said fibrous tissue forms agent and promotes regeneration.

3152. forming agent, the 3150th device, wherein said fibrous tissue promote blood vessel to take place.

3153. the 3150th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

3154. the 3150th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

3155. the 3150th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

3156. the 3150th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

3157. the 3150th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

3158. the 3150th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

3159. the 3150th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

3160. the 3150th device, wherein said fibrous tissue formation agent is silk or comprises silk.

3161. the 3150th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

3162. the 3150th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

3163. the 3150th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

3164. the 3150th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

3165. the 3150th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

3166. the 3150th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

3167. the 3150th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

3168. the 3150th device, wherein said fibrous tissue form agent and exist with particulate form.

3169. the 3150th device, wherein said compositions also comprises inflammatory cytokine.

3170. the 3150th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

3171. the 3150th device, wherein said compositions exists with the form of gel, paste or spray.

3172. the 3150th device, wherein said fibrous tissue form agent with bunch form exist.

3173. the 3150th device also comprises polymer.

3174. the 3150th device also comprises polymer support.

3175. the 3150th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

3176. the 3150th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

3177. the 3150th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

3178. the 3150th device also comprises coating, wherein said coating is placed on the surface of described device.

3179. the 3150th device also comprises coating, wherein said coating directly contacts described device.

3180. the 3150th device also comprises coating, wherein said coating contacts described device indirectly.

3181. the 3150th device also comprises coating, wherein said coating layer portion ground covers described device.

3182. the 3150th device also comprises coating, wherein said coating fully covers described device.

3183. the 3150th device also comprises coating, wherein said coating is uniform coating.

3184. the 3150th device also comprises coating, wherein said coating is uneven coating.

3185. the 3150th device also comprises coating, wherein said coating is a discontinuous coating.

3186. the 3150th device also comprises coating, wherein said coating is to form the coating of pattern.

3187. the 3150th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

3188. the 3150th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

3189. the 3150th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

3190. the 3150th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

3191. the 3150th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

3192. the 3150th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

3193. the 3150th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

3194. the 3150th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

3195. the 3150th device also comprises coating, wherein said coating also contains polymer.

3196. the 3150th device also comprises first coating with first compositions and second coating with second compositions.

3197. the 3150th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

3198. the 3150th device also comprises polymer.

3199. the 3150th device also comprises polymer support.

3200. the 3150th device also comprises polymer support, wherein said polymer support comprises copolymer.

3201. the 3150th device also comprises polymer support, wherein said polymer support comprises block copolymer.

3202. the 3150th device also comprises polymer support, wherein said polymer support comprises random copolymer.

3203. the 3150th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

3204. the 3150th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

3205. the 3150th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

3206. the 3150th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

3207. the 3150th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

3208. the 3150th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

3209. the 3150th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

3210. the 3150th device also comprises polymer support, wherein said polymer support comprises elastomer.

3211. the 3150th device also comprises polymer support, wherein said polymer support comprises hydrogel.

3212. the 3150th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

3213. the 3150th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

3214. the 3150th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

3215. the 3150th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

3216. the 3150th device also comprises polymer support, wherein said polymer support comprises macromonomer.

3217. the 3150th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

3218. the 3150th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

3219. the 3150th device also comprises lubricant coating.

3220. the 3150th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

3221. the 3150th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

3222. the 3150th device also comprises second forms of pharmacologically active agents.

3223. the 3150th device also comprises antiinflammatory.

3224. the 3150th device also comprises the medicament that suppresses infection.

3225. the 3150th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

3226. the 3150th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

3227. the 3150th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

3228. the 3150th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

3229. the 3150th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

3230. the 3150th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

3231. the 3150th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

3232. the 3150th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

3233. the 3150th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

3234. the 3150th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

3235. the 3150th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

3236. the 3150th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

3237. the 3150th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

3238. the 3150th device also comprises antithrombotic agent.

3239. the 3150th device also comprises developing agent.

3240. the 3150th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

3241. the 3150th device also comprises developing agent, wherein said developing agent comprises, barium, tantalum or technetium.

3242. the 3150th device also comprises developing agent, wherein said developing agent comprises MRI response material.

3243. the 3150th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

3244. the 3150th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

3245. the 3150th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

3246. the 3150th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

3247. the 3150th device also comprises the material that produces echo.

3248. the 3150th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

3249. the 3150th device, wherein said device is aseptic.

3250. the 3150th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

3251. the 3150th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

3252. the 3150th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

3253. the 3150th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

3254. the 3150th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

3255. the 3150th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

3256. the 3150th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

3257. the 3150th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

3258. the 3150th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

3259. the 3150th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

3260. the 3150th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

3261. the 3150th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

3262. the 3150th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

3263. the 3150th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

3264. the 3150th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

3265. the 3150th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

3266. the 3150th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

3267. the 3150th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

3268. the described fibrous tissue that the 3150th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

3269. the 3150th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3270. the 3150th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3271. the 3150th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3272. the 3150th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3273. the 3150th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3274. a medical apparatus that comprises shoulder implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

3275. the 3274th device, wherein said fibrous tissue forms agent and promotes regeneration.

3276. forming agent, the 3274th device, wherein said fibrous tissue promote blood vessel to take place.

3277. the 3274th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

3278. the 3274th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

3279. the 3274th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

3280. the 3274th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

3281. the 3274th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

3282. the 3274th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

3283. the 3274th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

3284. the 3274th device, wherein said fibrous tissue formation agent is silk or comprises silk.

3285. the 3274th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

3286. the 3274th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

3287. the 3274th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

3288. the 3274th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

3289. the 3274th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

3290. the 3274th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

3291. the 3274th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

3292. the 3274th device, wherein said fibrous tissue form agent and exist with particulate form.

3293. the 3274th device, wherein said compositions also comprises inflammatory cytokine.

3294. the 3274th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

3295. the 3274th device, wherein said compositions exists with the form of gel, paste or spray.

3296. the 3274th device, wherein said fibrous tissue form the form that agent is bunch.

3297. the 3274th device also comprises polymer.

3298. the 3274th device also comprises polymer support.

3299. the 3274th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

3300. the 3274th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

3301. the 3274th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

3302. the 3274th device also comprises coating, wherein said coating is placed on the surface of described device.

3303. the 3274th device also comprises coating, wherein said coating directly contacts described device.

3304. the 3274th device also comprises coating, wherein said coating contacts described device indirectly.

3305. the 3274th device also comprises coating, wherein said coating layer portion ground covers described device.

3306. the 3274th device also comprises coating, wherein said coating fully covers described device.

3307. the 3274th device also comprises coating, wherein said coating is uniform coating.

3308. the 3274th device also comprises coating, wherein said coating is uneven coating.

3309. the 3274th device also comprises coating, wherein said coating is a discontinuous coating.

3310. the 3274th device also comprises coating, wherein said coating is to form the coating of pattern.

3311. the 3274th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

3312. the 3274th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

3313. the 3274th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

3314. the 3274th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

3315. the 3274th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

3316. the 3274th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

3317. the 3274th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

3318. the 3274th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

3319. the 3274th device also comprises coating, wherein said coating also contains polymer.

3320. the 3274th device also comprises first coating with first compositions and second coating with second compositions.

3321. the 3274th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

3322. the 3274th device also comprises polymer.

3323. the 3274th device also comprises polymer support.

3324. the 3274th device also comprises polymer support, wherein said polymer support comprises copolymer.

3325. the 3274th device also comprises polymer support, wherein said polymer support comprises block copolymer.

3326. the 3274th device also comprises polymer support, wherein said polymer support comprises random copolymer.

3327. the 3274th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

3328. the 3274th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

3329. the 3274th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

3330. the 3274th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

3331. the 3274th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

3332. the 3274th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

3333. the 3274th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

3334. the 3274th device also comprises polymer support, wherein said polymer support comprises elastomer.

3335. the 3274th device also comprises polymer support, wherein said polymer support comprises hydrogel.

3336. the 3274th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

3337. the 3274th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

3338. the 3274th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

3339. the 3274th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

3340. the 3274th device also comprises polymer support, wherein said polymer support comprises macromonomer.

3341. the 3274th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

3342. the 3274th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

3343. the 3274th device also comprises lubricant coating.

3344. the 3274th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

3345. the 3274th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

3346. the 3274th device also comprises second forms of pharmacologically active agents.

3347. the 3274th device also comprises antiinflammatory.

3348. the 3274th device also comprises the medicament that suppresses infection.

3349. the 3274th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

3350. the 3274th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

3351. the 3274th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

3352. the 3274th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

3353. the 3274th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

3354. the 3274th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

3355. the 3274th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

3356. the 3274th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

3357. the 3274th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

3358. the 3274th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

3359. the 3274th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

3360. the 3274th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

3361. the 3274th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

3362. the 3274th device also comprises antithrombotic agent.

3363. the 3274th device also comprises developing agent.

3364. the 3274th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

3365. the 3274th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material also comprises, barium, tantalum or technetium.

3366. the 3274th device also comprises developing agent, wherein said developing agent comprises MRI response material.

3367. the 3274th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

3368. the 3274th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

3369. the 3274th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

3370. the 3274th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

3371. the 3274th device also comprises the material that produces echo.

3372. the 3274th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

3373. the 3274th device, wherein said device is aseptic.

3374. the 3274th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

3375. the 3274th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

3376. the 3274th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

3377. the 3274th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

3378. the 3274th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

3379. the 3274th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

3380. the 3274th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

3381. the 3274th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

3382. the 3274th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

3383. the 3274th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

3384. the 3274th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

3385. the 3274th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

3386. the 3274th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

3387. the 3274th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

3388. the 3274th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

3389. the 3274th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

3390. the 3274th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

3391. the 3274th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

3392. the described fibrous tissue that the 3274th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

3393. the 3274th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3394. the 3274th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3395. the 3274th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3396. the 3274th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3397. the 3274th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3398. the 3274th device, wherein said shoulder implant is a hemiarthroplasty.

3399. the 3274th device, wherein said shoulder implant is to take on substitute completely.

3400. one kind comprises the medical apparatus that finger or toe (digit) implant and fibrous tissue form agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

3401. the 3400th device, wherein said fibrous tissue forms agent and promotes regeneration.

3402. forming agent, the 3400th device, wherein said fibrous tissue promote blood vessel to take place.

3403. the 3400th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

3404. the 3400th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

3405. the 3400th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

3406. the 3400th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

3407. the 3400th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

3408. the 3400th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

3409. the 3400th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

3410. the 3400th device, wherein said fibrous tissue formation agent is silk or comprises silk.

3411. the 3400th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

3412. the 3400th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

3413. the 3400th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

3414. the 3400th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

3415. the 3400th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

3416. the 3400th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

3417. the 3400th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

3418. the 3400th device, wherein said fibrous tissue form agent and exist with particulate form.

3419. the 3400th device, wherein said compositions also comprises inflammatory cytokine.

3420. the 3400th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

3421. the 3400th device, wherein said compositions exists with the form of gel, paste or spray.

3422. the 3400th device, wherein said fibrous tissue form the form that agent is bunch.

3423. the 3400th device also comprises polymer.

3424. the 3400th device also comprises polymer support.

3425. the 3400th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

3426. the 3400th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

3427. the 3400th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

3428. the 3400th device also comprises coating, wherein said coating is placed on the surface of described device.

3429. the 3400th device also comprises coating, wherein said coating directly contacts described device.

3430. the 3400th device also comprises coating, wherein said coating contacts described device indirectly.

3431. the 3400th device also comprises coating, wherein said coating layer portion ground covers described device.

3432. the 3400th device also comprises coating, wherein said coating fully covers described device.

3433. the 3400th device also comprises coating, wherein said coating is uniform coating.

3434. the 3400th device also comprises coating, wherein said coating is uneven coating.

3435. the 3400th device also comprises coating, wherein said coating is a discontinuous coating.

3436. the 3400th device also comprises coating, wherein said coating is to form the coating of pattern.

3437. the 3400th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

3438. the 3400th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

3439. the 3400th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

3440. the 3400th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

3441. the 3400th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

3442. the 3400th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

3443. the 3400th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

3444. the 3400th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

3445. the 3400th device also comprises coating, wherein said coating also contains polymer.

3446. the 3400th device also comprises first coating with first compositions and second coating with second compositions.

3447. the 3400th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

3448. the 3400th device also comprises polymer.

3449. the 3400th device also comprises polymer support.

3450. the 3400th device also comprises polymer support, wherein said polymer support comprises copolymer.

3451. the 3400th device also comprises polymer support, wherein said polymer support comprises block copolymer.

3452. the 3400th device also comprises polymer support, wherein said polymer support comprises random copolymer.

3453. the 3400th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

3454. the 3400th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

3455. the 3400th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

3456. the 3400th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

3457. the 3400th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

3458. the 3400th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

3459. the 3400th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

3460. the 3400th device also comprises polymer support, wherein said polymer support comprises elastomer.

3461. the 3400th device also comprises polymer support, wherein said polymer support comprises hydrogel.

3462. the 3400th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

3463. the 3400th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

3464. the 3400th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

3465. the 3400th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

3466. the 3400th device also comprises polymer support, wherein said polymer support comprises macromonomer.

3467. the 3400th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

3468. the 3400th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

3469. the 3400th device also comprises lubricant coating.

3470. the 3400th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

3471. the 3400th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

3472. the 3400th device also comprises second forms of pharmacologically active agents.

3473. the 3400th device also comprises antiinflammatory.

3474. the 3400th device also comprises the medicament that suppresses infection.

3475. the 3400th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

3476. the 3400th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

3477. the 3400th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

3478. the 3400th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

3479. the 3400th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

3480. the 3400th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

3481. the 3400th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

3482. the 3400th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

3483. the 3400th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

3484. the 3400th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

3485. the 3400th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

3486. the 3400th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

3487. the 3400th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

3488. the 3400th device also comprises antithrombotic agent.

3489. the 3400th device also comprises developing agent.

3490. the 3400th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

3491. the 3400th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

3492. the 3400th device also comprises developing agent, wherein said developing agent comprises MRI response material.

3493. the 3400th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

3494. the 3400th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

3495. the 3400th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

3496. the 3400th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

3497. the 3400th device also comprises the material that produces echo.

3498. the 3400th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

3499. the 3400th device, wherein said device is aseptic.

3500. the 3400th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

3501. the 3400th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

3502. the 3400th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

3503. the 3400th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

3504. the 3400th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

3505. the 3400th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

3506. the 3400th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

3507. the 3400th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

3508. the 3400th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

3509. the 3400th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

3510. the 3400th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

3511. the 3400th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

3512. the 3400th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

3513. the 3400th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

3514. the 3400th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

3515. the 3400th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

3516. the 3400th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

3517. the 3400th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

3518. the described fibrous tissue that the 3400th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

3519. the 3400th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3520. the 3400th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3521. the 3400th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3522. the 3400th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3523. the 3400th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3524. one kind comprises the titanium fixture of the root portion that is used for replacing the natural teeth that loses and the medical apparatus that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

3525. the 3524th device, wherein said fibrous tissue forms agent and promotes regeneration.

3526. forming agent, the 3524th device, wherein said fibrous tissue promote blood vessel to take place.

3527. the 3524th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

3528. the 3524th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

3529. the 3524th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

3530. the 3524th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

3531. the 3524th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

3532. the 3524th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

3533. the 3524th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

3534. the 3524th device, wherein said fibrous tissue formation agent is silk or comprises silk.

3535. the 3524th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

3536. the 3524th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

3537. the 3524th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

3538. the 3524th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

3539. the 3524th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

3540. the 3524th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

3541. the 3524th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

3542. the 3524th device, wherein said fibrous tissue form agent and exist with particulate form.

3543. the 3524th device, wherein said compositions also comprises inflammatory cytokine.

3544. the 3524th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

3545. the 3524th device, wherein said compositions exists with the form of gel, paste or spray.

3546. the 3524th device, wherein said fibrous tissue form the form that agent is bunch.

3547. the 3524th device also comprises polymer.

3548. the 3524th device also comprises polymer support.

3549. the 3524th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

3550. the 3524th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

3551. the 3524th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

3552. the 3524th device also comprises coating, wherein said coating is placed on the surface of described device.

3553. the 3524th device also comprises coating, wherein said coating directly contacts described device.

3554. the 3524th device also comprises coating, wherein said coating contacts described device indirectly.

3555. the 3524th device also comprises coating, wherein said coating layer portion ground covers described device.

3556. the 3524th device also comprises coating, wherein said coating fully covers described device.

3557. the 3524th device also comprises coating, wherein said coating is uniform coating.

3558. the 3524th device also comprises coating, wherein said coating is uneven coating.

3559. the 3524th device also comprises coating, wherein said coating is a discontinuous coating.

3560. the 3524th device also comprises coating, wherein said coating is to form the coating of pattern.

3561. the 3524th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

3562. the 3524th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

3563. the 3524th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

3564. the 3524th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

3565. the 3524th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

3566. the 3524th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

3567. the 3524th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

3568. the 3524th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

3569. the 3524th device also comprises coating, wherein said coating also contains polymer.

3570. the 3524th device also comprises first coating with first compositions and second coating with second compositions.

3571. the 3524th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

3572. the 3524th device also comprises polymer.

3573. the 3524th device also comprises polymer support.

3574. the 3524th device also comprises polymer support, wherein said polymer support comprises copolymer.

3575. the 3524th device also comprises polymer support, wherein said polymer support comprises block copolymer.

3576. the 3524th device also comprises polymer support, wherein said polymer support comprises random copolymer.

3577. the 3524th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

3578. the 3524th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

3579. the 3524th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

3580. the 3524th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

3581. the 3524th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

3582. the 3524th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

3583. the 3524th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

3584. the 3524th device also comprises polymer support, wherein said polymer support comprises elastomer.

3585. the 3524th device also comprises polymer support, wherein said polymer support comprises hydrogel.

3586. the 3524th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

3587. the 3524th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

3588. the 3524th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

3589. the 3524th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

3590. the 3524th device also comprises polymer support, wherein said polymer support comprises macromonomer.

3591. the 3524th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

3592. the 3524th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

3593. the 3524th device also comprises lubricant coating.

3594. the 3524th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

3595. the 3524th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

3596. the 3524th device also comprises second forms of pharmacologically active agents.

3597. the 3524th device also comprises antiinflammatory.

3598. the 3524th device also comprises the medicament that suppresses infection.

3599. the 3524th device also comprises the medicament that suppresses infection, described medicament is an anthracycline.

3600. the 3524th device also comprises the medicament that suppresses infection, described medicament is a doxorubicin.

3601. the 3524th device also comprises the medicament that suppresses infection, described medicament is a mitoxantrone.

3602. the 3524th device also comprises the medicament that suppresses infection, described medicament is the fluorine pyrimidine.

3603. the 3524th device also comprises the medicament that suppresses infection, described medicament is 5-fluorouracil (5-FU).

3604. the 3524th device also comprises the medicament that suppresses infection, described medicament is an antifol.

3605. the 3524th device also comprises the medicament that suppresses infection, described medicament is a methotrexate.

3606. the 3524th device also comprises the medicament that suppresses infection, described medicament is a podophyllotoxin.

3607. the 3524th device also comprises the medicament that suppresses infection, described medicament is an etoposide.

3608. the 3524th device also comprises the medicament that suppresses infection, described medicament is a camptothecine.

3609. the 3524th device also comprises the medicament that suppresses infection, described medicament is a hydroxyurea.

3610. the 3524th device also comprises the medicament that suppresses infection, described medicament is a platinum complex.

3611. the 3524th device also comprises the medicament that suppresses infection, described medicament is a cisplatin.

3612. the 3524th device also comprises antithrombotic agent.

3613. the 3524th device also comprises developing agent.

3614. the 3524th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

3615. the 3524th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises, barium, tantalum or technetium.

3616. the 3524th device also comprises developing agent, wherein said developing agent comprises MRI response material.

3617. the 3524th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

3618. the 3524th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

3619. the 3524th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

3620. the 3524th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

3621. the 3524th device also comprises the material that produces echo.

3622. the 3524th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

3623. the 3524th device, wherein said device is aseptic.

3624. the 3524th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

3625. the 3524th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

3626. the 3524th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

3627. the 3524th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

3628. the 3524th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

3629. the 3524th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

3630. the 3524th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

3631. the 3524th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

3632. the 3524th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

3633. the 3524th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

3634. the 3524th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

3635. the 3524th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

3636. the 3524th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

3637. the 3524th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

3638. the 3524th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

3639. the 3524th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

3640. the 3524th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

3641. the 3524th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

3642. the described fibrous tissue that the 3524th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

3643. the 3524th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3644. the 3524th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3645. the 3524th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3646. the 3524th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3647. the 3524th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3648. a medical apparatus that comprises implant for into bones and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

3649. the 3648th device, wherein said fibrous tissue forms agent and promotes regeneration.

3650. forming agent, the 3648th device, wherein said fibrous tissue promote blood vessel to take place.

3651. the 3648th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

3652. the 3648th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

3653. the 3648th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

3654. the 3648th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

3655. the 3648th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

3656. the 3648th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

3657. the 3648th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

3658. the 3648th device, wherein said fibrous tissue formation agent is silk or comprises silk.

3659. the 3648th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

3660. the 3648th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

3661. the 3648th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

3662. the 3648th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

3663. the 3648th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

3664. the 3648th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

3665. the 3648th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

3666. the 3648th device, wherein said fibrous tissue form agent and exist with particulate form.

3667. the 3648th device, wherein said compositions also comprises inflammatory cytokine.

3668. the 3648th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

3669. the 3648th device, wherein said compositions exists with the form of gel, paste or spray.

3670. the 3648th device, wherein said fibrous tissue form the form that agent is bunch.

3671. the 3648th device also comprises polymer.

3672. the 3648th device also comprises polymer support.

3673. the 3648th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

3674. the 3648th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

3675. the 3648th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

3676. the 3648th device also comprises coating, wherein said coating is placed on the surface of described device.

3677. the 3648th device also comprises coating, wherein said coating directly contacts described device.

3678. the 3648th device also comprises coating, wherein said coating contacts described device indirectly.

3679. the 3648th device also comprises coating, wherein said coating layer portion ground covers described device.

3680. the 3648th device also comprises coating, wherein said coating fully covers described device.

3681. the 3648th device also comprises coating, wherein said coating is uniform coating.

3682. the 3648th device also comprises coating, wherein said coating is uneven coating.

3683. the 3648th device also comprises coating, wherein said coating is a discontinuous coating.

3684. the 3648th device also comprises coating, wherein said coating is to form the coating of pattern.

3685. the 3648th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

3686. the 3648th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

3687. the 3648th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

3688. the 3648th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

3689. the 3648th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

3690. the 3648th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

3691. the 3648th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

3692. the 3648th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

3693. the 3648th device also comprises coating, wherein said coating also contains polymer.

3694. the 3648th device also comprises first coating with first compositions and second coating with second compositions.

3695. the 3648th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

3696. the 3648th device also comprises polymer.

3697. the 3648th device also comprises polymer support.

3698. the 3648th device also comprises polymer support, wherein said polymer support comprises copolymer.

3699. the 3648th device also comprises polymer support, wherein said polymer support comprises block copolymer.

3700. the 3648th device also comprises polymer support, wherein said polymer support comprises random copolymer.

3701. the 3648th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

3702. the 3648th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

_3703.The 3648th device also comprises polymer support, and wherein said polymer support comprises hydrophilic polymer.

3704. the 3648th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

3705. the 3648th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

3706. the 3648th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

3707. the 3648th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

3708. the 3648th device also comprises polymer support, wherein said polymer support comprises elastomer.

3709. the 3648th device also comprises polymer support, wherein said polymer support comprises hydrogel.

3710. the 3648th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

3711. the 3648th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

3712. the 3648th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

3713. the 3648th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

3714. the 3648th device also comprises polymer support, wherein said polymer support comprises macromonomer.

3715. the 3648th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

3716. the 3648th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

3717. the 3648th device also comprises lubricant coating.

3718. the 3648th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

3719. the 3648th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

3720. the 3648th device also comprises second forms of pharmacologically active agents.

3721. the 3648th device also comprises antiinflammatory.

3722. the 3648th device also comprises the medicament that suppresses infection.

3723. the 3648th device also comprises the medicament that suppresses infection, described medicament is an anthracycline.

3724. the 3648th device also comprises the medicament that suppresses infection, described medicament is a doxorubicin.

3725. the 3648th device also comprises the medicament that suppresses infection, described medicament is a mitoxantrone.

3726. the 3648th device also comprises the medicament that suppresses infection, described medicament is the fluorine pyrimidine.

3727. the 3648th device also comprises the medicament that suppresses infection, described medicament is 5-fluorouracil (5-FU).

3728. the 3648th device also comprises the medicament that suppresses infection, described medicament is an antifol.

3729. the 3648th device also comprises the medicament that suppresses infection, described medicament is a methotrexate.

3730. the 3648th device also comprises the medicament that suppresses infection, described medicament is a podophyllotoxin.

3731. the 3648th device also comprises the medicament that suppresses infection, described medicament is an etoposide.

3732. the 3648th device also comprises the medicament that suppresses infection, described medicament is a camptothecine.

3733. the 3648th device also comprises the medicament that suppresses infection, described medicament is a hydroxyurea.

3734. the 3648th device also comprises the medicament that suppresses infection, described medicament is a platinum complex.

3735. the 3648th device also comprises the medicament that suppresses infection, described medicament is a cisplatin.

3736. the 3648th device also comprises antithrombotic agent.

3737. the 3648th device also comprises developing agent.

3738. the 3648th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

3739. the 3648th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

3740. the 3648th device also comprises developing agent, wherein said developing agent comprises MRI response material.

3741. the 3648th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

3742. the 3648th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

3743. the 3648th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

3744. the 3648th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

3745. the 3648th device also comprises the material that produces echo.

3746. the 3648th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

3747. the 3648th device, wherein said device is aseptic.

3748. the 3648th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

3749. the 3648th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

3750. the 3648th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

3751. the 3648th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

3752. the 3648th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

3753. the 3648th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

3754. the 3648th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

3755. the 3648th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

3756. the 3648th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

3757. the 3648th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

3758. the 3648th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

_3759.The 3648th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

3760. the 3648th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

3761. the 3648th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

3762. the 3648th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

3763. the 3648th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

3764. the 3648th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

3765. the 3648th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

3766. the described fibrous tissue that the 3648th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

3767. the 3648th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3768. the 3648th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3769. the 3648th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3770. the 3648th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3771. the 3648th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3772. a medical apparatus that comprises subperiosteum implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

3773. the 3772nd device, wherein said fibrous tissue forms agent and promotes regeneration.

3774. forming agent, the 3772nd device, wherein said fibrous tissue promote blood vessel to take place.

3775. the 3772nd device, wherein said fibrous tissue form agent and promote the fibroblast migration.

3776. the 3772nd device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

3777. the 3772nd device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

3778. the 3772nd device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

3779. the 3772nd device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

3780. the 3772nd device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

3781. the 3772nd device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

3782. the 3772nd device, wherein said fibrous tissue formation agent is silk or comprises silk.

3783. the 3772nd device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

3784. the 3772nd device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

3785. the 3772nd device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

3786. the 3772nd device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

3787. the 3772nd device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

3788. the 3772nd device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

3789. the 3772nd device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

3790. the 3772nd device, wherein said fibrous tissue form agent and exist with particulate form.

3791. the 3772nd device, wherein said compositions also comprises inflammatory cytokine.

3792. the 3772nd device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

3793. the 3772nd device, wherein said compositions exists with the form of gel, paste or spray.

3794. the 3772nd device, wherein said fibrous tissue form the form that agent is bunch.

3795. the 3772nd device also comprises polymer.

3796. the 3772nd device also comprises polymer support.

3797. the 3772nd device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

3798. the 3772nd device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

3799. the 3772nd device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

3800. the 3772nd device also comprises coating, wherein said coating is placed on the surface of described device.

3801. the 3772nd device also comprises coating, wherein said coating directly contacts described device.

3802. the 3772nd device also comprises coating, wherein said coating contacts described device indirectly.

3803. the 3772nd device also comprises coating, wherein said coating layer portion ground covers described device.

3804. the 3772nd device also comprises coating, wherein said coating fully covers described device.

3805. the 3772nd device also comprises coating, wherein said coating is uniform coating.

3806. the 3772nd device also comprises coating, wherein said coating is uneven coating.

3807. the 3772nd device also comprises coating, wherein said coating is a discontinuous coating.

3808. the 3772nd device also comprises coating, wherein said coating is to form the coating of pattern.

3809. the 3772nd device also comprises coating, wherein said coating has 100 μ m or littler thickness.

3810. the 3772nd device also comprises coating, wherein said coating has 10 μ m or littler thickness.

3811. the 3772nd device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

3812. the 3772nd device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

3813. the 3772nd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

3814. the 3772nd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

3815. the 3772nd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

3816. the 3772nd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

3817. the 3772nd device also comprises coating, wherein said coating also contains polymer.

3818. the 3772nd device also comprises first coating with first compositions and second coating with second compositions.

3819. the 3772nd device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

3820. the 3772nd device also comprises polymer.

3821. the 3772nd device also comprises polymer support.

3822. the 3772nd device also comprises polymer support, wherein said polymer support comprises copolymer.

3823. the 3772nd device also comprises polymer support, wherein said polymer support comprises block copolymer.

3824. the 3772nd device also comprises polymer support, wherein said polymer support comprises random copolymer.

3825. the 3772nd device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

3826. the 3772nd device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

3827. the 3772nd device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

3828. the 3772nd device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

3829. the 3772nd device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

3830. the 3772nd device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

3831. the 3772nd device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

3832. the 3772nd device also comprises polymer support, wherein said polymer support comprises elastomer.

3833. the 3772nd device also comprises polymer support, wherein said polymer support comprises hydrogel.

3834. the 3772nd device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

3835. the 3772nd device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

3836. the 3772nd device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

3837. the 3772nd device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

3838. the 3772nd device also comprises polymer support, wherein said polymer support comprises macromonomer.

3839. the 3772nd device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

3840. the 3772nd device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

3841. the 3772nd device also comprises lubricant coating.

3842. the 3772nd device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

3843. the 3772nd device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

3844. the 3772nd device also comprises second forms of pharmacologically active agents.

3845. the 3772nd device also comprises antiinflammatory.

3846. the 3772nd device also comprises the medicament that suppresses infection.

3847. the 3772nd device also comprises the medicament that suppresses infection, described medicament is an anthracycline.

3848. the 3772nd device also comprises the medicament that suppresses infection, described medicament is a doxorubicin.

3849. the 3772nd device also comprises the medicament that suppresses infection, described medicament is a mitoxantrone.

3850. the 3772nd device also comprises the medicament that suppresses infection, described medicament is the fluorine pyrimidine.

3851. the 3772nd device also comprises the medicament that suppresses infection, described medicament is 5-fluorouracil (5-FU).

3852. the 3772nd device also comprises the medicament that suppresses infection, described medicament is an antifol.

3853. the 3772nd device also comprises the medicament that suppresses infection, described medicament is a methotrexate.

3854. the 3772nd device also comprises the medicament that suppresses infection, described medicament is a podophyllotoxin.

3855. the 3772nd device also comprises the medicament that suppresses infection, described medicament is an etoposide.

3856. the 3772nd device also comprises the medicament that suppresses infection, described medicament is a camptothecine.

3857. the 3772nd device also comprises the medicament that suppresses infection, described medicament is a hydroxyurea.

3858. the 3772nd device also comprises the medicament that suppresses infection, described medicament is a platinum complex.

3859. the 3772nd device also comprises the medicament that suppresses infection, described medicament is a cisplatin.

3860. the 3772nd device also comprises antithrombotic agent.

3861. the 3772nd device also comprises developing agent.

3862. the 3772nd device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

3863. the 3772nd device also comprises developing agent, the radiopaque material of wherein said developing agent, and wherein said radiopaque material comprises barium, tantalum or technetium.

3864. the 3772nd device also comprises developing agent, wherein said developing agent comprises MRI response material.

3865. the 3772nd device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

3866. the 3772nd device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

3867. the 3772nd device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

3868. the 3772nd device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

3869. the 3772nd device also comprises the material that produces echo.

3870. the 3772nd device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

3871. the 3772nd device, wherein said device is aseptic.

3872. the 3772nd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

3873. the 3772nd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

3874. the 3772nd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

3875. the 3772nd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

3876. the 3772nd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

3877. the 3772nd device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

3878. the 3772nd device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

3879. the 3772nd device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

3880. the 3772nd device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

3881. the 3772nd device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

3882. the 3772nd device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

3883. the 3772nd device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

3884. the 3772nd device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

3885. the 3772nd device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

3886. the 3772nd device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

3887. the 3772nd device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

3888. the 3772nd device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

3889. the 3772nd device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

3890. the described fibrous tissue that the 3772nd device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

3891. the 3772nd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3892. the 3772nd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3893. the 3772nd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3894. the 3772nd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3895. the 3772nd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

3896. a medical apparatus that comprises guiding osteanagenesis (GBR) implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

3897. the 3896th device, wherein said fibrous tissue forms agent and promotes regeneration.

3898. forming agent, the 3896th device, wherein said fibrous tissue promote blood vessel to take place.

3899. the 3896th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

3900. the 3896th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

3901. the 3896th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

3902. the 3896th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

3903. the 3896th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

3904. the 3896th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

3905. the 3896th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

3906. the 3896th device, wherein said fibrous tissue formation agent is silk or comprises silk.

3907. the 3896th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

3908. the 3896th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

3909. the 3896th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

3910. the 3896th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

3911. the 3896th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

3912. the 3896th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

3913. the 3896th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

3914. the 3896th device, wherein said fibrous tissue form agent and exist with particulate form.

3915. the 3896th device, wherein said compositions also comprises inflammatory cytokine.

3916. the 3896th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

3917. the 3896th device, wherein said compositions exists with the form of gel, paste or spray.

3918. the 3896th device, wherein said fibrous tissue form the form that agent is bunch.

3919. the 3896th device also comprises polymer.

3920. the 3896th device also comprises polymer support.

3921. the 3896th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

3922. the 3896th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

3923. the 3896th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

3924. the 3896th device also comprises coating, wherein said coating is placed on the surface of described device.

3925. the 3896th device also comprises coating, wherein said coating directly contacts described device.

3926. the 3896th device also comprises coating, wherein said coating contacts described device indirectly.

3927. the 3896th device also comprises coating, wherein said coating layer portion ground covers described device.

3928. the 3896th device also comprises coating, wherein said coating fully covers described device.

3929. the 3896th device also comprises coating, wherein said coating is uniform coating.

3930. the 3896th device also comprises coating, wherein said coating is uneven coating.

3931. the 3896th device also comprises coating, wherein said coating is a discontinuous coating.

3932. the 3896th device also comprises coating, wherein said coating is to form the coating of pattern.

3933. the 3896th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

3934. the 3896th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

3935. the 3896th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

3936. the 3896th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

3937. the 3896th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

3938. the 3896th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

3939. the 3896th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

3940. the 3896th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

3941. the 3896th device also comprises coating, wherein said coating also contains polymer.

3942. the 3896th device also comprises first coating with first compositions and second coating with second compositions.

3943. the 3896th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

3944. the 3896th device also comprises polymer.

3945. the 3896th device also comprises polymer support.

3946. the 3896th device also comprises polymer support, wherein said polymer support comprises copolymer.

3947. the 3896th device also comprises polymer support, wherein said polymer support comprises block copolymer.

3948. the 3896th device also comprises polymer support, wherein said polymer support comprises random copolymer.

3949. the 3896th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

3950. the 3896th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

3951. the 3896th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

3952. the 3896th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

3953. the 3896th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

3954. the 3896th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

3955. the 3896th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

3956. the 3896th device also comprises polymer support, wherein said polymer support comprises elastomer.

3957. the 3896th device also comprises polymer support, wherein said polymer support comprises hydrogel.

3958. the 3896th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

3959. the 3896th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

3960. the 3896th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

3961. the 3896th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

3962. the 3896th device also comprises polymer support, wherein said polymer support comprises macromonomer.

3963. the 3896th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

3964. the 3896th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

3965. the 3896th device also comprises lubricant coating.

3966. the 3896th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

3967. the 3896th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

3968. the 3896th device also comprises second forms of pharmacologically active agents.

3969. the 3896th device also comprises antiinflammatory.

3970. the 3896th device also comprises the medicament that suppresses infection.

3971. the 3896th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

3972. the 3896th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

3973. the 3896th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

3974. the 3896th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

3975. the 3896th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

3976. the 3896th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

3977. the 3896th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

3978. the 3896th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

3979. the 3896th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

3980. the 3896th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

3981. the 3896th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

3982. the 3896th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

3983. the 3896th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

3984. the 3896th device also comprises antithrombotic agent.

3985. the 3896th device also comprises developing agent.

3986. the 3896th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

3987. the 3896th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

3988. the 3896th device also comprises developing agent, wherein said developing agent comprises MRI response material.

3989. the 3896th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

3990. the 3896th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

3991. the 3896th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

3992. the 3896th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

3993. the 3896th device also comprises the material that produces echo.

3994. the 3896th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

3995. the 3896th device, wherein said device is aseptic.

3996. the 3896th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

3997. the 3896th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

3998. the 3896th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

3999. the 3896th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

4000. the 3896th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

4001. the 3896th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

4002. the 3896th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

4003. the 3896th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

4004. the 3896th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

4005. the 3896th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

4006. the 3896th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

4007. the 3896th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

4008. the 3896th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

4009. the 3896th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

4010. the 3896th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

4011. the 3896th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

4012. the 3896th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

4013. the 3896th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

4014. the described fibrous tissue that the 3896th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

4015. the 3896th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4016. the 3896th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4017. the 3896th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4018. the 3896th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4019. the 3896th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4020. the 3896th device, wherein said GBR be fill the bone defective can resorbent bone substitute.

4021. one kind comprises the dental implant of the agglutination after the control periodontal and the medical apparatus that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

4022. the 4021st device, wherein said fibrous tissue forms agent and promotes regeneration.

4023. forming agent, the 4021st device, wherein said fibrous tissue promote blood vessel to take place.

4024. the 4021st device, wherein said fibrous tissue form agent and promote the fibroblast migration.

4025. the 4021st device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

4026. the 4021st device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

4027. the 4021st device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

4028. the 4021st device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

4029. the 4021st device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

4030. the 4021st device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

4031. the 4021st device, wherein said fibrous tissue formation agent is silk or comprises silk.

4032. the 4021st device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

4033. the 4021st device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

4034. the 4021st device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

4035. the 4021st device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

4036. the 4021st device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

4037. the 4021st device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

4038. the 4021st device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

4039. the 4021st device, wherein said fibrous tissue form agent and exist with particulate form.

4040. the 4021st device, wherein said compositions also comprises inflammatory cytokine.

4041. the 4021st device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

4042. the 4021st device, wherein said compositions exists with the form of gel, paste or spray.

4043. the 4021st device, wherein said fibrous tissue form the form that agent is bunch.

4044. the 4021st device also comprises polymer.

4045. the 4021st device also comprises polymer support.

4046. the 4021st device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

4047. the 4021st device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

4048. the 4021st device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

4049. the 4021st device also comprises coating, wherein said coating is placed on the surface of described device.

4050. the 4021st device also comprises coating, wherein said coating directly contacts described device.

4051. the 4021st device also comprises coating, wherein said coating contacts described device indirectly.

4052. the 4021st device also comprises coating, wherein said coating layer portion ground covers described device.

4053. the 4021st device also comprises coating, wherein said coating fully covers described device.

4054. the 4021st device also comprises coating, wherein said coating is uniform coating.

4055. the 4021st device also comprises coating, wherein said coating is uneven coating.

4056. the 4021st device also comprises coating, wherein said coating is a discontinuous coating.

4057. the 4021st device also comprises coating, wherein said coating is to form the coating of pattern.

4058. the 4021st device also comprises coating, wherein said coating has 100 μ m or littler thickness.

4059. the 4021st device also comprises coating, wherein said coating has 10 μ m or littler thickness.

4060. the 4021st device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

4061. the 4021st device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

4062. the 4021st device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

4063. the 4021st device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

4064. the 4021st device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

4065. the 4021st device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

4066. the 4021st device also comprises coating, wherein said coating also contains polymer.

4067. the 4021st device also comprises first coating with first compositions and second coating with second compositions.

4068. the 4021st device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

4069. the 4021st device also comprises polymer.

4070. the 4021st device also comprises polymer support.

4071. the 4021st device also comprises polymer support, wherein said polymer support comprises copolymer.

4072. the 4021st device also comprises polymer support, wherein said polymer support comprises block copolymer.

4073. the 4021st device also comprises polymer support, wherein said polymer support comprises random copolymer.

4074. the 4021st device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

4075. the 4021st device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

4076. the 4021st device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

4077. the 4021st device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

4078. the 4021st device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

4079. the 4021st device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

4080. the 4021st device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

4081. the 4021st device also comprises polymer support, wherein said polymer support comprises elastomer.

4082. the 4021st device also comprises polymer support, wherein said polymer support comprises hydrogel.

4083. the 4021st device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

4084. the 4021st device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

4085. the 4021st device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

4086. the 4021st device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

4087. the 4021st device also comprises polymer support, wherein said polymer support comprises macromonomer.

4088. the 4021st device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

4089. the 4021st device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

4090. the 4021st device also comprises lubricant coating.

4091. the 4021st device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

4092. the 4021st device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

4093. the 4021st device also comprises second forms of pharmacologically active agents.

4094. the 4021st device also comprises antiinflammatory.

4095. the 4021st device also comprises the medicament that suppresses infection.

4096. the 4021st device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

4097. the 4021st device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

4098. the 4021st device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

4099. the 4021st device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

4100. the 4021st device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

4101. the 4021st device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

4102. the 4021st device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

4103. the 4021st device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

4104. the 4021st device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

4105. the 4021st device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

4106. the 4021st device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

4107. the 4021st device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

4108. the 4021st device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

4109. the 4021st device also comprises antithrombotic agent.

4110. the 4021st device also comprises developing agent.

4111. the 4021st device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

4112. the 4021st device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

4113. the 4021st device also comprises developing agent, wherein said developing agent comprises MRI response material.

4114. the 4021st device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

4115. the 4021st device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

4116. the 4021st device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

4117. the 4021st device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

4118. the 4021st device also comprises the material that produces echo.

4119. the 4021st device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

4120. the 4021st device, wherein said device is aseptic.

4121. the 4021st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

4122. the 4021st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

4123. the 4021st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

4124. the 4021st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

4125. the 4021st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

4126. the 4021st device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

4127. the 4021st device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

4128. the 4021st device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

4129. the 4021st device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

4130. the 4021st device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

4131. the 4021st device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

4132. the 4021st device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

4133. the 4021st device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

4134. the 4021st device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

4135. the 4021st device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

4136. the 4021st device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

4137. the 4021st device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

4138. the 4021st device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

4139. the described fibrous tissue that the 4021st device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

4140. the 4021st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4141. the 4021st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4142. the 4021st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4143. the 4021st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4144. the 4021st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4145. a medical apparatus that comprises internal fixation implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

4146. the 4145th device, wherein said fibrous tissue forms agent and promotes regeneration.

4147. forming agent, the 4145th device, wherein said fibrous tissue promote blood vessel to take place.

4148. the 4145th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

4149. the 4145th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

4150. the 4145th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

4151. the 4145th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

4152. the 4145th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

4153. the 4145th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

4154. the 4145th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

4155. the 4145th device, wherein said fibrous tissue formation agent is silk or comprises silk.

4156. the 4145th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

4157. the 4145th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

4158. the 4145th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

4159. the 4145th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

4160. the 4145th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

4161. the 4145th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

4162. the 4145th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

4163. the 4145th device, wherein said fibrous tissue form agent and exist with particulate form.

4164. the 4145th device, wherein said compositions also comprises inflammatory cytokine.

4165. the 4145th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

4166. the 4145th device, wherein said compositions exists with the form of gel, paste or spray.

4167. the 4145th device, wherein said fibrous tissue form the form that agent is bunch.

4168. the 4145th device also comprises polymer.

4169. the 4145th device also comprises polymer support.

4170. the 4145th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

4171. the 4145th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

4172. the 4145th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

4173. the 4145th device also comprises coating, wherein said coating is placed on the surface of described device.

4174. the 4145th device also comprises coating, wherein said coating directly contacts described device.

4175. the 4145th device also comprises coating, wherein said coating contacts described device indirectly.

4176. the 4145th device also comprises coating, wherein said coating layer portion ground covers described device.

4177. the 4145th device also comprises coating, wherein said coating fully covers described device.

4178. the 4145th device also comprises coating, wherein said coating is uniform coating.

4179. the 4145th device also comprises coating, wherein said coating is uneven coating.

4180. the 4145th device also comprises coating, wherein said coating is a discontinuous coating.

4181. the 4145th device also comprises coating, wherein said coating is to form the coating of pattern.

4182. the 4145th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

4183. the 4145th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

4184. the 4145th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

4185. the 4145th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

4186. the 4145th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

4187. the 4145th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

4188. the 4145th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

4189. the 4145th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

4190. the 4145th device also comprises coating, wherein said coating also contains polymer.

4191. the 4145th device also comprises first coating with first compositions and second coating with second compositions.

4192. the 4145th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

4193. the 4145th device also comprises polymer.

4194. the 4145th device also comprises polymer support.

4195. the 4145th device also comprises polymer support, wherein said polymer support comprises copolymer.

4196. the 4145th device also comprises polymer support, wherein said polymer support comprises block copolymer.

4197. the 4145th device also comprises polymer support, wherein said polymer support comprises random copolymer.

4198. the 4145th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

4199. the 4145th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

4200. the 4145th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

4201. the 4145th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

4202. the 4145th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

4203. the 4145th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

4204. the 4145th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

4205. the 4145th device also comprises polymer support, wherein said polymer support comprises elastomer.

4206. the 4145th device also comprises polymer support, wherein said polymer support comprises hydrogel.

4207. the 4145th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

4208. the 4145th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

4209. the 4145th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

4210. the 4145th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

4211. the 4145th device also comprises polymer support, wherein said polymer support comprises macromonomer.

4212. the 4145th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

4213. the 4145th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

4214. the 4145th device also comprises lubricant coating.

4215. the 4145th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

4216. the 4145th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

4217. the 4145th device also comprises second forms of pharmacologically active agents.

4218. the 4145th device also comprises antiinflammatory.

4219. the 4145th device also comprises the medicament that suppresses infection.

4220. the 4145th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

4221. the 4145th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

4222. the 4145th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

4223. the 4145th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

4224. the 4145th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

4225. the 4145th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

4226. the 4145th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

4227. the 4145th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

4228. the 4145th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

4229. the 4145th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

4230. the 4145th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

4231. the 4145th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

4232. the 4145th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

4233. the 4145th device also comprises antithrombotic agent.

4234. the 4145th device also comprises developing agent.

4235. the 4145th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

4236. the 4145th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

4237. the 4145th device also comprises developing agent, wherein said developing agent comprises MRI response material.

4238. the 4145th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

4239. the 4145th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

4240. the 4145th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

4241. the 4145th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

4242. the 4145th device also comprises the material that produces echo.

4243. the 4145th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

4244. the 4145th device, wherein said device is aseptic.

4245. the 4145th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

4246. the 4145th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

4247. the 4145th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

4248. the 4145th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

4249. the 4145th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

4250. the 4145th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

4251. the 4145th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

4252. the 4145th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

4253. the 4145th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

4254. the 4145th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

4255. the 4145th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

4256. the 4145th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

4257. the 4145th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

4258. the 4145th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

4259. the 4145th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

4260. the 4145th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

4261. the 4145th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

4262. the 4145th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

4263. the described fibrous tissue that the 4145th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

4264. the 4145th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4265. the 4145th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4266. the 4145th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4267. the 4145th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4268. the 4145th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4269. a medical apparatus that comprises external fixation implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

4270. the 4269th device, wherein said fibrous tissue forms agent and promotes regeneration.

4271. forming agent, the 4269th device, wherein said fibrous tissue promote blood vessel to take place.

4272. the 4269th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

4273. the 4269th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

4274. the 4269th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

4275. the 4269th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

4276. the 4269th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

4277. the 4269th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

4278. the 4269th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

4279. the 4269th device, wherein said fibrous tissue formation agent is silk or comprises silk.

4280. the 4269th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

4281. the 4269th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

4282. the 4269th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

4283. the 4269th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

4284. the 4269th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

4285. the 4269th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

4286. the 4269th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

4287. the 4269th device, wherein said fibrous tissue form agent and exist with particulate form.

4288. the 4269th device, wherein said compositions also comprises inflammatory cytokine.

4289. the 4269th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

4290. the 4269th device, wherein said compositions exists with the form of gel, paste or spray.

4291. the 4269th device, wherein said fibrous tissue form the form that agent is bunch.

4292. the 4269th device also comprises polymer.

4293. the 4269th device also comprises polymer support.

4294. the 4269th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

4295. the 4269th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

4296. the 4269th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

4297. the 4269th device also comprises coating, wherein said coating is placed on the surface of described device.

4298. the 4269th device also comprises coating, wherein said coating directly contacts described device.

4299. the 4269th device also comprises coating, wherein said coating contacts described device indirectly.

4300. the 4269th device also comprises coating, wherein said coating layer portion ground covers described device.

4301. the 4269th device also comprises coating, wherein said coating fully covers described device.

4302. the 4269th device also comprises coating, wherein said coating is uniform coating.

4303. the 4269th device also comprises coating, wherein said coating is uneven coating.

4304. the 4269th device also comprises coating, wherein said coating is a discontinuous coating.

4305. the 4269th device also comprises coating, wherein said coating is to form the coating of pattern.

4306. the 4269th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

4307. the 4269th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

4308. the 4269th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

4309. the 4269th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

4310. the 4269th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

4311. the 4269th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

4312. the 4269th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

4313. the 4269th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

4314. the 4269th device also comprises coating, wherein said coating also contains polymer.

4315. the 4269th device also comprises first coating with first compositions and second coating with second compositions.

4316. the 4269th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

4317. the 4269th device also comprises polymer.

4318. the 4269th device also comprises polymer support.

4319. the 4269th device also comprises polymer support, wherein said polymer support comprises copolymer.

4320. the 4269th device also comprises polymer support, wherein said polymer support comprises block copolymer.

4321. the 4269th device also comprises polymer support, wherein said polymer support comprises random copolymer.

4322. the 4269th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

4323. the 4269th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

4324. the 4269th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

4325. the 4269th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

4326. the 4269th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

4327. the 4269th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

4328. the 4269th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

4329. the 4269th device also comprises polymer support, wherein said polymer support comprises elastomer.

4330. the 4269th device also comprises polymer support, wherein said polymer support comprises hydrogel.

4331. the 4269th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

4332. the 4269th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

4333. the 4269th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

4334. the 4269th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

4335. the 4269th device also comprises polymer support, wherein said polymer support comprises macromonomer.

4336. the 4269th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

4337. the 4269th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

4338. the 4269th device also comprises lubricant coating.

4339. the 4269th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

4340. the 4269th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

4341. the 4269th device also comprises second forms of pharmacologically active agents.

4342. the 4269th device also comprises antiinflammatory.

4343. the 4269th device also comprises the medicament that suppresses infection.

4344. the 4269th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

4345. the 4269th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

4346. the 4269th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

4347. the 4269th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

4348. the 4269th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

4349. the 4269th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

4350. the 4269th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

4351. the 4269th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

4352. the 4269th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

4353. the 4269th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

4354. the 4269th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

4355. the 4269th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

4356. the 4269th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

4357. the 4269th device also comprises antithrombotic agent.

4358. the 4269th device also comprises developing agent.

4359. the 4269th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

4360. the 4269th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

4361. the 4269th device also comprises developing agent, wherein said developing agent comprises MRI response material.

4362. the 4269th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

4363. the 4269th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

4364. the 4269th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

4365. the 4269th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

4366. the 4269th device also comprises the material that produces echo.

4367. the 4269th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

4368. the 4269th device, wherein said device is aseptic.

4369. the 4269th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

4370. the 4269th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

4371. the 4269th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

4372. the 4269th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

4373. the 4269th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

4374. the 4269th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

4375. the 4269th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

4376. the 4269th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

4377. the 4269th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

4378. the 4269th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

4379. the 4269th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

4380. the 4269th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

4381. the 4269th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

4382. the 4269th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

4383. the 4269th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

4384. the 4269th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

4385. the 4269th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

4386. the 4269th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

4387. the described fibrous tissue that the 4269th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

4388. the 4269th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4389. the 4269th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4390. the 4269th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4391. the 4269th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4392. the 4269th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4393. a medical apparatus that comprises hold-down screw and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

4394. the 4393rd device, wherein said fibrous tissue forms agent and promotes regeneration.

4395. forming agent, the 4393rd device, wherein said fibrous tissue promote blood vessel to take place.

4396. the 4393rd device, wherein said fibrous tissue form agent and promote the fibroblast migration.

4397. the 4393rd device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

4398. the 4393rd device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

4399. the 4393rd device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

4400. the 4393rd device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

4401. the 4393rd device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

4402. the 4393rd device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

4403. the 4393rd device, wherein said fibrous tissue formation agent is silk or comprises silk.

4404. the 4393rd device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

4405. the 4393rd device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

4406. the 4393rd device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

4407. the 4393rd device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

4408. the 4393rd device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

4409. the 4393rd device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

4410. the 4393rd device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

4411. the 4393rd device, wherein said fibrous tissue form agent and exist with particulate form.

4412. the 4393rd device, wherein said compositions also comprises inflammatory cytokine.

4413. the 4393rd device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

4414. the 4393rd device, wherein said compositions exists with the form of gel, paste or spray.

4415. the 4393rd device, wherein said fibrous tissue form the form that agent is bunch.

4416. the 4393rd device also comprises polymer.

4417. the 4393rd device also comprises polymer support.

4418. the 4393rd device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

4419. the 4393rd device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

4420. the 4393rd device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

4421. the 4393rd device also comprises coating, wherein said coating is placed on the surface of described device.

4422. the 4393rd device also comprises coating, wherein said coating directly contacts described device.

4423. the 4393rd device also comprises coating, wherein said coating contacts described device indirectly.

4424. the 4393rd device also comprises coating, wherein said coating layer portion ground covers described device.

4425. the 4393rd device also comprises coating, wherein said coating fully covers described device.

4426. the 4393rd device also comprises coating, wherein said coating is uniform coating.

4427. the 4393rd device also comprises coating, wherein said coating is uneven coating.

4428. the 4393rd device also comprises coating, wherein said coating is a discontinuous coating.

4429. the 4393rd device also comprises coating, wherein said coating is to form the coating of pattern.

4430. the 4393rd device also comprises coating, wherein said coating has 100 μ m or littler thickness.

4431. the 4393rd device also comprises coating, wherein said coating has 10 μ m or littler thickness.

4432. the 4393rd device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

4433. the 4393rd device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

4434. the 4393rd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

4435. the 4393rd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

4436. the 4393rd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

4437. the 4393rd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

4438. the 4393rd device also comprises coating, wherein said coating also contains polymer.

4439. the 4393rd device also comprises first coating with first compositions and second coating with second compositions.

4440. the 4393rd device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

4441. the 4393rd device also comprises polymer.

4442. the 4393rd device also comprises polymer support.

4443. the 4393rd device also comprises polymer support, wherein said polymer support comprises copolymer.

4444. the 4393rd device also comprises polymer support, wherein said polymer support comprises block copolymer.

4445. the 4393rd device also comprises polymer support, wherein said polymer support comprises random copolymer.

4446. the 4393rd device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

4447. the 4393rd device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

4448. the 4393rd device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

4449. the 4393rd device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

4450. the 4393rd device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

4451. the 4393rd device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

4452. the 4393rd device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

4453. the 4393rd device also comprises polymer support, wherein said polymer support comprises elastomer.

4454. the 4393rd device also comprises polymer support, wherein said polymer support comprises hydrogel.

4455. the 4393rd device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

4456. the 4393rd device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

4457. the 4393rd device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

4458. the 4393rd device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

4459. the 4393rd device also comprises polymer support, wherein said polymer support comprises macromonomer.

4460. the 4393rd device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

4461. the 4393rd device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

4462. the 4393rd device also comprises lubricant coating.

4463. the 4393rd device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

4464. the 4393rd device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

4465. the 4393rd device also comprises second forms of pharmacologically active agents.

4466. the 4393rd device also comprises antiinflammatory.

4467. the 4393rd device also comprises the medicament that suppresses infection.

4468. the 4393rd device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

4469. the 4393rd device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

4470. the 4393rd device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

4471. the 4393rd device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

4472. the 4393rd device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

4473. the 4393rd device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

4474. the 4393rd device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

4475. the 4393rd device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

4476. the 4393rd device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

4477. the 4393rd device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

4478. the 4393rd device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

4479. the 4393rd device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

4480. the 4393rd device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

4481. the 4393rd device also comprises antithrombotic agent.

4482. the 4393rd device also comprises developing agent.

4483. the 4393rd device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

4484. the 4393rd device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

4485. the 4393rd device also comprises developing agent, wherein said developing agent comprises MRI response material.

4486. the 4393rd device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

4487. the 4393rd device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

4488. the 4393rd device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

4489. the 4393rd device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

4490. the 4393rd device also comprises the material that produces echo.

4491. the 4393rd device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

4492. the 4393rd device, wherein said device is aseptic.

4493. the 4393rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

4494. the 4393rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

4495. the 4393rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

4496. the 4393rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

4497. the 4393rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

4498. the 4393rd device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

4499. the 4393rd device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

4500. the 4393rd device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

4501. the 4393rd device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

4502. the 4393rd device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

4503. the 4393rd device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

4504. the 4393rd device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

4505. the 4393rd device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

4506. the 4393rd device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

4507. the 4393rd device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

4508. the 4393rd device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

4509. the 4393rd device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

4510. the 4393rd device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

4511. the described fibrous tissue that the 4393rd device, the surface of wherein said device comprise less than 0.01 μ g forms the apparatus surface that agent/mm2 uses described fibrous tissue formation agent.

4512. the 4393rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4513. the 4393rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4514. the 4393rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4515. the 4393rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4516. the 4393rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4517. the 4393rd device, wherein said hold-down screw is biodegradable.

4518. the 4393rd device, wherein said hold-down screw are not biodegradable.

4519. a medical apparatus that comprises interference (interferential) screw and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

4520. the 4519th device, wherein said fibrous tissue forms agent and promotes regeneration.

4521. forming agent, the 4519th device, wherein said fibrous tissue promote blood vessel to take place.

4522. the 4519th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

4523. the 4519th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

4524. the 4519th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

4525. the 4519th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

4526. the 4519th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

4527. the 4519th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

4528. the 4519th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

4529. the 4519th device, wherein said fibrous tissue formation agent is silk or comprises silk.

4530. the 4519th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

4531. the 4519th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

4532. the 4519th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

4533. the 4519th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

4534. the 4519th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

4535. the 4519th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

4536. the 4519th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

4537. the 4519th device, wherein said fibrous tissue form agent and exist with particulate form.

4538. the 4519th device, wherein said compositions also comprises inflammatory cytokine.

4539. the 4519th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

4540. the 4519th device, wherein said compositions exists with the form of gel, paste or spray.

4541. the 4519th device, wherein said fibrous tissue form the form that agent is bunch.

4542. the 4519th device also comprises polymer.

4543. the 4519th device also comprises polymer support.

4544. the 4519th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

4545. the 4519th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

4546. the 4519th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

4547. the 4519th device also comprises coating, wherein said coating is placed on the surface of described device.

4548. the 4519th device also comprises coating, wherein said coating directly contacts described device.

4549. the 4519th device also comprises coating, wherein said coating contacts described device indirectly.

4550. the 4519th device also comprises coating, wherein said coating layer portion ground covers described device.

4551. the 4519th device also comprises coating, wherein said coating fully covers described device.

4552. the 4519th device also comprises coating, wherein said coating is uniform coating.

4553. the 4519th device also comprises coating, wherein said coating is uneven coating.

4554. the 4519th device also comprises coating, wherein said coating is a discontinuous coating.

4555. the 4519th device also comprises coating, wherein said coating is to form the coating of pattern.

4556. the 4519th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

4557. the 4519th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

4558. the 4519th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

4559. the 4519th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

4560. the 4519th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

4561. the 4519th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

4562. the 4519th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

4563. the 4519th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

4564. the 4519th device also comprises coating, wherein said coating also contains polymer.

4565. the 4519th device also comprises first coating with first compositions and second coating with second compositions.

4566. the 4519th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

4567. the 4519th device also comprises polymer.

4568. the 4519th device also comprises polymer support.

4569. the 4519th device also comprises polymer support, wherein said polymer support comprises copolymer.

4570. the 4519th device also comprises polymer support, wherein said polymer support comprises block copolymer.

4571. the 4519th device also comprises polymer support, wherein said polymer support comprises random copolymer.

4572. the 4519th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

4573. the 4519th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

4574. the 4519th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

4575. the 4519th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

4576. the 4519th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

4577. the 4519th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

4578. the 4519th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

4579. the 4519th device also comprises polymer support, wherein said polymer support comprises elastomer.

4580. the 4519th device also comprises polymer support, wherein said polymer support comprises hydrogel.

4581. the 4519th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

4582. the 4519th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

4583. the 4519th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

4584. the 4519th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

4585. the 4519th device also comprises polymer support, wherein said polymer support comprises macromonomer.

4586. the 4519th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

4587. the 4519th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

4588. the 4519th device also comprises lubricant coating.

4589. the 4519th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

4590. the 4519th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

4591. the 4519th device also comprises second forms of pharmacologically active agents.

4592. the 4519th device also comprises antiinflammatory.

4593. the 4519th device also comprises the medicament that suppresses infection.

4594. the 4519th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

4595. the 4519th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

4596. the 4519th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

4597. the 4519th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

4598. the 4519th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

4599. the 4519th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

4600. the 4519th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

4601. the 4519th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

4602. the 4519th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

4603. the 4519th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

4604. the 4519th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

4605. the 4519th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

4606. the 4519th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

4607. the 4519th device also comprises antithrombotic agent.

4608. the 4519th device also comprises developing agent.

4609. the 4519th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

4610. the 4519th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

4611. the 4519th device also comprises developing agent, wherein said developing agent comprises MRI response material.

4612. the 4519th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

4613. the 4519th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

4614. the 4519th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

4615. the 4519th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

4616. the 4519th device also comprises the material that produces echo.

4617. the 4519th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

4618. the 4519th device, wherein said device is aseptic.

4619. the 4519th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

4620. the 4519th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

4621. the 4519th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

4622. the 4519th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

4623. the 4519th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

4624. the 4519th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

4625. the 4519th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

4626. the 4519th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

4627. the 4519th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

4628. the 4519th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

4629. the 4519th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

4630. the 4519th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

4631. the 4519th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

4632. the 4519th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

4633. the 4519th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

4634. the 4519th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

4635. the 4519th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

4636. the 4519th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

4637. the described fibrous tissue that the 4519th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

4638. the 4519th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4639. the 4519th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4640. the 4519th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4641. the 4519th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4642. the 4519th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4643. the 4519th device, wherein said interference screw is biodegradable.

4644. the 4519th device, wherein said interference screw is not biodegradable.

4645. a medical apparatus that comprises rotor screw and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

4646. the 4645th device, wherein said fibrous tissue forms agent and promotes regeneration.

4647. forming agent, the 4645th device, wherein said fibrous tissue promote blood vessel to take place.

4648. the 4645th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

4649. the 4645th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

4650. the 4645th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

4651. the 4645th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

4652. the 4645th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

4653. the 4645th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

4654. the 4645th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

4655. the 4645th device, wherein said fibrous tissue formation agent is silk or comprises silk.

4656. the 4645th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

4657. the 4645th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

4658. the 4645th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

4659. the 4645th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

4660. the 4645th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

4661. the 4645th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

4662. the 4645th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

4663. the 4645th device, wherein said fibrous tissue form agent and exist with particulate form.

4664. the 4645th device, wherein said compositions also comprises inflammatory cytokine.

4665. the 4645th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

4666. the 4645th device, wherein said compositions exists with the form of gel, paste or spray.

4667. the 4645th device, wherein said fibrous tissue form the form that agent is bunch.

4668. the 4645th device also comprises polymer.

4669. the 4645th device also comprises polymer support.

4670. the 4645th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

4671. the 4645th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

4672. the 4645th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

4673. the 4645th device also comprises coating, wherein said coating is placed on the surface of described device.

4674. the 4645th device also comprises coating, wherein said coating directly contacts described device.

4675. the 4645th device also comprises coating, wherein said coating contacts described device indirectly.

4676. the 4645th device also comprises coating, wherein said coating layer portion ground covers described device.

4677. the 4645th device also comprises coating, wherein said coating fully covers described device.

4678. the 4645th device also comprises coating, wherein said coating is uniform coating.

4679. the 4645th device also comprises coating, wherein said coating is uneven coating.

4680. the 4645th device also comprises coating, wherein said coating is a discontinuous coating.

4681. the 4645th device also comprises coating, wherein said coating is to form the coating of pattern.

4682. the 4645th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

4683. the 4645th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

4684. the 4645th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

4685. the 4645th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

4686. the 4645th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

4687. the 4645th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

4688. the 4645th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

4689. the 4645th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

4690. the 4645th device also comprises coating, wherein said coating also contains polymer.

4691. the 4645th device also comprises first coating with first compositions and second coating with second compositions.

4692. the 4645th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

4693. the 4645th device also comprises polymer.

4694. the 4645th device also comprises polymer support.

4695. the 4645th device also comprises polymer support, wherein said polymer support comprises copolymer.

4696. the 4645th device also comprises polymer support, wherein said polymer support comprises block copolymer.

4697. the 4645th device also comprises polymer support, wherein said polymer support comprises random copolymer.

4698. the 4645th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

4699. the 4645th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

4700. the 4645th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

4701. the 4645th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

4702. the 4645th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

4703. the 4645th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

4704. the 4645th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

4705. the 4645th device also comprises polymer support, wherein said polymer support comprises elastomer.

4706. the 4645th device also comprises polymer support, wherein said polymer support comprises hydrogel.

4707. the 4645th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

4708. the 4645th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

4709. the 4645th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

4710. the 4645th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

4711. the 4645th device also comprises polymer support, wherein said polymer support comprises macromonomer.

4712. the 4645th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

4713. the 4645th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

4714. the 4645th device also comprises lubricant coating.

4715. the 4645th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

4716. the 4645th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

4717. the 4645th device also comprises second forms of pharmacologically active agents.

4718. the 4645th device also comprises antiinflammatory.

4719. the 4645th device also comprises the medicament that suppresses infection.

4720. the 4645th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

4721. the 4645th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

4722. the 4645th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

4723. the 4645th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

4724. the 4645th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

4725. the 4645th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

4726. the 4645th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

4727. the 4645th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

4728. the 4645th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

4729. the 4645th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

4730. the 4645th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

4731. the 4645th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

4732. the 4645th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

4733. the 4645th device also comprises antithrombotic agent.

4734. the 4645th device also comprises developing agent.

4735. the 4645th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

4736. the 4645th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

4737. the 4645th device also comprises developing agent, wherein said developing agent comprises MRI response material.

4738. the 4645th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

4739. the 4645th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

4740. the 4645th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

4741. the 4645th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

4742. the 4645th device also comprises the material that produces echo.

4743. the 4645th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

4744. the 4645th device, wherein said device is aseptic.

4745. the 4645th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

4746. the 4645th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

4747. the 4645th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

4748. the 4645th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

4749. the 4645th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

4750. the 4645th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

4751. the 4645th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

4752. the 4645th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

4753. the 4645th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

4754. the 4645th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

4755. the 4645th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

4756. the 4645th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

4757. the 4645th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

4758. the 4645th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

4759. the 4645th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

4760. the 4645th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

4761. the 4645th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

4762. the 4645th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

4763. the described fibrous tissue that the 4645th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

4764. the 4645th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4765. the 4645th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4766. the 4645th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4767. the 4645th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4768. the 4645th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4769. a medical apparatus that comprises plate (plate) implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

4770. the 4769th device, wherein said fibrous tissue forms agent and promotes regeneration.

4771. forming agent, the 4769th device, wherein said fibrous tissue promote blood vessel to take place.

4772. the 4769th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

4773. the 4769th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

4774. the 4769th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

4775. the 4769th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

4776. the 4769th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

4777. the 4769th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

4778. the 4769th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

4779. the 4769th device, wherein said fibrous tissue formation agent is silk or comprises silk.

4780. the 4769th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

4781. the 4769th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

4782. the 4769th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

4783. the 4769th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

4784. the 4769th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

4785. the 4769th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

4786. the 4769th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

4787. the 4769th device, wherein said fibrous tissue form agent and exist with particulate form.

4788. the 4769th device, wherein said compositions also comprises inflammatory cytokine.

4789. the 4769th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

4790. the 4769th device, wherein said compositions exists with the form of gel, paste or spray.

4791. the 4769th device, wherein said fibrous tissue form the form that agent is bunch.

4792. the 4769th device also comprises polymer.

4793. the 4769th device also comprises polymer support.

4794. the 4769th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

4795. the 4769th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

4796. the 4769th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

4797. the 4769th device also comprises coating, wherein said coating is placed on the surface of described device.

4798. the 4769th device also comprises coating, wherein said coating directly contacts described device.

4799. the 4769th device also comprises coating, wherein said coating contacts described device indirectly.

4800. the 4769th device also comprises coating, wherein said coating layer portion ground covers described device.

4801. the 4769th device also comprises coating, wherein said coating fully covers described device.

4802. the 4769th device also comprises coating, wherein said coating is uniform coating.

4803. the 4769th device also comprises coating, wherein said coating is uneven coating.

4804. the 4769th device also comprises coating, wherein said coating is a discontinuous coating.

4805. the 4769th device also comprises coating, wherein said coating is to form the coating of pattern.

4806. the 4769th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

4807. the 4769th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

4808. the 4769th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

4809. the 4769th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

4810. the 4769th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

4811. the 4769th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

4812. the 4769th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

4813. the 4769th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

4814. the 4769th device also comprises coating, wherein said coating also contains polymer.

4815. the 4769th device also comprises first coating with first compositions and second coating with second compositions.

4816. the 4769th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

4817. the 4769th device also comprises polymer.

4818. the 4769th device also comprises polymer support.

4819. the 4769th device also comprises polymer support, wherein said polymer support comprises copolymer.

4820. the 4769th device also comprises polymer support, wherein said polymer support comprises block copolymer.

4821. the 4769th device also comprises polymer support, wherein said polymer support comprises random copolymer.

4822. the 4769th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

4823. the 4769th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

4824. the 4769th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

4825. the 4769th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

4826. the 4769th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

4827. the 4769th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

4828. the 4769th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

4829. the 4769th device also comprises polymer support, wherein said polymer support comprises elastomer.

4830. the 4769th device also comprises polymer support, wherein said polymer support comprises hydrogel.

4831. the 4769th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

4832. the 4769th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

4833. the 4769th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

4834. the 4769th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

4835. the 4769th device also comprises polymer support, wherein said polymer support comprises macromonomer.

4836. the 4769th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

4837. the 4769th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

4838. the 4769th device also comprises lubricant coating.

4839. the 4769th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

4840. the 4769th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

4841. the 4769th device also comprises second forms of pharmacologically active agents.

4842. the 4769th device also comprises antiinflammatory.

4843. the 4769th device also comprises the medicament that suppresses infection.

4844. the 4769th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

4845. the 4769th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

4846. the 4769th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

4847. the 4769th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

4848. the 4769th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

4849. the 4769th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

4850. the 4769th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

4851. the 4769th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

4852. the 4769th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

4853. the 4769th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

4854. the 4769th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

4855. the 4769th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

4856. the 4769th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

4857. the 4769th device also comprises antithrombotic agent.

4858. the 4769th device also comprises developing agent.

4859. the 4769th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

4860. the 4769th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

4861. the 4769th device also comprises developing agent, wherein said developing agent comprises MRI response material.

4862. the 4769th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

4863. the 4769th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

4864. the 4769th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

4865. the 4769th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

4866. the 4769th device also comprises the material that produces echo.

4867. the 4769th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

4868. the 4769th device, wherein said device is aseptic.

4869. the 4769th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

4870. the 4769th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

4871. the 4769th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

4872. the 4769th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

4873. the 4769th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

4874. the 4769th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

4875. the 4769th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

4876. the 4769th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

4877. the 4769th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

4878. the 4769th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

4879. the 4769th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

4880. the 4769th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

4881. the 4769th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

4882. the 4769th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

4883. the 4769th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

4884. the 4769th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

4885. the 4769th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

4886. the 4769th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

4887. the described fibrous tissue that the 4769th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

4888. the 4769th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4889. the 4769th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4890. the 4769th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4891. the 4769th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4892. the 4769th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

4893. a medical apparatus that comprises tinsel (wire) implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

4894. the 4893rd device, wherein said fibrous tissue forms agent and promotes regeneration.

4895. forming agent, the 4893rd device, wherein said fibrous tissue promote blood vessel to take place.

4896. the 4893rd device, wherein said fibrous tissue form agent and promote the fibroblast migration.

4897. the 4893rd device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

4898. the 4893rd device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

4899. the 4893rd device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

4900. the 4893rd device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

4901. the 4893rd device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

4902. the 4893rd device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

4903. the 4893rd device, wherein said fibrous tissue formation agent is silk or comprises silk.

4904. the 4893rd device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

4905. the 4893rd device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

4906. the 4893rd device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

4907. the 4893rd device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

4908. the 4893rd device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

4909. the 4893rd device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

4910. the 4893rd device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

4911. the 4893rd device, wherein said fibrous tissue form agent and exist with particulate form.

4912. the 4893rd device, wherein said compositions also comprises inflammatory cytokine.

4913. the 4893rd device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

4914. the 4893rd device, wherein said compositions exists with the form of gel, paste or spray.

4915. the 4893rd device, wherein said fibrous tissue form the form that agent is bunch.

4916. the 4893rd device also comprises polymer.

4917. the 4893rd device also comprises polymer support.

4918. the 4893rd device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

4919. the 4893rd device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

4920. the 4893rd device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

4921. the 4893rd device also comprises coating, wherein said coating is placed on the surface of described device.

4922. the 4893rd device also comprises coating, wherein said coating directly contacts described device.

4923. the 4893rd device also comprises coating, wherein said coating contacts described device indirectly.

4924. the 4893rd device also comprises coating, wherein said coating layer portion ground covers described device.

4925. the 4893rd device also comprises coating, wherein said coating fully covers described device.

4926. the 4893rd device also comprises coating, wherein said coating is uniform coating.

4927. the 4893rd device also comprises coating, wherein said coating is uneven coating.

4928. the 4893rd device also comprises coating, wherein said coating is a discontinuous coating.

4929. the 4893rd device also comprises coating, wherein said coating is to form the coating of pattern.

4930. the 4893rd device also comprises coating, wherein said coating has 100 μ m or littler thickness.

4931. the 4893rd device also comprises coating, wherein said coating has 10 μ m or littler thickness.

4932. the 4893rd device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

4933. the 4893rd device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

4934. the 4893rd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

4935. the 4893rd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

4936. the 4893rd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

4937. the 4893rd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

4938. the 4893rd device also comprises coating, wherein said coating also contains polymer.

4939. the 4893rd device also comprises first coating with first compositions and second coating with second compositions.

4940. the 4893rd device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

4941. the 4893rd device also comprises polymer.

4942. the 4893rd device also comprises polymer support.

4943. the 4893rd device also comprises polymer support, wherein said polymer support comprises copolymer.

4944. the 4893rd device also comprises polymer support, wherein said polymer support comprises block copolymer.

4945. the 4893rd device also comprises polymer support, wherein said polymer support comprises random copolymer.

4946. the 4893rd device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

4947. the 4893rd device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

4948. the 4893rd device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

4949. the 4893rd device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

4950. the 4893rd device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

4951. the 4893rd device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

4952. the 4893rd device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

4953. the 4893rd device also comprises polymer support, wherein said polymer support comprises elastomer.

4954. the 4893rd device also comprises polymer support, wherein said polymer support comprises hydrogel.

4955. the 4893rd device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

4956. the 4893rd device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

4957. the 4893rd device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

4958. the 4893rd device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

4959. the 4893rd device also comprises polymer support, wherein said polymer support comprises macromonomer.

4960. the 4893rd device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

4961. the 4893rd device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

4962. the 4893rd device also comprises lubricant coating.

4963. the 4893rd device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

4964. the 4893rd device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

4965. the 4893rd device also comprises second forms of pharmacologically active agents.

4966. the 4893rd device also comprises antiinflammatory.

4967. the 4893rd device also comprises the medicament that suppresses infection.

4968. the 4893rd device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

4969. the 4893rd device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

4970. the 4893rd device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

4971. the 4893rd device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

4972. the 4893rd device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

4973. the 4893rd device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

4974. the 4893rd device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

4975. the 4893rd device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

4976. the 4893rd device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

4977. the 4893rd device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

4978. the 4893rd device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

4979. the 4893rd device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

4980. the 4893rd device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

4981. the 4893rd device also comprises antithrombotic agent.

4982. the 4893rd device also comprises developing agent.

4983. the 4893rd device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

4984. the 4893rd device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

4985. the 4893rd device also comprises developing agent, wherein said developing agent comprises MRI response material.

4986. the 4893rd device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

4987. the 4893rd device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

4988. the 4893rd device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

4989. the 4893rd device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

4990. the 4893rd device also comprises the material that produces echo.

4991. the 4893rd device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

4992. the 4893rd device, wherein said device is aseptic.

4993. the 4893rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

4994. the 4893rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

4995. the 4893rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

4996. the 4893rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

4997. the 4893rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

4998. the 4893rd device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

4999. the 4893rd device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

5000. the 4893rd device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

5001. the 4893rd device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

5002. the 4893rd device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

5003. the 4893rd device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

5004. the 4893rd device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

5005. the 4893rd device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

5006. the 4893rd device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

5007. the 4893rd device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

5008. the 4893rd device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

5009. the 4893rd device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

5010. the 4893rd device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

5011. the described fibrous tissue that the 4893rd device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

5012. the 4893rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5013. the 4893rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5014. the 4893rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5015. the 4893rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5016. the 4893rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5017. a medical apparatus that comprises collagen protein implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

5018. the 5017th device, wherein said fibrous tissue forms agent and promotes regeneration.

5019. forming agent, the 5017th device, wherein said fibrous tissue promote blood vessel to take place.

5020. the 5017th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

5021. the 5017th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

5022. the 5017th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

5023. the 5017th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

5024. the 5017th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

5025. the 5017th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

5026. the 5017th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

5027. the 5017th device, wherein said fibrous tissue formation agent is silk or comprises silk.

5028. the 5017th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

5029. the 5017th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

5030. the 5017th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

5031. the 5017th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

5032. the 5017th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

5033. the 5017th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

5034. the 5017th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

5035. the 5017th device, wherein said fibrous tissue form agent and exist with particulate form.

5036. the 5017th device, wherein said compositions also comprises inflammatory cytokine.

5037. the 5017th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

5038. the 5017th device, wherein said compositions exists with the form of gel, paste or spray.

5039. the 5017th device, wherein said fibrous tissue form the form that agent is bunch.

5040. the 5017th device also comprises polymer.

5041. the 5017th device also comprises polymer support.

5042. the 5017th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

5043. the 5017th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

5044. the 5017th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

5045. the 5017th device also comprises coating, wherein said coating is placed on the surface of described device.

5046. the 5017th device also comprises coating, wherein said coating directly contacts described device.

5047. the 5017th device also comprises coating, wherein said coating contacts described device indirectly.

5048. the 5017th device also comprises coating, wherein said coating layer portion ground covers described device.

5049. the 5017th device also comprises coating, wherein said coating fully covers described device.

5050. the 5017th device also comprises coating, wherein said coating is uniform coating.

5051. the 5017th device also comprises coating, wherein said coating is uneven coating.

5052. the 5017th device also comprises coating, wherein said coating is a discontinuous coating.

5053. the 5017th device also comprises coating, wherein said coating is to form the coating of pattern.

5054. the 5017th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

5055. the 5017th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

5056. the 5017th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

5057. the 5017th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

5058. the 5017th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

5059. the 5017th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

5060. the 5017th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

5061. the 5017th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

5062. the 5017th device also comprises coating, wherein said coating also contains polymer.

5063. the 5017th device also comprises first coating with first compositions and second coating with second compositions.

5064. the 5017th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

5065. the 5017th device also comprises polymer.

5066. the 5017th device also comprises polymer support.

5067. the 5017th device also comprises polymer support, wherein said polymer support comprises copolymer.

5068. the 5017th device also comprises polymer support, wherein said polymer support comprises block copolymer.

5069. the 5017th device also comprises polymer support, wherein said polymer support comprises random copolymer.

5070. the 5017th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

5071. the 5017th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

5072. the 5017th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

5073. the 5017th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

5074. the 5017th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

5075. the 5017th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

5076. the 5017th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

5077. the 5017th device also comprises polymer support, wherein said polymer support comprises elastomer.

5078. the 5017th device also comprises polymer support, wherein said polymer support comprises hydrogel.

5079. the 5017th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

5080. the 5017th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

5081. the 5017th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

5082. the 5017th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

5083. the 5017th device also comprises polymer support, wherein said polymer support comprises macromonomer.

5084. the 5017th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

5085. the 5017th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

5086. the 5017th device also comprises lubricant coating.

5087. the 5017th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

5088. the 5017th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

5089. the 5017th device also comprises second forms of pharmacologically active agents.

5090. the 5017th device also comprises antiinflammatory.

5091. the 5017th device also comprises the medicament that suppresses infection.

5092. the 5017th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

5093. the 5017th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

5094. the 5017th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

5095. the 5017th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

5096. the 5017th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

5097. the 5017th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

5098. the 5017th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

5099. the 5017th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

5100. the 5017th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

5101. the 5017th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

5102. the 5017th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

5103. the 5017th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

5104. the 5017th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

5105. the 5017th device also comprises antithrombotic agent.

5106. the 5017th device also comprises developing agent.

5107. the 5017th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

5108. the 5017th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

5109. the 5017th device also comprises developing agent, wherein said developing agent comprises MRI response material.

5110. the 5017th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

5111. the 5017th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

5112. the 5017th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

5113. the 5017th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

5114. the 5017th device also comprises the material that produces echo.

5115. the 5017th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

5116. the 5017th device, wherein said device is aseptic.

5117. the 5017th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

5118. the 5017th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

5119. the 5017th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

5120. the 5017th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

5121. the 5017th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

5122. the 5017th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

5123. the 5017th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

5124. the 5017th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

5125. the 5017th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

5126. the 5017th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

5127. the 5017th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

5128. the 5017th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

5129. the 5017th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

5130. the 5017th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

5131. the 5017th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

5132. the 5017th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

5133. the 5017th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

5134. the 5017th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

5135. the described fibrous tissue that the 5017th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

5136. the 5017th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5137. the 5017th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5138. the 5017th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5139. the 5017th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5140. the 5017th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5141. a medical apparatus that comprises fallopian tube implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

5142. the 5141st device, wherein said fibrous tissue forms agent and promotes regeneration.

5143. forming agent, the 5141st device, wherein said fibrous tissue promote blood vessel to take place.

5144. the 5141st device, wherein said fibrous tissue form agent and promote the fibroblast migration.

5145. the 5141st device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

5146. the 5141st device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

5147. the 5141st device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

5148. the 5141st device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

5149. the 5141st device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

5150. the 5141st device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

5151. the 5141st device, wherein said fibrous tissue formation agent is silk or comprises silk.

5152. the 5141st device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

5153. the 5141st device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

5154. the 5141st device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

5155. the 5141st device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

5156. the 5141st device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

5157. the 5141st device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

5158. the 5141st device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

5159. the 5141st device, wherein said fibrous tissue form agent and exist with particulate form.

5160. the 5141st device, wherein said compositions also comprises inflammatory cytokine.

5161. the 5141st device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

5162. the 5141st device, wherein said compositions exists with the form of gel, paste or spray.

5163. the 5141st device, wherein said fibrous tissue form the form that agent is bunch.

5164. the 5141st device also comprises polymer.

5165. the 5141st device also comprises polymer support.

5166. the 5141st device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

5167. the 5141st device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

5168. the 5141st device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

5169. the 5141st device also comprises coating, wherein said coating is placed on the surface of described device.

5170. the 5141st device also comprises coating, wherein said coating directly contacts described device.

5171. the 5141st device also comprises coating, wherein said coating contacts described device indirectly.

5172. the 5141st device also comprises coating, wherein said coating layer portion ground covers described device.

5173. the 5141st device also comprises coating, wherein said coating fully covers described device.

5174. the 5141st device also comprises coating, wherein said coating is uniform coating.

5175. the 5141st device also comprises coating, wherein said coating is uneven coating.

5176. the 5141st device also comprises coating, wherein said coating is a discontinuous coating.

5177. the 5141st device also comprises coating, wherein said coating is to form the coating of pattern.

5178. the 5141st device also comprises coating, wherein said coating has 100 μ m or littler thickness.

5179. the 5141st device also comprises coating, wherein said coating has 10 μ m or littler thickness.

5180. the 5141st device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

5181. the 5141st device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

5182. the 5141st device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

5183. the 5141st device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

5184. the 5141st device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

5185. the 5141st device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

5186. the 5141st device also comprises coating, wherein said coating also contains polymer.

5187. the 5141st device also comprises first coating with first compositions and second coating with second compositions.

5188. the 5141st device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

5189. the 5141st device also comprises polymer.

5190. the 5141st device also comprises polymer support.

5191. the 5141st device also comprises polymer support, wherein said polymer support comprises copolymer.

5192. the 5141st device also comprises polymer support, wherein said polymer support comprises block copolymer.

5193. the 5141st device also comprises polymer support, wherein said polymer support comprises random copolymer.

5194. the 5141st device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

5195. the 5141st device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

5196. the 5141st device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

5197. the 5141st device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

5198. the 5141st device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

5199. the 5141st device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

5200. the 5141st device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

5201. the 5141st device also comprises polymer support, wherein said polymer support comprises elastomer.

5202. the 5141st device also comprises polymer support, wherein said polymer support comprises hydrogel.

5203. the 5141st device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

5204. the 5141st device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

5205. the 5141st device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

5206. the 5141st device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

5207. the 5141st device also comprises polymer support, wherein said polymer support comprises macromonomer.

5208. the 5141st device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

5209. the 5141st device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

5210. the 5141st device also comprises lubricant coating.

5211. the 5141st device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

5212. the 5141st device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

5213. the 5141st device also comprises second forms of pharmacologically active agents.

5214. the 5141st device also comprises antiinflammatory.

5215. the 5141st device also comprises the medicament that suppresses infection.

5216. the 5141st device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

5217. the 5141st device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

5218. the 5141st device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

5219. the 5141st device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

5220. the 5141st device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

5221. the 5141st device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

5222. the 5141st device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

5223. the 5141st device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

5224. the 5141st device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

5225. the 5141st device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

5226. the 5141st device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

5227. the 5141st device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

5228. the 5141st device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

5229. the 5141st device also comprises antithrombotic agent.

5230. the 5141st device also comprises developing agent.

5231. the 5141st device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

5232. the 5141st device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

5233. the 5141st device also comprises developing agent, wherein said developing agent comprises MRI response material.

5234. the 5141st device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

5235. the 5141st device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

5236. the 5141st device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

5237. the 5141st device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

5238. the 5141st device also comprises the material that produces echo.

5239. the 5141st device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

5240. the 5141st device, wherein said device is aseptic.

5241. the 5141st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

5242. the 5141st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

5243. the 5141st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

5244. the 5141st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

5245. the 5141st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

5246. the 5141st device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

5247. the 5141st device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

5248. the 5141st device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

5249. the 5141st device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

5250. the 5141st device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

5251. the 5141st device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

5252. the 5141st device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

5253. the 5141st device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

5254. the 5141st device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

5255. the 5141st device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

5256. the 5141st device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

5257. the 5141st device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

5258. the 5141st device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

5259. the described fibrous tissue that the 5141st device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

5260. the 5141st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5261. the 5141st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5262. the 5141st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5263. the 5141st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5264. the 5141st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5265. the 5141st device, wherein said fallopian tube implant is injectable.

5266. the 5141st device, wherein said fallopian tube implant are fallopian tube (fallopian tumbe) inaccessible.

5267. the 5141st device, wherein said fallopian tube implant are intrauterine device (coil) fallopian tube implants.

5268. the 5141st device, wherein said fallopian tube implant are contraception uterus implants.

5269. a medical apparatus that comprises transcatheter inaccessible implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

5270. the 5269th device, wherein said fibrous tissue forms agent and promotes regeneration.

5271. forming agent, the 5269th device, wherein said fibrous tissue promote blood vessel to take place.

5272. the 5269th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

5273. the 5269th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

5274. the 5269th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

5275. the 5269th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

5276. the 5269th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

5277. the 5269th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

5278. the 5269th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

5279. the 5269th device, wherein said fibrous tissue formation agent is silk or comprises silk.

5280. the 5269th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

5281. the 5269th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

5282. the 5269th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

5283. the 5269th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

5284. the 5269th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

5285. the 5269th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

5286. the 5269th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

5287. the 5269th device, wherein said fibrous tissue form agent and exist with particulate form.

5288. the 5269th device, wherein said compositions also comprises inflammatory cytokine.

5289. the 5269th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

5290. the 5269th device, wherein said compositions exists with the form of gel, paste or spray.

5291. the 5269th device, wherein said fibrous tissue form the form that agent is bunch.

5292. the 5269th device also comprises polymer.

5293. the 5269th device also comprises polymer support.

5294. the 5269th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

5295. the 5269th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

5296. the 5269th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

5297. the 5269th device also comprises coating, wherein said coating is placed on the surface of described device.

5298. the 5269th device also comprises coating, wherein said coating directly contacts described device.

5299. the 5269th device also comprises coating, wherein said coating contacts described device indirectly.

5300. the 5269th device also comprises coating, wherein said coating layer portion ground covers described device.

5301. the 5269th device also comprises coating, wherein said coating fully covers described device.

5302. the 5269th device also comprises coating, wherein said coating is uniform coating.

5303. the 5269th device also comprises coating, wherein said coating is uneven coating.

5304. the 5269th device also comprises coating, wherein said coating is a discontinuous coating.

5305. the 5269th device also comprises coating, wherein said coating is to form the coating of pattern.

5306. the 5269th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

5307. the 5269th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

5308. the 5269th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

5309. the 5269th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

5310. the 5269th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

5311. the 5269th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

5312. the 5269th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

5313. the 5269th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

5314. the 5269th device also comprises coating, wherein said coating also contains polymer.

5315. the 5269th device also comprises first coating with first compositions and second coating with second compositions.

5316. the 5269th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

5317. the 5269th device also comprises polymer.

5318. the 5269th device also comprises polymer support.

5319. the 5269th device also comprises polymer support, wherein said polymer support comprises copolymer.

5320. the 5269th device also comprises polymer support, wherein said polymer support comprises block copolymer.

5321. the 5269th device also comprises polymer support, wherein said polymer support comprises random copolymer.

5322. the 5269th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

5323. the 5269th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

5324. the 5269th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

5325. the 5269th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

5326. the 5269th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

5327. the 5269th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

5328. the 5269th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

5329. the 5269th device also comprises polymer support, wherein said polymer support comprises elastomer.

5330. the 5269th device also comprises polymer support, wherein said polymer support comprises hydrogel.

5331. the 5269th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

5332. the 5269th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

5333. the 5269th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

5334. the 5269th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

5335. the 5269th device also comprises polymer support, wherein said polymer support comprises macromonomer.

5336. the 5269th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

5337. the 5269th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

5338. the 5269th device also comprises lubricant coating.

5339. the 5269th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

5340. the 5269th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

5341. the 5269th device also comprises second forms of pharmacologically active agents.

5342. the 5269th device also comprises antiinflammatory.

5343. the 5269th device also comprises the medicament that suppresses infection.

5344. the 5269th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

5345. the 5269th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

5346. the 5269th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

5347. the 5269th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

5348. the 5269th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

5349. the 5269th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

5350. the 5269th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

5351. the 5269th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

5352. the 5269th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

5353. the 5269th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

5354. the 5269th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

5355. the 5269th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

5356. the 5269th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

5357. the 5269th device also comprises antithrombotic agent.

5358. the 5269th device also comprises developing agent.

5359. the 5269th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

5360. the 5269th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

5361. the 5269th device also comprises developing agent, wherein said developing agent comprises MRI response material.

5362. the 5269th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

5363. the 5269th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

5364. the 5269th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

5365. the 5269th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

5366. the 5269th device also comprises the material that produces echo.

5367. the 5269th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

5368. the 5269th device, wherein said device is aseptic.

5369. the 5269th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

5370. the 5269th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

5371. the 5269th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

5372. the 5269th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

5373. the 5269th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

5374. the 5269th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

5375. the 5269th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

5376. the 5269th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

5377. the 5269th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

5378. the 5269th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

5379. the 5269th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

5380. the 5269th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

5381. the 5269th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

5382. the 5269th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

5383. the 5269th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

5384. the 5269th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

5385. the 5269th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

5386. the 5269th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

5387. the described fibrous tissue that the 5269th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

5388. the 5269th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5389. the 5269th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5390. the 5269th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5391. the 5269th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5392. the 5269th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5393. a medical apparatus that comprises prosthese anal sphincter and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

5394. the 5393rd device, wherein said fibrous tissue forms agent and promotes regeneration.

5395. forming agent, the 5393rd device, wherein said fibrous tissue promote blood vessel to take place.

5396. the 5393rd device, wherein said fibrous tissue form agent and promote the fibroblast migration.

5397. the 5393rd device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

5398. the 5393rd device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

5399. the 5393rd device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

5400. the 5393rd device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

5401. the 5393rd device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

5402. the 5393rd device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

5403. the 5393rd device, wherein said fibrous tissue formation agent is silk or comprises silk.

5404. the 5393rd device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

5405. the 5393rd device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

5406. the 5393rd device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

5407. the 5393rd device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

5408. the 5393rd device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

5409. the 5393rd device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

5410. the 5393rd device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

5411. the 5393rd device, wherein said fibrous tissue form agent and exist with particulate form.

5412. the 5393rd device, wherein said compositions also comprises inflammatory cytokine.

5413. the 5393rd device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

5414. the 5393rd device, wherein said compositions exists with the form of gel, paste or spray.

5415. the 5393rd device, wherein said fibrous tissue form the form that agent is bunch.

5416. the 5393rd device also comprises polymer.

5417. the 5393rd device also comprises polymer support.

5418. the 5393rd device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

5419. the 5393rd device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

5420. the 5393rd device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

5421. the 5393rd device also comprises coating, wherein said coating is placed on the surface of described device.

5422. the 5393rd device also comprises coating, wherein said coating directly contacts described device.

5423. the 5393rd device also comprises coating, wherein said coating contacts described device indirectly.

5424. the 5393rd device also comprises coating, wherein said coating layer portion ground covers described device.

5425. the 5393rd device also comprises coating, wherein said coating fully covers described device.

5426. the 5393rd device also comprises coating, wherein said coating is uniform coating.

5427. the 5393rd device also comprises coating, wherein said coating is uneven coating.

5428. the 5393rd device also comprises coating, wherein said coating is a discontinuous coating.

5429. the 5393rd device also comprises coating, wherein said coating is to form the coating of pattern.

5430. the 5393rd device also comprises coating, wherein said coating has 100 μ m or littler thickness.

5431. the 5393rd device also comprises coating, wherein said coating has 10 μ m or littler thickness.

5432. the 5393rd device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

5433. the 5393rd device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

5434. the 5393rd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

5435. the 5393rd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

5436. the 5393rd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

5437. the 5393rd device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

5438. the 5393rd device also comprises coating, wherein said coating also contains polymer.

5439. the 5393rd device also comprises first coating with first compositions and second coating with second compositions.

5440. the 5393rd device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

5441. the 5393rd device also comprises polymer.

5442. the 5393rd device also comprises polymer support.

5443. the 5393rd device also comprises polymer support, wherein said polymer support comprises copolymer.

5444. the 5393rd device also comprises polymer support, wherein said polymer support comprises block copolymer.

5445. the 5393rd device also comprises polymer support, wherein said polymer support comprises random copolymer.

5446. the 5393rd device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

5447. the 5393rd device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

5448. the 5393rd device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

5449. the 5393rd device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

5450. the 5393rd device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

5451. the 5393rd device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

5452. the 5393rd device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

5453. the 5393rd device also comprises polymer support, wherein said polymer support comprises elastomer.

5454. the 5393rd device also comprises polymer support, wherein said polymer support comprises hydrogel.

5455. the 5393rd device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

5456. the 5393rd device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

5457. the 5393rd device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

5458. the 5393rd device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

5459. the 5393rd device also comprises polymer support, wherein said polymer support comprises macromonomer.

5460. the 5393rd device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

5461. the 5393rd device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

5462. the 5393rd device also comprises lubricant coating.

5463. the 5393rd device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

5464. the 5393rd device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

5465. the 5393rd device also comprises second forms of pharmacologically active agents.

5466. the 5393rd device also comprises antiinflammatory.

5467. the 5393rd device also comprises the medicament that suppresses infection.

5468. the 5393rd device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

5469. the 5393rd device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

5470. the 5393rd device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

5471. the 5393rd device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

5472. the 5393rd device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

5473. the 5393rd device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

5474. the 5393rd device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

5475. the 5393rd device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

5476. the 5393rd device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

5477. the 5393rd device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

5478. the 5393rd device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

5479. the 5393rd device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

5480. the 5393rd device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

5481. the 5393rd device also comprises antithrombotic agent.

5482. the 5393rd device also comprises developing agent.

5483. the 5393rd device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

5484. the 5393rd device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

5485. the 5393rd device also comprises developing agent, wherein said developing agent comprises MRI response material.

5486. the 5393rd device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

5487. the 5393rd device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

5488. the 5393rd device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

5489. the 5393rd device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

5490. the 5393rd device also comprises the material that produces echo.

5491. the 5393rd device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

5492. the 5393rd device, wherein said device is aseptic.

5493. the 5393rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

5494. the 5393rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

5495. the 5393rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

5496. the 5393rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

5497. the 5393rd device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

5498. the 5393rd device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

5499. the 5393rd device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

5500. the 5393rd device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

5501. the 5393rd device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

5502. the 5393rd device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

5503. the 5393rd device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

5504. the 5393rd device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

5505. the 5393rd device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

5506. the 5393rd device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

5507. the 5393rd device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

5508. the 5393rd device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

5509. the 5393rd device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

5510. the 5393rd device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

5511. the described fibrous tissue that the 5393rd device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

5512. the 5393rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5513. the 5393rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5514. the 5393rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5515. the 5393rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5516. the 5393rd device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5517. a medical apparatus that comprises fallopian tube stent and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

5518. the 5517th device, wherein said fibrous tissue forms agent and promotes regeneration.

5519. forming agent, the 5517th device, wherein said fibrous tissue promote blood vessel to take place.

5520. the 5517th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

5521. the 5517th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

5522. the 5517th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

5523. the 5517th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

5524. the 5517th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

5525. the 5517th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

5526. the 5517th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

5527. the 5517th device, wherein said fibrous tissue formation agent is silk or comprises silk.

5528. the 5517th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

5529. the 5517th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

5530. the 5517th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

5531. the 5517th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

5532. the 5517th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

5533. the 5517th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

5534. the 5517th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

5535. the 5517th device, wherein said fibrous tissue form agent and exist with particulate form.

5536. the 5517th device, wherein said compositions also comprises inflammatory cytokine.

5537. the 5517th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

5538. the 5517th device, wherein said compositions exists with the form of gel, paste or spray.

5539. the 5517th device, wherein said fibrous tissue form the form that agent is bunch.

5540. the 5517th device also comprises polymer.

5541. the 5517th device also comprises polymer support.

5542. the 5517th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

5543. the 5517th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

5544. the 5517th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

5545. the 5517th device also comprises coating, wherein said coating is placed on the surface of described device.

5546. the 5517th device also comprises coating, wherein said coating directly contacts described device.

5547. the 5517th device also comprises coating, wherein said coating contacts described device indirectly.

5548. the 5517th device also comprises coating, wherein said coating layer portion ground covers described device.

5549. the 5517th device also comprises coating, wherein said coating fully covers described device.

5550. the 5517th device also comprises coating, wherein said coating is uniform coating.

5551. the 5517th device also comprises coating, wherein said coating is uneven coating.

5552. the 5517th device also comprises coating, wherein said coating is a discontinuous coating.

5553. the 5517th device also comprises coating, wherein said coating is to form the coating of pattern.

5554. the 5517th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

5555. the 5517th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

5556. the 5517th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

5557. the 5517th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

5558. the 5517th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

5559. the 5517th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

5560. the 5517th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

5561. the 5517th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

5562. the 5517th device also comprises coating, wherein said coating also contains polymer.

5563. the 5517th device also comprises first coating with first compositions and second coating with second compositions.

5564. the 5517th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

5565. the 5517th device also comprises polymer.

5566. the 5517th device also comprises polymer support.

5567. the 5517th device also comprises polymer support, wherein said polymer support comprises copolymer.

5568. the 5517th device also comprises polymer support, wherein said polymer support comprises block copolymer.

5569. the 5517th device also comprises polymer support, wherein said polymer support comprises random copolymer.

5570. the 5517th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

5571. the 5517th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

5572. the 5517th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

5573. the 5517th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

5574. the 5517th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

5575. the 5517th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

5576. the 5517th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

5577. the 5517th device also comprises polymer support, wherein said polymer support comprises elastomer.

5578. the 5517th device also comprises polymer support, wherein said polymer support comprises hydrogel.

5579. the 5517th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

5580. the 5517th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

5581. the 5517th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

5582. the 5517th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

5583. the 5517th device also comprises polymer support, wherein said polymer support comprises macromonomer.

5584. the 5517th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

5585. the 5517th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

5586. the 5517th device also comprises lubricant coating.

5587. the 5517th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

5588. the 5517th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

5589. the 5517th device also comprises second forms of pharmacologically active agents.

5590. the 5517th device also comprises antiinflammatory.

5591. the 5517th device also comprises the medicament that suppresses infection.

5592. the 5517th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

5593. the 5517th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

5594. the 5517th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

5595. the 5517th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

5596. the 5517th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

5597. the 5517th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

5598. the 5517th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

5599. the 5517th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

5600. the 5517th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

5601. the 5517th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

5602. the 5517th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

5603. the 5517th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

5604. the 5517th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

5605. the 5517th device also comprises antithrombotic agent.

5606. the 5517th device also comprises developing agent.

5607. the 5517th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

5608. the 5517th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

5609. the 5517th device also comprises developing agent, wherein said developing agent comprises MRI response material.

5610. the 5517th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

5611. the 5517th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

5612. the 5517th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

5613. the 5517th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

5614. the 5517th device also comprises the material that produces echo.

5615. the 5517th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

5616. the 5517th device, wherein said device is aseptic.

5617. the 5517th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

5618. the 5517th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

5619. the 5517th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

5620. the 5517th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

5621. the 5517th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

5622. the 5517th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

5623. the 5517th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

5624. the 5517th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

5625. the 5517th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

5626. the 5517th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

5627. the 5517th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

5628. the 5517th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

5629. the 5517th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

5630. the 5517th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

5631. the 5517th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

5632. the 5517th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

5633. the 5517th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

5634. the 5517th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

5635. the described fibrous tissue that the 5517th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

5636. the 5517th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5637. the 5517th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5638. the 5517th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5639. the 5517th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5640. the 5517th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5641. a medical apparatus that comprises deferent duct implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

5642. the 5641st device, wherein said fibrous tissue forms agent and promotes regeneration.

5643. forming agent, the 5641st device, wherein said fibrous tissue promote blood vessel to take place.

5644. the 5641st device, wherein said fibrous tissue form agent and promote the fibroblast migration.

5645. the 5641st device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

5646. the 5641st device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

5647. the 5641st device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

5648. the 5641st device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

5649. the 5641st device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

5650. the 5641st device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

5651. the 5641st device, wherein said fibrous tissue formation agent is silk or comprises silk.

5652. the 5641st device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

5653. the 5641st device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

5654. the 5641st device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

5655. the 5641st device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

5656. the 5641st device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

5657. the 5641st device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

5658. the 5641st device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

5659. the 5641st device, wherein said fibrous tissue form agent and exist with particulate form.

5660. the 5641st device, wherein said compositions also comprises inflammatory cytokine.

5661. the 5641st device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

5662. the 5641st device, wherein said compositions exists with the form of gel, paste or spray.

5663. the 5641st device, wherein said fibrous tissue form the form that agent is bunch.

5664. the 5641st device also comprises polymer.

5665. the 5641st device also comprises polymer support.

5666. the 5641st device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

5667. the 5641st device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

5668. the 5641st device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

5669. the 5641st device also comprises coating, wherein said coating is placed on the surface of described device.

5670. the 5641st device also comprises coating, wherein said coating directly contacts described device.

5671. the 5641st device also comprises coating, wherein said coating contacts described device indirectly.

5672. the 5641st device also comprises coating, wherein said coating layer portion ground covers described device.

5673. the 5641st device also comprises coating, wherein said coating fully covers described device.

5674. the 5641st device also comprises coating, wherein said coating is uniform coating.

5675. the 5641st device also comprises coating, wherein said coating is uneven coating.

5676. the 5641st device also comprises coating, wherein said coating is a discontinuous coating.

5677. the 5641st device also comprises coating, wherein said coating is to form the coating of pattern.

5678. the 5641st device also comprises coating, wherein said coating has 100 μ m or littler thickness.

5679. the 5641st device also comprises coating, wherein said coating has 10 μ m or littler thickness.

5680. the 5641st device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

5681. the 5641st device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

5682. the 5641st device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

5683. the 5641st device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

5684. the 5641st device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

5685. the 5641st device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

5686. the 5641st device also comprises coating, wherein said coating also contains polymer.

5687. the 5641st device also comprises first coating with first compositions and second coating with second compositions.

5688. the 5641st device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

5689. the 5641st device also comprises polymer.

5690. the 5641st device also comprises polymer support.

5691. the 5641st device also comprises polymer support, wherein said polymer support comprises copolymer.

5692. the 5641st device also comprises polymer support, wherein said polymer support comprises block copolymer.

5693. the 5641st device also comprises polymer support, wherein said polymer support comprises random copolymer.

5694. the 5641st device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

5695. the 5641st device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

5696. the 5641st device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

5697. the 5641st device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

5698. the 5641st device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

5699. the 5641st device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

5700. the 5641st device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

5701. the 5641st device also comprises polymer support, wherein said polymer support comprises elastomer.

5702. the 5641st device also comprises polymer support, wherein said polymer support comprises hydrogel.

5703. the 5641st device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

5704. the 5641st device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

5705. the 5641st device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

5706. the 5641st device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

5707. the 5641st device also comprises polymer support, wherein said polymer support comprises macromonomer.

5708. the 5641st device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

5709. the 5641st device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

5710. the 5641st device also comprises lubricant coating.

5711. the 5641st device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

5712. the 5641st device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

5713. the 5641st device also comprises second forms of pharmacologically active agents.

5714. the 5641st device also comprises antiinflammatory.

5715. the 5641st device also comprises the medicament that suppresses infection.

5716. the 5641st device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

5717. the 5641st device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

5718. the 5641st device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

5719. the 5641st device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

5720. the 5641st device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

5721. the 5641st device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

5722. the 5641st device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

5723. the 5641st device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

5724. the 5641st device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

5725. the 5641st device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

5726. the 5641st device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

5727. the 5641st device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

5728. the 5641st device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

5729. the 5641st device also comprises antithrombotic agent.

5730. the 5641st device also comprises developing agent.

5731. the 5641st device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

5732. the 5641st device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

5733. the 5641st device also comprises developing agent, wherein said developing agent comprises MRI response material.

5734. the 5641st device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

5735. the 5641st device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

5736. the 5641st device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

5737. the 5641st device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

5738. the 5641st device also comprises the material that produces echo.

5739. the 5641st device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

5740. the 5641st device, wherein said device is aseptic.

5741. the 5641st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

5742. the 5641st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

5743. the 5641st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

5744. the 5641st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

5745. the 5641st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

5746. the 5641st device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

5747. the 5641st device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

5748. the 5641st device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

5749. the 5641st device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

5750. the 5641st device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

5751. the 5641st device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

5752. the 5641st device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

5753. the 5641st device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

5754. the 5641st device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

5755. the 5641st device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

5756. the 5641st device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

5757. the 5641st device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

5758. the 5641st device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

5759. the described fibrous tissue that the 5641st device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

5760. the 5641st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5761. the 5641st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5762. the 5641st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5763. the 5641st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5764. the 5641st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5765. the 5641st device, wherein said deferent duct implant is injectable.

5766. the 5641st device, wherein said deferent duct implant is the vasectomy suture.

5767. the 5641st device, wherein said deferent duct implant are vasectomy folders (clip).

5768. a medical apparatus that comprises gastric restriction (gastric restriction) implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

5769. the 5768th device, wherein said fibrous tissue forms agent and promotes regeneration.

5770. forming agent, the 5768th device, wherein said fibrous tissue promote blood vessel to take place.

5771. the 5768th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

5772. the 5768th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

5773. the 5768th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

5774. the 5768th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

5775. the 5768th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

5776. the 5768th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

5777. the 5768th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

5778. the 5768th device, wherein said fibrous tissue formation agent is silk or comprises silk.

5779. the 5768th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

5780. the 5768th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

5781. the 5768th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

5782. the 5768th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

5783. the 5768th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

5784. the 5768th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

5785. the 5768th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

5786. the 5768th device, wherein said fibrous tissue form agent and exist with particulate form.

5787. the 5768th device, wherein said compositions also comprises inflammatory cytokine.

5788. the 5768th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

5789. the 5768th device, wherein said compositions exists with the form of gel, paste or spray.

5790. the 5768th device, wherein said fibrous tissue form the form that agent is bunch.

5791. the 5768th device also comprises polymer.

5792. the 5768th device also comprises polymer support.

5793. the 5768th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

5794. the 5768th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

5795. the 5768th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

5796. the 5768th device also comprises coating, wherein said coating is placed on the surface of described device.

5797. the 5768th device also comprises coating, wherein said coating directly contacts described device.

5798. the 5768th device also comprises coating, wherein said coating contacts described device indirectly.

5799. the 5768th device also comprises coating, wherein said coating layer portion ground covers described device.

5800. the 5768th device also comprises coating, wherein said coating fully covers described device.

5801. the 5768th device also comprises coating, wherein said coating is uniform coating.

5802. the 5768th device also comprises coating, wherein said coating is uneven coating.

5803. the 5768th device also comprises coating, wherein said coating is a discontinuous coating.

5804. the 5768th device also comprises coating, wherein said coating is to form the coating of pattern.

5805. the 5768th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

5806. the 5768th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

5807. the 5768th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

5808. the 5768th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

5809. the 5768th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

5810. the 5768th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

5811. the 5768th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

5812. the 5768th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

5813. the 5768th device also comprises coating, wherein said coating also contains polymer.

5814. the 5768th device also comprises first coating with first compositions and second coating with second compositions.

5815. the 5768th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

5816. the 5768th device also comprises polymer.

5817. the 5768th device also comprises polymer support.

5818. the 5768th device also comprises polymer support, wherein said polymer support comprises copolymer.

5819. the 5768th device also comprises polymer support, wherein said polymer support comprises block copolymer.

5820. the 5768th device also comprises polymer support, wherein said polymer support comprises random copolymer.

5821. the 5768th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

5822. the 5768th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

5823. the 5768th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

5824. the 5768th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

5825. the 5768th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

5826. the 5768th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

5827. the 5768th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

5828. the 5768th device also comprises polymer support, wherein said polymer support comprises elastomer.

5829. the 5768th device also comprises polymer support, wherein said polymer support comprises hydrogel.

5830. the 5768th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

5831. the 5768th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

5832. the 5768th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

5833. the 5768th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

5834. the 5768th device also comprises polymer support, wherein said polymer support comprises macromonomer.

5835. the 5768th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

5836. the 5768th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

5837. the 5768th device also comprises lubricant coating.

5838. the 5768th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

5839. the 5768th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

5840. the 5768th device also comprises second forms of pharmacologically active agents.

5841. the 5768th device also comprises antiinflammatory.

5842. the 5768th device also comprises the medicament that suppresses infection.

5843. the 5768th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

5844. the 5768th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

5845. the 5768th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

5846. the 5768th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

5847. the 5768th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

5848. the 5768th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

5849. the 5768th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

5850. the 5768th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

5851. the 5768th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

5852. the 5768th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

5853. the 5768th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

5854. the 5768th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

5855. the 5768th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

5856. the 5768th device also comprises antithrombotic agent.

5857. the 5768th device also comprises developing agent.

5858. the 5768th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

5859. the 5768th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

5860. the 5768th device also comprises developing agent, wherein said developing agent comprises MRI response material.

5861. the 5768th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

5862. the 5768th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

5863. the 5768th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

5864. the 5768th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

5865. the 5768th device also comprises the material that produces echo.

5866. the 5768th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

5867. the 5768th device, wherein said device is aseptic.

5868. the 5768th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

5869. the 5768th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

5870. the 5768th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

5871. the 5768th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

5872. the 5768th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

5873. the 5768th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

5874. the 5768th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

5875. the 5768th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

5876. the 5768th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

5877. the 5768th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

5878. the 5768th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

5879. the 5768th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

5880. the 5768th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

5881. the 5768th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

5882. the 5768th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

5883. the 5768th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

5884. the 5768th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

5885. the 5768th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

5886. the described fibrous tissue that the 5768th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

5887. the 5768th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5888. the 5768th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5889. the 5768th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5890. the 5768th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5891. the 5768th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

5892. the 5768th device, wherein said gastric restriction implant is expandable cover.

5893. the 5768th device, wherein said gastric restriction implant is the occupancy device.

5894. one kind comprises the medical apparatus that intracavity implant and the fibrous tissue based on suture of separating stomach forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

5895. the 5894th device, wherein said fibrous tissue forms agent and promotes regeneration.

5896. forming agent, the 5894th device, wherein said fibrous tissue promote blood vessel to take place.

5897. the 5894th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

5898. the 5894th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

5899. the 5894th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

5900. the 5894th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

5901. the 5894th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

5902. the 5894th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

5903. the 5894th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

5904. the 5894th device, wherein said fibrous tissue formation agent is silk or comprises silk.

5905. the 5894th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

5906. the 5894th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

5907. the 5894th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

5908. the 5894th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

5909. the 5894th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

5910. the 5894th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

5911. the 5894th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

5912. the 5894th device, wherein said fibrous tissue form agent and exist with particulate form.

5913. the 5894th device, wherein said compositions also comprises inflammatory cytokine.

5914. the 5894th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

5915. the 5894th device, wherein said compositions exists with the form of gel, paste or spray.

5916. the 5894th device, wherein said fibrous tissue form the form that agent is bunch.

5917. the 5894th device also comprises polymer.

5918. the 5894th device also comprises polymer support.

5919. the 5894th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

5920. the 5894th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

5921. the 5894th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

5922. the 5894th device also comprises coating, wherein said coating is placed on the surface of described device.

5923. the 5894th device also comprises coating, wherein said coating directly contacts described device.

5924. the 5894th device also comprises coating, wherein said coating contacts described device indirectly.

5925. the 5894th device also comprises coating, wherein said coating layer portion ground covers described device.

5926. the 5894th device also comprises coating, wherein said coating fully covers described device.

5927. the 5894th device also comprises coating, wherein said coating is uniform coating.

5928. the 5894th device also comprises coating, wherein said coating is uneven coating.

5929. the 5894th device also comprises coating, wherein said coating is a discontinuous coating.

5930. the 5894th device also comprises coating, wherein said coating is to form the coating of pattern.

5931. the 5894th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

5932. the 5894th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

5933. the 5894th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

5934. the 5894th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

5935. the 5894th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

5936. the 5894th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

5937. the 5894th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

5938. the 5894th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

5939. the 5894th device also comprises coating, wherein said coating also contains polymer.

5940. the 5894th device also comprises first coating with first compositions and second coating with second compositions.

5941. the 5894th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

5942. the 5894th device also comprises polymer.

5943. the 5894th device also comprises polymer support.

5944. the 5894th device also comprises polymer support, wherein said polymer support comprises copolymer.

5945. the 5894th device also comprises polymer support, wherein said polymer support comprises block copolymer.

5946. the 5894th device also comprises polymer support, wherein said polymer support comprises random copolymer.

5947. the 5894th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

5948. the 5894th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

5949. the 5894th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

5950. the 5894th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

5951. the 5894th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

5952. the 5894th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

5953. the 5894th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

5954. the 5894th device also comprises polymer support, wherein said polymer support comprises elastomer.

5955. the 5894th device also comprises polymer support, wherein said polymer support comprises hydrogel.

5956. the 5894th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

5957. the 5894th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

5958. the 5894th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

5959. the 5894th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

5960. the 5894th device also comprises polymer support, wherein said polymer support comprises macromonomer.

5961. the 5894th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

5962. the 5894th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

5963. the 5894th device also comprises lubricant coating.

5964. the 5894th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

5965. the 5894th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

5966. the 5894th device also comprises second forms of pharmacologically active agents.

5967. the 5894th device also comprises antiinflammatory.

5968. the 5894th device also comprises the medicament that suppresses infection.

5969. the 5894th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

5970. the 5894th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

5971. the 5894th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

5972. the 5894th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

5973. the 5894th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

5974. the 5894th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

5975. the 5894th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

5976. the 5894th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

5977. the 5894th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

5978. the 5894th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

5979. the 5894th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

5980. the 5894th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

5981. the 5894th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

5982. the 5894th device also comprises antithrombotic agent.

5983. the 5894th device also comprises developing agent.

5984. the 5894th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

5985. the 5894th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

5986. the 5894th device also comprises developing agent, wherein said developing agent comprises MRI response material.

5987. the 5894th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

5988. the 5894th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

5989. the 5894th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

5990. the 5894th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

5991. the 5894th device also comprises the material that produces echo.

5992. the 5894th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

5993. the 5894th device, wherein said device is aseptic.

5994. the 5894th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

5995. the 5894th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

5996. the 5894th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

5997. the 5894th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

5998. the 5894th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

5999. the 5894th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

6000. the 5894th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

6001. the 5894th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

6002. the 5894th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

6003. the 5894th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

6004. the 5894th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

6005. the 5894th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

6006. the 5894th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

6007. the 5894th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

6008. the 5894th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

6009. the 5894th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

6010. the 5894th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

6011. the 5894th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

6012. the described fibrous tissue that the 5894th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

6013. the 5894th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6014. the 5894th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6015. the 5894th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6016. the 5894th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6017. the 5894th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6018. a medical apparatus that comprises electricity irritation implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

6019. the 6018th device, wherein said fibrous tissue forms agent and promotes regeneration.

6020. forming agent, the 6018th device, wherein said fibrous tissue promote blood vessel to take place.

6021. the 6018th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

6022. the 6018th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

6023. the 6018th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

6024. the 6018th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

6025. the 6018th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

6026. the 6018th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

6027. the 6018th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

6028. the 6018th device, wherein said fibrous tissue formation agent is silk or comprises silk.

6029. the 6018th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

6030. the 6018th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

6031. the 6018th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

6032. the 6018th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

6033. the 6018th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

6034. the 6018th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

6035. the 6018th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

6036. the 6018th device, wherein said fibrous tissue form agent and exist with particulate form.

6037. the 6018th device, wherein said compositions also comprises inflammatory cytokine.

6038. the 6018th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

6039. the 6018th device, wherein said compositions exists with the form of gel, paste or spray.

6040. the 6018th device, wherein said fibrous tissue form the form that agent is bunch.

6041. the 6018th device also comprises polymer.

6042. the 6018th device also comprises polymer support.

6043. the 6018th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

6044. the 6018th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

6045. the 6018th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

6046. the 6018th device also comprises coating, wherein said coating is placed on the surface of described device.

6047. the 6018th device also comprises coating, wherein said coating directly contacts described device.

6048. the 6018th device also comprises coating, wherein said coating contacts described device indirectly.

6049. the 6018th device also comprises coating, wherein said coating layer portion ground covers described device.

6050. the 6018th device also comprises coating, wherein said coating fully covers described device.

6051. the 6018th device also comprises coating, wherein said coating is uniform coating.

6052. the 6018th device also comprises coating, wherein said coating is uneven coating.

6053. the 6018th device also comprises coating, wherein said coating is a discontinuous coating.

6054. the 6018th device also comprises coating, wherein said coating is to form the coating of pattern.

6055. the 6018th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

6056. the 6018th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

6057. the 6018th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

6058. the 6018th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

6059. the 6018th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

6060. the 6018th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

6061. the 6018th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

6062. the 6018th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

6063. the 6018th device also comprises coating, wherein said coating also contains polymer.

6064. the 6018th device also comprises first coating with first compositions and second coating with second compositions.

6065. the 6018th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

6066. the 6018th device also comprises polymer.

6067. the 6018th device also comprises polymer support.

6068. the 6018th device also comprises polymer support, wherein said polymer support comprises copolymer.

6069. the 6018th device also comprises polymer support, wherein said polymer support comprises block copolymer.

6070. the 6018th device also comprises polymer support, wherein said polymer support comprises random copolymer.

6071. the 6018th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

6072. the 6018th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

6073. the 6018th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

6074. the 6018th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

6075. the 6018th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

6076. the 6018th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

6077. the 6018th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

6078. the 6018th device also comprises polymer support, wherein said polymer support comprises elastomer.

6079. the 6018th device also comprises polymer support, wherein said polymer support comprises hydrogel.

6080. the 6018th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

6081. the 6018th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

6082. the 6018th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

6083. the 6018th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

6084. the 6018th device also comprises polymer support, wherein said polymer support comprises macromonomer.

6085. the 6018th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

6086. the 6018th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

6087. the 6018th device also comprises lubricant coating.

6088. the 6018th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

6089. the 6018th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

6090. the 6018th device also comprises second forms of pharmacologically active agents.

6091. the 6018th device also comprises antiinflammatory.

6092. the 6018th device also comprises the medicament that suppresses infection.

6093. the 6018th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

6094. the 6018th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

6095. the 6018th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

6096. the 6018th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

6097. the 6018th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

6098. the 6018th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

6099. the 6018th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

6100. the 6018th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

6101. the 6018th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

6102. the 6018th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

6103. the 6018th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

6104. the 6018th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

6105. the 6018th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

6106. the 6018th device also comprises antithrombotic agent.

6107. the 6018th device also comprises developing agent.

6108. the 6018th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

6109. the 6018th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

6110. the 6018th device also comprises developing agent, wherein said developing agent comprises MRI response material.

6111. the 6018th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

6112. the 6018th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

6113. the 6018th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

6114. the 6018th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

6115. the 6018th device also comprises the material that produces echo.

6116. the 6018th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

6117. the 6018th device, wherein said device is aseptic.

6118. the 6018th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

6119. the 6018th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

6120. the 6018th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

6121. the 6018th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

6122. the 6018th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

6123. the 6018th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

6124. the 6018th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

6125. the 6018th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

6126. the 6018th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

6127. the 6018th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

6128. the 6018th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

6129. the 6018th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

6130. the 6018th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

6131. the 6018th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

6132. the 6018th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

6133. the 6018th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

6134. the 6018th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

6135. the 6018th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

6136. the described fibrous tissue that the 6018th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

6137. the 6018th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6138. the 6018th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6139. the 6018th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6140. the 6018th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6141. the 6018th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6142. the 6018th device, wherein said electricity irritation implant is the nerve electric stimulation implant.

6143. the 6018th device, wherein said electricity irritation implant are non-nerve electric stimulation implants.

6144. a medical apparatus that comprises soft palate implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

6145. the 6144th device, wherein said fibrous tissue forms agent and promotes regeneration.

6146. forming agent, the 6144th device, wherein said fibrous tissue promote blood vessel to take place.

6147. the 6144th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

6148. the 6144th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

6149. the 6144th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

6150. the 6144th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

6151. the 6144th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

6152. the 6144th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

6153. the 6144th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

6154. the 6144th device, wherein said fibrous tissue formation agent is silk or comprises silk.

6155. the 6144th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

6156. the 6144th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

6157. the 6144th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

6158. the 6144th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

6159. the 6144th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

6160. the 6144th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

6161. the 6144th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

6162. the 6144th device, wherein said fibrous tissue form agent and exist with particulate form.

6163. the 6144th device, wherein said compositions also comprises inflammatory cytokine.

6164. the 6144th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

6165. the 6144th device, wherein said compositions exists with the form of gel, paste or spray.

6166. the 6144th device, wherein said fibrous tissue form the form that agent is bunch.

6167. the 6144th device also comprises polymer.

6168. the 6144th device also comprises polymer support.

6169. the 6144th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

6170. the 6144th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

6171. the 6144th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

6172. the 6144th device also comprises coating, wherein said coating is placed on the surface of described device.

6173. the 6144th device also comprises coating, wherein said coating directly contacts described device.

6174. the 6144th device also comprises coating, wherein said coating contacts described device indirectly.

6175. the 6144th device also comprises coating, wherein said coating layer portion ground covers described device.

6176. the 6144th device also comprises coating, wherein said coating fully covers described device.

6177. the 6144th device also comprises coating, wherein said coating is uniform coating.

6178. the 6144th device also comprises coating, wherein said coating is uneven coating.

6179. the 6144th device also comprises coating, wherein said coating is a discontinuous coating.

6180. the 6144th device also comprises coating, wherein said coating is to form the coating of pattern.

6181. the 6144th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

6182. the 6144th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

6183. the 6144th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

6184. the 6144th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

6185. the 6144th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

6186. the 6144th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

6187. the 6144th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

6188. the 6144th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

6189. the 6144th device also comprises coating, wherein said coating also contains polymer.

6190. the 6144th device also comprises first coating with first compositions and second coating with second compositions.

6191. the 6144th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

6192. the 6144th device also comprises polymer.

6193. the 6144th device also comprises polymer support.

6194. the 6144th device also comprises polymer support, wherein said polymer support comprises copolymer.

6195. the 6144th device also comprises polymer support, wherein said polymer support comprises block copolymer.

6196. the 6144th device also comprises polymer support, wherein said polymer support comprises random copolymer.

6197. the 6144th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

6198. the 6144th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

6199. the 6144th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

6200. the 6144th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

6201. the 6144th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

6202. the 6144th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

6203. the 6144th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

6204. the 6144th device also comprises polymer support, wherein said polymer support comprises elastomer.

6205. the 6144th device also comprises polymer support, wherein said polymer support comprises hydrogel.

6206. the 6144th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

6207. the 6144th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

6208. the 6144th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

6209. the 6144th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

6210. the 6144th device also comprises polymer support, wherein said polymer support comprises macromonomer.

6211. the 6144th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

6212. the 6144th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

6213. the 6144th device also comprises lubricant coating.

6214. the 6144th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

6215. the 6144th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

6216. the 6144th device also comprises second forms of pharmacologically active agents.

6217. the 6144th device also comprises antiinflammatory.

6218. the 6144th device also comprises the medicament that suppresses infection.

6219. the 6144th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

6220. the 6144th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

6221. the 6144th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

6222. the 6144th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

6223. the 6144th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

6224. the 6144th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

6225. the 6144th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

6226. the 6144th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

6227. the 6144th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

6228. the 6144th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

6229. the 6144th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

6230. the 6144th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

6231. the 6144th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

6232. the 6144th device also comprises antithrombotic agent.

6233. the 6144th device also comprises developing agent.

6234. the 6144th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

6235. the 6144th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

6236. the 6144th device also comprises developing agent, wherein said developing agent comprises MRI response material.

6237. the 6144th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

6238. the 6144th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

6239. the 6144th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

6240. the 6144th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

6241. the 6144th device also comprises the material that produces echo.

6242. the 6144th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

6243. the 6144th device, wherein said device is aseptic.

6244. the 6144th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

6245. the 6144th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

6246. the 6144th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

6247. the 6144th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

6248. the 6144th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

6249. the 6144th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

6250. the 6144th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

6251. the 6144th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

6252. the 6144th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

6253. the 6144th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

6254. the 6144th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

6255. the 6144th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

6256. the 6144th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

6257. the 6144th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

6258. the 6144th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

6259. the 6144th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

6260. the 6144th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

6261. the 6144th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

6262. the described fibrous tissue that the 6144th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

6263. the 6144th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6264. the 6144th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6265. the 6144th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6266. the 6144th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6267. the 6144th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6268. the 6144th device, wherein said soft palate implant is injectable.

6269. a medical apparatus that comprises blood vessel coil (vascular coil) implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

6270. the 6269th device, wherein said fibrous tissue forms agent and promotes regeneration.

6271. forming agent, the 6269th device, wherein said fibrous tissue promote blood vessel to take place.

6272. the 6269th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

6273. the 6269th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

6274. the 6269th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

6275. the 6269th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

6276. the 6269th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

6277. the 6269th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

6278. the 6269th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

6279. the 6269th device, wherein said fibrous tissue formation agent is silk or comprises silk.

6280. the 6269th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

6281. the 6269th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

6282. the 6269th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

6283. the 6269th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

6284. the 6269th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

6285. the 6269th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

6286. the 6269th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

6287. the 6269th device, wherein said fibrous tissue form agent and exist with particulate form.

6288. the 6269th device, wherein said compositions also comprises inflammatory cytokine.

6289. the 6269th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

6290. the 6269th device, wherein said compositions exists with the form of gel, paste or spray.

6291. the 6269th device, wherein said fibrous tissue form the form that agent is bunch.

6292. the 6269th device also comprises polymer.

6293. the 6269th device also comprises polymer support.

6294. the 6269th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

6295. the 6269th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

6296. the 6269th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

6297. the 6269th device also comprises coating, wherein said coating is placed on the surface of described device.

6298. the 6269th device also comprises coating, wherein said coating directly contacts described device.

6299. the 6269th device also comprises coating, wherein said coating contacts described device indirectly.

6300. the 6269th device also comprises coating, wherein said coating layer portion ground covers described device.

6301. the 6269th device also comprises coating, wherein said coating fully covers described device.

6302. the 6269th device also comprises coating, wherein said coating is uniform coating.

6303. the 6269th device also comprises coating, wherein said coating is uneven coating.

6304. the 6269th device also comprises coating, wherein said coating is a discontinuous coating.

6305. the 6269th device also comprises coating, wherein said coating is to form the coating of pattern.

6306. the 6269th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

6307. the 6269th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

6308. the 6269th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

6309. the 6269th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

6310. the 6269th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

6311. the 6269th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

6312. the 6269th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

6313. the 6269th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

6314. the 6269th device also comprises coating, wherein said coating also contains polymer.

6315. the 6269th device also comprises first coating with first compositions and second coating with second compositions.

6316. the 6269th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

6317. the 6269th device also comprises polymer.

6318. the 6269th device also comprises polymer support.

6319. the 6269th device also comprises polymer support, wherein said polymer support comprises copolymer.

6320. the 6269th device also comprises polymer support, wherein said polymer support comprises block copolymer.

6321. the 6269th device also comprises polymer support, wherein said polymer support comprises random copolymer.

6322. the 6269th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

6323. the 6269th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

6324. the 6269th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

6325. the 6269th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

6326. the 6269th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

6327. the 6269th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

6328. the 6269th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

6329. the 6269th device also comprises polymer support, wherein said polymer support comprises elastomer.

6330. the 6269th device also comprises polymer support, wherein said polymer support comprises hydrogel.

6331. the 6269th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

6332. the 6269th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

6333. the 6269th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

6334. the 6269th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

6335. the 6269th device also comprises polymer support, wherein said polymer support comprises macromonomer.

6336. the 6269th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

6337. the 6269th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

6338. the 6269th device also comprises lubricant coating.

6339. the 6269th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

6340. the 6269th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

6341. the 6269th device also comprises second forms of pharmacologically active agents.

6342. the 6269th device also comprises antiinflammatory.

6343. the 6269th device also comprises the medicament that suppresses infection.

6344. the 6269th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

6345. the 6269th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

6346. the 6269th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

6347. the 6269th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

6348. the 6269th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

6349. the 6269th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

6350. the 6269th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

6351. the 6269th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

6352. the 6269th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

6353. the 6269th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

6354. the 6269th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

6355. the 6269th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

6356. the 6269th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

6357. the 6269th device also comprises antithrombotic agent.

6358. the 6269th device also comprises developing agent.

6359. the 6269th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

6360. the 6269th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

6361. the 6269th device also comprises developing agent, wherein said developing agent comprises MRI response material.

6362. the 6269th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

6363. the 6269th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

6364. the 6269th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

6365. the 6269th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

6366. the 6269th device also comprises the material that produces echo.

6367. the 6269th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

6368. the 6269th device, wherein said device is aseptic.

6369. the 6269th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

6370. the 6269th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

6371. the 6269th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

6372. the 6269th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

6373. the 6269th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

6374. the 6269th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

6375. the 6269th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

6376. the 6269th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

6377. the 6269th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

6378. the 6269th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

6379. the 6269th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

6380. the 6269th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

6381. the 6269th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

6382. the 6269th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

6383. the 6269th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

6384. the 6269th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

6385. the 6269th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

6386. the 6269th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

6387. the described fibrous tissue that the 6269th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

6388. the 6269th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6389. the 6269th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6390. the 6269th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6391. the 6269th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6392. the 6269th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6393. the 6269th device, wherein said vascular coil implant is made up of porous flexible PTFE material.

6394. the 6269th device, wherein said vascular coil implant is made up of biological active component.

6395. the 6269th device, wherein said vascular coil implant is an any biological inert.

6396. the 6269th device, wherein said vascular coil implant have second state (secondary stage) after first state (primary stage) and the insertion before insertion.

6397. a medical apparatus that comprises vascular occlusion coil implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

6398. the 6397th device, wherein said fibrous tissue forms agent and promotes regeneration.

6399. forming agent, the 6397th device, wherein said fibrous tissue promote blood vessel to take place.

6400. the 6397th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

6401. the 6397th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

6402. the 6397th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

6403. the 6397th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

6404. the 6397th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

6405. the 6397th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

6406. the 6397th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

6407. the 6397th device, wherein said fibrous tissue formation agent is silk or comprises silk.

6408. the 6397th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

6409. the 6397th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

6410. the 6397th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

6411. the 6397th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

6412. the 6397th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

6413. the 6397th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

6414. the 6397th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

6415. the 6397th device, wherein said fibrous tissue form agent and exist with particulate form.

6416. the 6397th device, wherein said compositions also comprises inflammatory cytokine.

6417. the 6397th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

6418. the 6397th device, wherein said compositions exists with the form of gel, paste or spray.

6419. the 6397th device, wherein said fibrous tissue form the form that agent is bunch.

6420. the 6397th device also comprises polymer.

6421. the 6397th device also comprises polymer support.

6422. the 6397th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

6423. the 6397th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

6424. the 6397th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

6425. the 6397th device also comprises coating, wherein said coating is placed on the surface of described device.

6426. the 6397th device also comprises coating, wherein said coating directly contacts described device.

6427. the 6397th device also comprises coating, wherein said coating contacts described device indirectly.

6428. the 6397th device also comprises coating, wherein said coating layer portion ground covers described device.

6429. the 6397th device also comprises coating, wherein said coating fully covers described device.

6430. the 6397th device also comprises coating, wherein said coating is uniform coating.

6431. the 6397th device also comprises coating, wherein said coating is uneven coating.

6432. the 6397th device also comprises coating, wherein said coating is a discontinuous coating.

6433. the 6397th device also comprises coating, wherein said coating is to form the coating of pattern.

6434. the 6397th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

6435. the 6397th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

6436. the 6397th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

6437. the 6397th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

6438. the 6397th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

6439. the 6397th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

6440. the 6397th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

6441. the 6397th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

6442. the 6397th device also comprises coating, wherein said coating also contains polymer.

6443. the 6397th device also comprises first coating with first compositions and second coating with second compositions.

6444. the 6397th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

6445. the 6397th device also comprises polymer.

6446. the 6397th device also comprises polymer support.

6447. the 6397th device also comprises polymer support, wherein said polymer support comprises copolymer.

6448. the 6397th device also comprises polymer support, wherein said polymer support comprises block copolymer.

6449. the 6397th device also comprises polymer support, wherein said polymer support comprises random copolymer.

6450. the 6397th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

6451. the 6397th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

6452. the 6397th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

6453. the 6397th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

6454. the 6397th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

6455. the 6397th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

6456. the 6397th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

6457. the 6397th device also comprises polymer support, wherein said polymer support comprises elastomer.

6458. the 6397th device also comprises polymer support, wherein said polymer support comprises hydrogel.

6459. the 6397th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

6460. the 6397th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

6461. the 6397th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

6462. the 6397th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

6463. the 6397th device also comprises polymer support, wherein said polymer support comprises macromonomer.

6464. the 6397th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

6465. the 6397th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

6466. the 6397th device also comprises lubricant coating.

6467. the 6397th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

6468. the 6397th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

6469. the 6397th device also comprises second forms of pharmacologically active agents.

6470. the 6397th device also comprises antiinflammatory.

6471. the 6397th device also comprises the medicament that suppresses infection.

6472. the 6397th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

6473. the 6397th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

6474. the 6397th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

6475. the 6397th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

6476. the 6397th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

6477. the 6397th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

6478. the 6397th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

6479. the 6397th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

6480. the 6397th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

6481. the 6397th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

6482. the 6397th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

6483. the 6397th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

6484. the 6397th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

6485. the 6397th device also comprises antithrombotic agent.

6486. the 6397th device also comprises developing agent.

6487. the 6397th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

6488. the 6397th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

6489. the 6397th device also comprises developing agent, wherein said developing agent comprises MRI response material.

6490. the 6397th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

6491. the 6397th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

6492. the 6397th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

6493. the 6397th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

6494. the 6397th device also comprises the material that produces echo.

6495. the 6397th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

6496. the 6397th device, wherein said device is aseptic.

6497. the 6397th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

6498. the 6397th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

6499. the 6397th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

6500. the 6397th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

6501. the 6397th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

6502. the 6397th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

6503. the 6397th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

6504. the 6397th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

6505. the 6397th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

6506. the 6397th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

6507. the 6397th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

6508. the 6397th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

6509. the 6397th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

6510. the 6397th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

6511. the 6397th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

6512. the 6397th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

6513. the 6397th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

6514. the 6397th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

6515. the described fibrous tissue that the 6397th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

6516. the 6397th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6517. the 6397th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6518. the 6397th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6519. the 6397th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6520. the 6397th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6521. a medical apparatus that comprises vascular occlusion implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

6522. the 6521st device, wherein said fibrous tissue forms agent and promotes regeneration.

6523. forming agent, the 6521st device, wherein said fibrous tissue promote blood vessel to take place.

6524. the 6521st device, wherein said fibrous tissue form agent and promote the fibroblast migration.

6525. the 6521st device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

6526. the 6521st device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

6527. the 6521st device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

6528. the 6521st device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

6529. the 6521st device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

6530. the 6521st device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

6531. the 6521st device, wherein said fibrous tissue formation agent is silk or comprises silk.

6532. the 6521st device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

6533. the 6521st device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

6534. the 6521st device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

6535. the 6521st device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

6536. the 6521st device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

6537. the 6521st device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

6538. the 6521st device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

6539. the 6521st device, wherein said fibrous tissue form agent and exist with particulate form.

6540. the 6521st device, wherein said compositions also comprises inflammatory cytokine.

6541. the 6521st device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

6542. the 6521st device, wherein said compositions exists with the form of gel, paste or spray.

6543. the 6521st device, wherein said fibrous tissue form the form that agent is bunch.

6544. the 6521st device also comprises polymer.

6545. the 6521st device also comprises polymer support.

6546. the 6521st device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

6547. the 6521st device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

6548. the 6521st device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

6549. the 6521st device also comprises coating, wherein said coating is placed on the surface of described device.

6550. the 6521st device also comprises coating, wherein said coating directly contacts described device.

6551. the 6521st device also comprises coating, wherein said coating contacts described device indirectly.

6552. the 6521st device also comprises coating, wherein said coating layer portion ground covers described device.

6553. the 6521st device also comprises coating, wherein said coating fully covers described device.

6554. the 6521st device also comprises coating, wherein said coating is uniform coating.

6555. the 6521st device also comprises coating, wherein said coating is uneven coating.

6556. the 6521st device also comprises coating, wherein said coating is a discontinuous coating.

6557. the 6521st device also comprises coating, wherein said coating is to form the coating of pattern.

6558. the 6521st device also comprises coating, wherein said coating has 100 μ m or littler thickness.

6559. the 6521st device also comprises coating, wherein said coating has 10 μ m or littler thickness.

6560. the 6521st device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

6561. the 6521st device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

6562. the 6521st device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

6563. the 6521st device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

6564. the 6521st device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

6565. the 6521st device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

6566. the 6521st device also comprises coating, wherein said coating also contains polymer.

6567. the 6521st device also comprises first coating with first compositions and second coating with second compositions.

6568. the 6521st device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

6569. the 6521st device also comprises polymer.

6570. the 6521st device also comprises polymer support.

6571. the 6521st device also comprises polymer support, wherein said polymer support comprises copolymer.

6572. the 6521st device also comprises polymer support, wherein said polymer support comprises block copolymer.

6573. the 6521st device also comprises polymer support, wherein said polymer support comprises random copolymer.

6574. the 6521st device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

6575. the 6521st device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

6576. the 6521st device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

6577. the 6521st device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

6578. the 6521st device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

6579. the 6521st device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

6580. the 6521st device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

6581. the 6521st device also comprises polymer support, wherein said polymer support comprises elastomer.

6582. the 6521st device also comprises polymer support, wherein said polymer support comprises hydrogel.

6583. the 6521st device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

6584. the 6521st device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

6585. the 6521st device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

6586. the 6521st device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

6587. the 6521st device also comprises polymer support, wherein said polymer support comprises macromonomer.

6588. the 6521st device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

6589. the 6521st device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

6590. the 6521st device also comprises lubricant coating.

6591. the 6521st device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

6592. the 6521st device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

6593. the 6521st device also comprises second forms of pharmacologically active agents.

6594. the 6521st device also comprises antiinflammatory.

6595. the 6521st device also comprises the medicament that suppresses infection.

6596. the 6521st device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

6597. the 6521st device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

6598. the 6521st device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

6599. the 6521st device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

6600. the 6521st device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

6601. the 6521st device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

6602. the 6521st device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

6603. the 6521st device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

6604. the 6521st device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

6605. the 6521st device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

6606. the 6521st device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

6607. the 6521st device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

6608. the 6521st device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

6609. the 6521st device also comprises antithrombotic agent.

6610. the 6521st device also comprises developing agent.

6611. the 6521st device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

6612. the 6521st device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

6613. the 6521st device also comprises developing agent, wherein said developing agent comprises MRI response material.

6614. the 6521st device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

6615. the 6521st device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

6616. the 6521st device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

6617. the 6521st device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

6618. the 6521st device also comprises the material that produces echo.

6619. the 6521st device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

6620. the 6521st device, wherein said device is aseptic.

6621. the 6521st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

6622. the 6521st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

6623. the 6521st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

6624. the 6521st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

6625. the 6521st device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

6626. the 6521st device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

6627. the 6521st device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

6628. the 6521st device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

6629. the 6521st device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

6630. the 6521st device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

6631. the 6521st device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

6632. the 6521st device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

6633. the 6521st device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

6634. the 6521st device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

6635. the 6521st device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

6636. the 6521st device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

6637. the 6521st device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

6638. the 6521st device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

6639. the described fibrous tissue that the 6521st device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

6640. the 6521st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6641. the 6521st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6642. the 6521st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6643. the 6521st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6644. the 6521st device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6645. one kind comprises the vascular occlusion implant of non-coiling and the medical apparatus that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

6646. the 6645th device, wherein said fibrous tissue forms agent and promotes regeneration.

6647. forming agent, the 6645th device, wherein said fibrous tissue promote blood vessel to take place.

6648. the 6645th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

6649. the 6645th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

6650. the 6645th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

6651. the 6645th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

6652. the 6645th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

6653. the 6645th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

6654. the 6645th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

6655. the 6645th device, wherein said fibrous tissue formation agent is silk or comprises silk.

6656. the 6645th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

6657. the 6645th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

6658. the 6645th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

6659. the 6645th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

6660. the 6645th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

6661. the 6645th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

6662. the 6645th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

6663. the 6645th device, wherein said fibrous tissue form agent and exist with particulate form.

6664. the 6645th device, wherein said compositions also comprises inflammatory cytokine.

6665. the 6645th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

6666. the 6645th device, wherein said compositions exists with the form of gel, paste or spray.

6667. the 6645th device, wherein said fibrous tissue form the form that agent is bunch.

6668. the 6645th device also comprises polymer.

6669. the 6645th device also comprises polymer support.

6670. the 6645th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

6671. the 6645th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

6672. the 6645th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

6673. the 6645th device also comprises coating, wherein said coating is placed on the surface of described device.

6674. the 6645th device also comprises coating, wherein said coating directly contacts described device.

6675. the 6645th device also comprises coating, wherein said coating contacts described device indirectly.

6676. the 6645th device also comprises coating, wherein said coating layer portion ground covers described device.

6677. the 6645th device also comprises coating, wherein said coating fully covers described device.

6678. the 6645th device also comprises coating, wherein said coating is uniform coating.

6679. the 6645th device also comprises coating, wherein said coating is uneven coating.

6680. the 6645th device also comprises coating, wherein said coating is a discontinuous coating.

6681. the 6645th device also comprises coating, wherein said coating is to form the coating of pattern.

6682. the 6645th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

6683. the 6645th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

6684. the 6645th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

6685. the 6645th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

6686. the 6645th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

6687. the 6645th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

6688. the 6645th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

6689. the 6645th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

6690. the 6645th device also comprises coating, wherein said coating also contains polymer.

6691. the 6645th device also comprises first coating with first compositions and second coating with second compositions.

6692. the 6645th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

6693. the 6645th device also comprises polymer.

6694. the 6645th device also comprises polymer support.

6695. the 6645th device also comprises polymer support, wherein said polymer support comprises copolymer.

6696. the 6645th device also comprises polymer support, wherein said polymer support comprises block copolymer.

6697. the 6645th device also comprises polymer support, wherein said polymer support comprises random copolymer.

6698. the 6645th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

6699. the 6645th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

6700. the 6645th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

6701. the 6645th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

6702. the 6645th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

6703. the 6645th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

6704. the 6645th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

6705. the 6645th device also comprises polymer support, wherein said polymer support comprises elastomer.

6706. the 6645th device also comprises polymer support, wherein said polymer support comprises hydrogel.

6707. the 6645th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

6708. the 6645th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

6709. the 6645th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

6710. the 6645th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

6711. the 6645th device also comprises polymer support, wherein said polymer support comprises macromonomer.

6712. the 6645th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

6713. the 6645th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

6714. the 6645th device also comprises lubricant coating.

6715. the 6645th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

6716. the 6645th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

6717. the 6645th device also comprises second forms of pharmacologically active agents.

6718. the 6645th device also comprises antiinflammatory.

6719. the 6645th device also comprises the medicament that suppresses infection.

6720. the 6645th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

6721. the 6645th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

6722. the 6645th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

6723. the 6645th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

6724. the 6645th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

6725. the 6645th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

6726. the 6645th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

6727. the 6645th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

6728. the 6645th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

6729. the 6645th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

6730. the 6645th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

6731. the 6645th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

6732. the 6645th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

6733. the 6645th device also comprises antithrombotic agent.

6734. the 6645th device also comprises developing agent.

6735. the 6645th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

6736. the 6645th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

6737. the 6645th device also comprises developing agent, wherein said developing agent comprises MRI response material.

6738. the 6645th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

6739. the 6645th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

6740. the 6645th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

6741. the 6645th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

6742. the 6645th device also comprises the material that produces echo.

6743. the 6645th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

6744. the 6645th device, wherein said device is aseptic.

6745. the 6645th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

6746. the 6645th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

6747. the 6645th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

6748. the 6645th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

6749. the 6645th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

6750. the 6645th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

6751. the 6645th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

6752. the 6645th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

6753. the 6645th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

6754. the 6645th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

6755. the 6645th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

6756. the 6645th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

6757. the 6645th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

6758. the 6645th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

6759. the 6645th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

6760. the 6645th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

6761. the 6645th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

6762. the 6645th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

6763. the described fibrous tissue that the 6645th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

6764. the 6645th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6765. the 6645th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6766. the 6645th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6767. the 6645th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6768. the 6645th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6769. the 6645th device, wherein said vascular occlusion implant is expandable.

6770. a medical apparatus that comprises hernia mesh (mesh) implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

6771. the 6770th device, wherein said fibrous tissue forms agent and promotes regeneration.

6772. forming agent, the 6770th device, wherein said fibrous tissue promote blood vessel to take place.

6773. the 6770th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

6774. the 6770th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

6775. the 6770th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

6776. the 6770th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

6777. the 6770th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

6778. the 6770th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

6779. the 6770th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

6780. the 6770th device, wherein said fibrous tissue formation agent is silk or comprises silk.

6781. the 6770th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

6782. the 6770th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

6783. the 6770th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

6784. the 6770th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

6785. the 6770th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

6786. the 6770th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

6787. the 6770th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

6788. the 6770th device, wherein said fibrous tissue form agent and exist with particulate form.

6789. the 6770th device, wherein said compositions also comprises inflammatory cytokine.

6790. the 6770th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

6791. the 6770th device, wherein said compositions exists with the form of gel, paste or spray.

6792. the 6770th device, wherein said fibrous tissue form the form that agent is bunch.

6793. the 6770th device also comprises polymer.

6794. the 6770th device also comprises polymer support.

6795. the 6770th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

6796. the 6770th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

6797. the 6770th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

6798. the 6770th device also comprises coating, wherein said coating is placed on the surface of described device.

6799. the 6770th device also comprises coating, wherein said coating directly contacts described device.

6800. the 6770th device also comprises coating, wherein said coating contacts described device indirectly.

6801. the 6770th device also comprises coating, wherein said coating layer portion ground covers described device.

6802. the 6770th device also comprises coating, wherein said coating fully covers described device.

6803. the 6770th device also comprises coating, wherein said coating is uniform coating.

6804. the 6770th device also comprises coating, wherein said coating is uneven coating.

6805. the 6770th device also comprises coating, wherein said coating is a discontinuous coating.

6806. the 6770th device also comprises coating, wherein said coating is to form the coating of pattern.

6807. the 6770th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

6808. the 6770th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

6809. the 6770th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

6810. the 6770th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

6811. the 6770th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

6812. the 6770th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

6813. the 6770th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

6814. the 6770th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

6815. the 6770th device also comprises coating, wherein said coating also contains polymer.

6816. the 6770th device also comprises first coating with first compositions and second coating with second compositions.

6817. the 6770th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

6818. the 6770th device also comprises polymer.

6819. the 6770th device also comprises polymer support.

6820. the 6770th device also comprises polymer support, wherein said polymer support comprises copolymer.

6821. the 6770th device also comprises polymer support, wherein said polymer support comprises block copolymer.

6822. the 6770th device also comprises polymer support, wherein said polymer support comprises random copolymer.

6823. the 6770th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

6824. the 6770th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

6825. the 6770th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

6826. the 6770th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

6827. the 6770th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

6828. the 6770th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

6829. the 6770th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

6830. the 6770th device also comprises polymer support, wherein said polymer support comprises elastomer.

6831. the 6770th device also comprises polymer support, wherein said polymer support comprises hydrogel.

6832. the 6770th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

6833. the 6770th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

6834. the 6770th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

6835. the 6770th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

6836. the 6770th device also comprises polymer support, wherein said polymer support comprises macromonomer.

6837. the 6770th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

6838. the 6770th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

6839. the 6770th device also comprises lubricant coating.

6840. the 6770th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

6841. the 6770th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

6842. the 6770th device also comprises second forms of pharmacologically active agents.

6843. the 6770th device also comprises antiinflammatory.

6844. the 6770th device also comprises the medicament that suppresses infection.

6845. the 6770th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

6846. the 6770th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

6847. the 6770th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

6848. the 6770th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

6849. the 6770th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

6850. the 6770th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

6851. the 6770th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

6852. the 6770th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

6853. the 6770th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

6854. the 6770th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

6855. the 6770th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

6856. the 6770th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

6857. the 6770th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

6858. the 6770th device also comprises antithrombotic agent.

6859. the 6770th device also comprises developing agent.

6860. the 6770th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

6861. the 6770th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

6862. the 6770th device also comprises developing agent, wherein said developing agent comprises MRI response material.

6863. the 6770th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

6864. the 6770th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

6865. the 6770th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

6866. the 6770th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

6867. the 6770th device also comprises the material that produces echo.

6868. the 6770th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

6869. the 6770th device, wherein said device is aseptic.

6870. the 6770th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

6871. the 6770th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

6872. the 6770th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

6873. the 6770th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

6874. the 6770th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

6875. the 6770th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

6876. the 6770th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

6877. the 6770th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

6878. the 6770th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

6879. the 6770th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

6880. the 6770th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

6881. the 6770th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

6882. the 6770th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

6883. the 6770th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

6884. the 6770th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

6885. the 6770th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

6886. the 6770th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

6887. the 6770th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

6888. the described fibrous tissue that the 6770th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

6889. the 6770th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6890. the 6770th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6891. the 6770th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6892. the 6770th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6893. the 6770th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

6894. the 6770th device, wherein said hernia net implant is expandable.

6895. a medical apparatus that comprises surgical operation film (film) implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

6896. the 6895th device, wherein said fibrous tissue forms agent and promotes regeneration.

6897. forming agent, the 6895th device, wherein said fibrous tissue promote blood vessel to take place.

6898. the 6895th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

6899. the 6895th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

6900. the 6895th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

6901. the 6895th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

6902. the 6895th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

6903. the 6895th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

6904. the 6895th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

6905. the 6895th device, wherein said fibrous tissue formation agent is silk or comprises silk.

6906. the 6895th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

6907. the 6895th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

6908. the 6895th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

6909. the 6895th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

6910. the 6895th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

6911. the 6895th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

6912. the 6895th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

6913. the 6895th device, wherein said fibrous tissue form agent and exist with particulate form.

6914. the 6895th device, wherein said compositions also comprises inflammatory cytokine.

6915. the 6895th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

6916. the 6895th device, wherein said compositions exists with the form of gel, paste or spray.

6917. the 6895th device, wherein said fibrous tissue form the form that agent is bunch.

6918. the 6895th device also comprises polymer.

6919. the 6895th device also comprises polymer support.

6920. the 6895th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

6921. the 6895th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

6922. the 6895th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

6923. the 6895th device also comprises coating, wherein said coating is placed on the surface of described device.

6924. the 6895th device also comprises coating, wherein said coating directly contacts described device.

6925. the 6895th device also comprises coating, wherein said coating contacts described device indirectly.

6926. the 6895th device also comprises coating, wherein said coating layer portion ground covers described device.

6927. the 6895th device also comprises coating, wherein said coating fully covers described device.

6928. the 6895th device also comprises coating, wherein said coating is uniform coating.

6929. the 6895th device also comprises coating, wherein said coating is uneven coating.

6930. the 6895th device also comprises coating, wherein said coating is a discontinuous coating.

6931. the 6895th device also comprises coating, wherein said coating is to form the coating of pattern.

6932. the 6895th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

6933. the 6895th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

6934. the 6895th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

6935. the 6895th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

6936. the 6895th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

6937. the 6895th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

6938. the 6895th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

6939. the 6895th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

6940. the 6895th device also comprises coating, wherein said coating also contains polymer.

6941. the 6895th device also comprises first coating with first compositions and second coating with second compositions.

6942. the 6895th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

6943. the 6895th device also comprises polymer.

6944. the 6895th device also comprises polymer support.

6945. the 6895th device also comprises polymer support, wherein said polymer support comprises copolymer.

6946. the 6895th device also comprises polymer support, wherein said polymer support comprises block copolymer.

6947. the 6895th device also comprises polymer support, wherein said polymer support comprises random copolymer.

6948. the 6895th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

6949. the 6895th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

6950. the 6895th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

6951. the 6895th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

6952. the 6895th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

6953. the 6895th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

6954. the 6895th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

6955. the 6895th device also comprises polymer support, wherein said polymer support comprises elastomer.

6956. the 6895th device also comprises polymer support, wherein said polymer support comprises hydrogel.

6957. the 6895th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

6958. the 6895th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

6959. the 6895th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

6960. the 6895th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

6961. the 6895th device also comprises polymer support, wherein said polymer support comprises macromonomer.

6962. the 6895th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

6963. the 6895th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

6964. the 6895th device also comprises lubricant coating.

6965. the 6895th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

6966. the 6895th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

6967. the 6895th device also comprises second forms of pharmacologically active agents.

6968. the 6895th device also comprises antiinflammatory.

6969. the 6895th device also comprises the medicament that suppresses infection.

6970. the 6895th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

6971. the 6895th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

6972. the 6895th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

6973. the 6895th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

6974. the 6895th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

6975. the 6895th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

6976. the 6895th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

6977. the 6895th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

6978. the 6895th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

6979. the 6895th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

6980. the 6895th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

6981. the 6895th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

6982. the 6895th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

6983. the 6895th device also comprises antithrombotic agent.

6984. the 6895th device also comprises developing agent.

6985. the 6895th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

6986. the 6895th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

6987. the 6895th device also comprises developing agent, wherein said developing agent comprises MRI response material.

6988. the 6895th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

6989. the 6895th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

6990. the 6895th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

6991. the 6895th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

6992. the 6895th device also comprises the material that produces echo.

6993. the 6895th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

6994. the 6895th device, wherein said device is aseptic.

6995. the 6895th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

6996. the 6895th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

6997. the 6895th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

6998. the 6895th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

6999. the 6895th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

7000. the 6895th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

7001. the 6895th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

7002. the 6895th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

7003. the 6895th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

7004. the 6895th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

7005. the 6895th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

7006. the 6895th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

7007. the 6895th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

7008. the 6895th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

7009. the 6895th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

7010. the 6895th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

7011. the 6895th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

7012. the 6895th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

7013. the described fibrous tissue that the 6895th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

7014. the 6895th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7015. the 6895th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7016. the 6895th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7017. the 6895th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7018. the 6895th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7019. a medical apparatus that comprises spinal fusion device and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

7020. the 7019th device, wherein said fibrous tissue forms agent and promotes regeneration.

7021. forming agent, the 7019th device, wherein said fibrous tissue promote blood vessel to take place.

7022. the 7019th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

7023. the 7019th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

7024. the 7019th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

7025. the 7019th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

7026. the 7019th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

7027. the 7019th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

7028. the 7019th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

7029. the 7019th device, wherein said fibrous tissue formation agent is silk or comprises silk.

7030. the 7019th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

7031. the 7019th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

7032. the 7019th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

7033. the 7019th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

7034. the 7019th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

7035. the 7019th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

7036. the 7019th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

7037. the 7019th device, wherein said fibrous tissue form agent and exist with particulate form.

7038. the 7019th device, wherein said compositions also comprises inflammatory cytokine.

7039. the 7019th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

7040. the 7019th device, wherein said compositions exists with the form of gel, paste or spray.

7041. the 7019th device, wherein said fibrous tissue form the form that agent is bunch.

7042. the 7019th device also comprises polymer.

7043. the 7019th device also comprises polymer support.

7044. the 7019th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

7045. the 7019th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

7046. the 7019th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

7047. the 7019th device also comprises coating, wherein said coating is placed on the surface of described device.

7048. the 7019th device also comprises coating, wherein said coating directly contacts described device.

7049. the 7019th device also comprises coating, wherein said coating contacts described device indirectly.

7050. the 7019th device also comprises coating, wherein said coating layer portion ground covers described device.

7051. the 7019th device also comprises coating, wherein said coating fully covers described device.

7052. the 7019th device also comprises coating, wherein said coating is uniform coating.

7053. the 7019th device also comprises coating, wherein said coating is uneven coating.

7054. the 7019th device also comprises coating, wherein said coating is a discontinuous coating.

7055. the 7019th device also comprises coating, wherein said coating is to form the coating of pattern.

7056. the 7019th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

7057. the 7019th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

7058. the 7019th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

7059. the 7019th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

7060. the 7019th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

7061. the 7019th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

7062. the 7019th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

7063. the 7019th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

7064. the 7019th device also comprises coating, wherein said coating also contains polymer.

7065. the 7019th device also comprises first coating with first compositions and second coating with second compositions.

7066. the 7019th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

7067. the 7019th device also comprises polymer.

7068. the 7019th device also comprises polymer support.

7069. the 7019th device also comprises polymer support, wherein said polymer support comprises copolymer.

7070. the 7019th device also comprises polymer support, wherein said polymer support comprises block copolymer.

7071. the 7019th device also comprises polymer support, wherein said polymer support comprises random copolymer.

7072. the 7019th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

7073. the 7019th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

7074. the 7019th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

7075. the 7019th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

7076. the 7019th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

7077. the 7019th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

7078. the 7019th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

7079. the 7019th device also comprises polymer support, wherein said polymer support comprises elastomer.

7080. the 7019th device also comprises polymer support, wherein said polymer support comprises hydrogel.

7081. the 7019th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

7082. the 7019th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

7083. the 7019th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

7084. the 7019th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

7085. the 7019th device also comprises polymer support, wherein said polymer support comprises macromonomer.

7086. the 7019th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

7087. the 7019th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

7088. the 7019th device also comprises lubricant coating.

7089. the 7019th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

7090. the 7019th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

7091. the 7019th device also comprises second forms of pharmacologically active agents.

7092. the 7019th device also comprises antiinflammatory.

7093. the 7019th device also comprises the medicament that suppresses infection.

7094. the 7019th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

7095. the 7019th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

7096. the 7019th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

7097. the 7019th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

7098. the 7019th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

7099. the 7019th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

7100. the 7019th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

7101. the 7019th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

7102. the 7019th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

7103. the 7019th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

7104. the 7019th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

7105. the 7019th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

7106. the 7019th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

7107. the 7019th device also comprises antithrombotic agent.

7108. the 7019th device also comprises developing agent.

7109. the 7019th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

7110. the 7019th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

7111. the 7019th device also comprises developing agent, wherein said developing agent comprises MRI response material.

7112. the 7019th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

7113. the 7019th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

7114. the 7019th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

7115. the 7019th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

7116. the 7019th device also comprises the material that produces echo.

7117. the 7019th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

7118. the 7019th device, wherein said device is aseptic.

7119. the 7019th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

7120. the 7019th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

7121. the 7019th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

7122. the 7019th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

7123. the 7019th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

7124. the 7019th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

7125. the 7019th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

7126. the 7019th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

7127. the 7019th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

7128. the 7019th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

7129. the 7019th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

7130. the 7019th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

7131. the 7019th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

7132. the 7019th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

7133. the 7019th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

7134. the 7019th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

7135. the 7019th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

7136. the 7019th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

7137. the described fibrous tissue that the 7019th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

7138. the 7019th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7139. the 7019th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7140. the 7019th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7141. the 7019th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7142. the 7019th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7143. the 7019th device, wherein said spinal fusion device are to merge basket (basket).

7144. the 7019th device, wherein said spinal fusion device are fusion cage (casge) devices.

7145. the 7019th device, wherein said spinal fusion device are amboceptor box (interbodycase).

7146. the 7019th device, wherein said spinal fusion device are the amboceptor implants.

7147. the 7019th device, wherein said spinal fusion device are the fusion cage fixtures.

7148. the 7019th device, wherein said spinal fusion device are to merge stable cavity (chamber).

7149. the 7019th device, wherein said spinal fusion device are the fusion cage fixing heads.

7150. the 7019th device, wherein said spinal fusion device is a bone anchoring device.

7151. the 7019th device, wherein said spinal fusion device are the stationarity hone lamellas.

7152. the 7019th device, wherein said spinal fusion device are the stationarity bone screw.

7153. the 7019th device, wherein said spinal fusion device is a tissue filler.

7154. the 7019th device, wherein said spinal fusion device are bone cement (cement).

7155. the 7019th device, wherein said spinal fusion device are allograft's materials.

7156. the 7019th device, wherein said spinal fusion device are the autograft materials.

7157. the 7019th device, wherein said spinal fusion device are the collagen protein implants.

7158. the 7019th device, wherein said spinal fusion device is injectable.

7159. one kind forms the medical apparatus of agent every inaccessible sticking patch and fibrous tissue in comprising, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

7160. the 7159th device, wherein said fibrous tissue forms agent and promotes regeneration.

7161. forming agent, the 7159th device, wherein said fibrous tissue promote blood vessel to take place.

7162. the 7159th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

7163. the 7159th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

7164. the 7159th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

7165. the 7159th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

7166. the 7159th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

7167. the 7159th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

7168. the 7159th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

7169. the 7159th device, wherein said fibrous tissue formation agent is silk or comprises silk.

7170. the 7159th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

7171. the 7159th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

7172. the 7159th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

7173. the 7159th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

7174. the 7159th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

7175. the 7159th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

7176. the 7159th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

7177. the 7159th device, wherein said fibrous tissue form agent and exist with particulate form.

7178. the 7159th device, wherein said compositions also comprises inflammatory cytokine.

7179. the 7159th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

7180. the 7159th device, wherein said compositions exists with the form of gel, paste or spray.

7181. the 7159th device, wherein said fibrous tissue form the form that agent is bunch.

7182. the 7159th device also comprises polymer.

7183. the 7159th device also comprises polymer support.

7184. the 7159th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

7185. the 7159th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

7186. the 7159th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

7187. the 7159th device also comprises coating, wherein said coating is placed on the surface of described device.

7188. the 7159th device also comprises coating, wherein said coating directly contacts described device.

7189. the 7159th device also comprises coating, wherein said coating contacts described device indirectly.

7190. the 7159th device also comprises coating, wherein said coating layer portion ground covers described device.

7191. the 7159th device also comprises coating, wherein said coating fully covers described device.

7192. the 7159th device also comprises coating, wherein said coating is uniform coating.

7193. the 7159th device also comprises coating, wherein said coating is uneven coating.

7194. the 7159th device also comprises coating, wherein said coating is a discontinuous coating.

7195. the 7159th device also comprises coating, wherein said coating is to form the coating of pattern.

7196. the 7159th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

7197. the 7159th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

7198. the 7159th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

7199. the 7159th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

7200. the 7159th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

7201. the 7159th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

7202. the 7159th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

7203. the 7159th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

7204. the 7159th device also comprises coating, wherein said coating also contains polymer.

7205. the 7159th device also comprises first coating with first compositions and second coating with second compositions.

7206. the 7159th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

7207. the 7159th device also comprises polymer.

7208. the 7159th device also comprises polymer support.

7209. the 7159th device also comprises polymer support, wherein said polymer support comprises copolymer.

7210. the 7159th device also comprises polymer support, wherein said polymer support comprises block copolymer.

7211. the 7159th device also comprises polymer support, wherein said polymer support comprises random copolymer.

7212. the 7159th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

7213. the 7159th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

7214. the 7159th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

7215. the 7159th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

7216. the 7159th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

7217. the 7159th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

7218. the 7159th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

7219. the 7159th device also comprises polymer support, wherein said polymer support comprises elastomer.

7220. the 7159th device also comprises polymer support, wherein said polymer support comprises hydrogel.

7221. the 7159th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

7222. the 7159th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

7223. the 7159th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

7224. the 7159th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

7225. the 7159th device also comprises polymer support, wherein said polymer support comprises macromonomer.

7226. the 7159th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

7227. the 7159th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

7228. the 7159th device also comprises lubricant coating.

7229. the 7159th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

7230. the 7159th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

7231. the 7159th device also comprises second forms of pharmacologically active agents.

7232. the 7159th device also comprises antiinflammatory.

7233. the 7159th device also comprises the medicament that suppresses infection.

7234. the 7159th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

7235. the 7159th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

7236. the 7159th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

7237. the 7159th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

7238. the 7159th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

7239. the 7159th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

7240. the 7159th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

7241. the 7159th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

7242. the 7159th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

7243. the 7159th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

7244. the 7159th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

7245. the 7159th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

7246. the 7159th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

7247. the 7159th device also comprises antithrombotic agent.

7248. the 7159th device also comprises developing agent.

7249. the 7159th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

7250. the 7159th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

7251. the 7159th device also comprises developing agent, wherein said developing agent comprises MRI response material.

7252. the 7159th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

7253. the 7159th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

7254. the 7159th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

7255. the 7159th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

7256. the 7159th device also comprises the material that produces echo.

7257. the 7159th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

7258. the 7159th device, wherein said device is aseptic.

7259. the 7159th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

7260. the 7159th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

7261. the 7159th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

7262. the 7159th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

7263. the 7159th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

7264. the 7159th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

7265. the 7159th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

7266. the 7159th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

7267. the 7159th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

7268. the 7159th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

7269. the 7159th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

7270. the 7159th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

7271. the 7159th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

7272. the 7159th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

7273. the 7159th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

7274. the 7159th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

7275. the 7159th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

7276. the 7159th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

7277. the described fibrous tissue that the 7159th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

7278. the 7159th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7279. the 7159th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7280. the 7159th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7281. the 7159th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7282. the 7159th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7283. the 7159th device, wherein said in inaccessible sticking patch is every closing device.

7284. the 7159th device, wherein said in every inaccessible sticking patch be the shunting closing device.

7285. the 7159th device is intracardiac closer every inaccessible sticking patch in wherein said.

7286. the 7159th device is the closure dish every inaccessible sticking patch in wherein said.

7287. the 7159th device is damaged closed-system every inaccessible sticking patch in wherein said.

7288. the 7159th device is a part flow arrangement in the blood vessel every inaccessible sticking patch in wherein said.

7289. a medical apparatus that comprises intracavity fastener (fasterner) and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

7290. the 7289th device, wherein said fibrous tissue forms agent and promotes regeneration.

7291. forming agent, the 7289th device, wherein said fibrous tissue promote blood vessel to take place.

7292. the 7289th device, wherein said fibrous tissue form agent and promote the fibroblast migration.

7293. the 7289th device, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

7294. the 7289th device, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

7295. the 7289th device, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

7296. the 7289th device, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

7297. the 7289th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

7298. the 7289th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

7299. the 7289th device, wherein said fibrous tissue formation agent is silk or comprises silk.

7300. the 7289th device, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

7301. the 7289th device, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

7302. the 7289th device, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

7303. the 7289th device, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

7304. the 7289th device, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

7305. the 7289th device, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

7306. the 7289th device, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

7307. the 7289th device, wherein said fibrous tissue form agent and exist with particulate form.

7308. the 7289th device, wherein said compositions also comprises inflammatory cytokine.

7309. the 7289th device, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

7310. the 7289th device, wherein said compositions exists with the form of gel, paste or spray.

7311. the 7289th device, wherein said fibrous tissue form the form that agent is bunch.

7312. the 7289th device also comprises polymer.

7313. the 7289th device also comprises polymer support.

7314. the 7289th device, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

7315. the 7289th device, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

7316. the 7289th device also comprises coating, wherein said coating comprises described fibrous tissue and forms agent.

7317. the 7289th device also comprises coating, wherein said coating is placed on the surface of described device.

7318. the 7289th device also comprises coating, wherein said coating directly contacts described device.

7319. the 7289th device also comprises coating, wherein said coating contacts described device indirectly.

7320. the 7289th device also comprises coating, wherein said coating layer portion ground covers described device.

7321. the 7289th device also comprises coating, wherein said coating fully covers described device.

7322. the 7289th device also comprises coating, wherein said coating is uniform coating.

7323. the 7289th device also comprises coating, wherein said coating is uneven coating.

7324. the 7289th device also comprises coating, wherein said coating is a discontinuous coating.

7325. the 7289th device also comprises coating, wherein said coating is to form the coating of pattern.

7326. the 7289th device also comprises coating, wherein said coating has 100 μ m or littler thickness.

7327. the 7289th device also comprises coating, wherein said coating has 10 μ m or littler thickness.

7328. the 7289th device also comprises coating, this installs later on and the surface adhesion of this device wherein said coating in deployment.

7329. the 7289th device also comprises coating, wherein said coating in room temperature 1 year the time interim be stable.

7330. the 7289th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

7331. the 7289th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

7332. the 7289th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

7333. the 7289th device also comprises coating, wherein said fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

7334. the 7289th device also comprises coating, wherein said coating also contains polymer.

7335. the 7289th device also comprises first coating with first compositions and second coating with second compositions.

7336. the 7289th device also comprises first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

7337. the 7289th device also comprises polymer.

7338. the 7289th device also comprises polymer support.

7339. the 7289th device also comprises polymer support, wherein said polymer support comprises copolymer.

7340. the 7289th device also comprises polymer support, wherein said polymer support comprises block copolymer.

7341. the 7289th device also comprises polymer support, wherein said polymer support comprises random copolymer.

7342. the 7289th device also comprises polymer support, wherein said polymer support comprises biodegradable polymer.

7343. the 7289th device also comprises polymer support, wherein said polymer support comprises not biodegradable polymer.

7344. the 7289th device also comprises polymer support, wherein said polymer support comprises hydrophilic polymer.

7345. the 7289th device also comprises polymer support, wherein said polymer support comprises hydrophobic polymer.

7346. the 7289th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophilic-structure territory.

7347. the 7289th device also comprises polymer support, wherein said polymer support comprises the polymer with hydrophobic domains.

7348. the 7289th device also comprises polymer support, wherein said polymer support comprises non-conductive polymer.

7349. the 7289th device also comprises polymer support, wherein said polymer support comprises elastomer.

7350. the 7289th device also comprises polymer support, wherein said polymer support comprises hydrogel.

7351. the 7289th device also comprises polymer support, wherein said polymer support comprises siloxane polymer.

7352. the 7289th device also comprises polymer support, wherein said polymer support comprises hydrocarbon polymer.

7353. the 7289th device also comprises polymer support, wherein said polymer support comprises the styrene derived polymers.

7354. the 7289th device also comprises polymer support, wherein said polymer support comprises butadiene polymer.

7355. the 7289th device also comprises polymer support, wherein said polymer support comprises macromonomer.

7356. the 7289th device also comprises polymer support, wherein said polymer support comprises poly-(ethylene glycol) polymer.

7357. the 7289th device also comprises polymer support, wherein said polymer support comprises amorphous polymer.

7358. the 7289th device also comprises lubricant coating.

7359. the 7289th device, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

7360. the 7289th device, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

7361. the 7289th device also comprises second forms of pharmacologically active agents.

7362. the 7289th device also comprises antiinflammatory.

7363. the 7289th device also comprises the medicament that suppresses infection.

7364. the 7289th device also comprises the medicament that suppresses infection, wherein said medicament is an anthracycline.

7365. the 7289th device also comprises the medicament that suppresses infection, wherein said medicament is a doxorubicin.

7366. the 7289th device also comprises the medicament that suppresses infection, wherein said medicament is a mitoxantrone.

7367. the 7289th device also comprises the medicament that suppresses infection, wherein said medicament is the fluorine pyrimidine.

7368. the 7289th device also comprises the medicament that suppresses infection, wherein said medicament is 5-fluorouracil (5-FU).

7369. the 7289th device also comprises the medicament that suppresses infection, wherein said medicament is an antifol.

7370. the 7289th device also comprises the medicament that suppresses infection, wherein said medicament is a methotrexate.

7371. the 7289th device also comprises the medicament that suppresses infection, wherein said medicament is a podophyllotoxin.

7372. the 7289th device also comprises the medicament that suppresses infection, wherein said medicament is an etoposide.

7373. the 7289th device also comprises the medicament that suppresses infection, wherein said medicament is a camptothecine.

7374. the 7289th device also comprises the medicament that suppresses infection, wherein said medicament is a hydroxyurea.

7375. the 7289th device also comprises the medicament that suppresses infection, wherein said medicament is a platinum complex.

7376. the 7289th device also comprises the medicament that suppresses infection, wherein said medicament is a cisplatin.

7377. the 7289th device also comprises antithrombotic agent.

7378. the 7289th device also comprises developing agent.

7379. the 7289th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

7380. the 7289th device also comprises developing agent, wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

7381. the 7289th device also comprises developing agent, wherein said developing agent comprises MRI response material.

7382. the 7289th device also comprises developing agent, wherein said developing agent comprises gadolinium chelate compound.

7383. the 7289th device also comprises developing agent, wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

7384. the 7289th device also comprises developing agent, wherein said developing agent comprises iron oxide compound.

7385. the 7289th device also comprises developing agent, wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

7386. the 7289th device also comprises the material that produces echo.

7387. the 7289th device also comprises the material that produces echo, the material of wherein said generation echo exists with the form of coating.

7388. the 7289th device, wherein said device is aseptic.

7389. the 7289th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

7390. the 7289th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

7391. the 7289th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

7392. the 7289th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

7393. the 7289th device, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

7394. the 7289th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

7395. the 7289th device, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

7396. the 7289th device, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

7397. the 7289th device, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

7398. the 7289th device, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

7399. the 7289th device, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

7400. the 7289th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

7401. the 7289th device, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

7402. the 7289th device, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

7403. the 7289th device, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

7404. the 7289th device, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

7405. the 7289th device, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

7406. the 7289th device, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

7407. the described fibrous tissue that the 7289th device, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

7408. the 7289th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7409. the 7289th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7410. the 7289th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7411. the 7289th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7412. the 7289th device, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7413. one kind prepares injectable method for compositions, it comprises fibrous tissue is formed the combination of agent and filler.

7414. the 7413rd method, wherein said fibrous tissue form agent and promote the fibrosis effect and promote regeneration.

7415. forming agent, the 7413rd method, wherein said fibrous tissue promote blood vessel to take place.

7416. the 7413rd method, wherein said fibrous tissue form the migration of agent fibroblast.

7417. the 7413rd method, wherein said fibrous tissue forms the agent fibroblast proliferation.

7418. the 7413rd method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

7419. the 7413rd method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

Be or comprise the ductus arteriosus wall stimulant 7420. the 7413rd method, wherein said fibrous tissue form agent.

7421. the 7413rd method, wherein said fibrous tissue formation agent is silk or comprises silk.

7422. the 7413rd method, wherein said fibrous tissue form agent and are silkworm silk or comprise silkworm silk.

7423. the 7413rd method, wherein said fibrous tissue form agent and are spider silks or comprise spider silk.

7424. the 7413rd method, wherein said fibrous tissue formation agent is the reorganization silk or comprises the reorganization silk.

7425. the 7413rd method, wherein said fibrous tissue form agent and are raw silks or comprise raw silk.

7426. the 7413rd method, wherein said fibrous tissue form agent and are hydrolyzed-silks or comprise hydrolyzed-silk.

7427. the 7413rd method, wherein said fibrous tissue formation agent is acid-treated silk or comprises acid-treated silk.

7428. it is the silk of acidylate or the silk that comprises acidylate that the 7413rd method, wherein said fibrous tissue form agent.

7429. the 7413rd method, wherein said fibrous tissue formation agent exists with the form of chain.

7430. the 7413rd method, wherein said fibrous tissue form agent with bunch form exist.

7431. the 7413rd method, wherein said fibrous tissue formation agent exists with the form of microgranule.

7432. the 7413rd method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

7433. the 7413rd method, wherein said fibrous tissue form agent and are Talcums or comprise Talcum.

7434. the 7413rd method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

7435. the 7413rd method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

7436. the 7413rd method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

7437. the 7413rd method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

7438. the 7413rd method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

7439. the 7413rd method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

7440. the 7439th method, wherein said fiber is biodegradable.

7441. comprising, the 7440th method, wherein said biodegradable line be selected from by polyester polyanhydride, poly-(acid anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen protein, chitosan, hyaluronic acid, chromic catgut, alginate, starch, the material in the group that cellulose and cellulose esters are formed.

7442. the 7439th method, wherein said line are not biodegradable.

7443. the 7442nd method, wherein said not biodegradable line comprise the material that is selected from the group of being made up of polyester, polyurethanes, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

7444. the 7439th method, wherein said line is coated with polymer.

7445. the 7439th method, wherein said line is coated with medicament, and described medicament is induced the intravital fibre modification reaction of described patient.

7446. the 7439th method, wherein said line is coated with medicament, and described medicament is induced the intravital osteogenic response of described patient.

7447. the 7413rd method, wherein said fibrous tissue form agent and exist with particulate form.

7448. the 7447th method, wherein said microgranule are biodegradable granules.

7449. comprising, the 7448th method, wherein said biodegradable granule be selected from by polyester polyanhydride, poly-(acid anhydride ester), poly-(ester-acid amide), poly-(ester-urea), poe, poly phosphate, poly-phosphazine, polybutylcyanoacrylate, collagen protein, chitosan, hyaluronic acid, chromic catgut, alginate, starch, the material in the group that cellulose and cellulose esters are formed.

7450. the 7447th method, wherein said granule are not biodegradable.

7451. the 7450th method, wherein said not biodegradable granule comprise the material that is selected from the group of being made up of polyester, polyurethanes, siloxanes, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylates and silk.

7452. the 7447th method, wherein said granule are the particulate form that is selected from a member in the group of being made up of silk, Talcum, starch, glass, silicate, Silicon stone, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral matter, polymethyl methacrylate, silver nitrate, Inorganic Non-metallic Materials (ceramic) and other inorganic particles.

7453. the 7447th method, wherein said line is coated with polymer.

7454. the 7447th method, wherein said line is coated with medicament, and described medicament is induced the intravital fibre modification reaction of described patient.

7455. the 7447th method, wherein said granule are coated with a member that is selected from the group of being made up of silk, Talcum, starch, glass, silicate, silicon dioxide, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral matter, polymethyl methacrylate, silver nitrate, Inorganic Non-metallic Materials and other inorganic particles.

7456. the 7447th method, wherein said granule is coated with medicament, and described medicament is induced the intravital osteogenic response of described patient.

7457. the 7413rd method, wherein said compositions also comprises the promote osteogenesis agent.

7458. the 7457th method, wherein the promote osteogenesis agent is a bone morphogenetic protein.

7459. the 7457th method, wherein the promote osteogenesis agent is an osteogenic growth factor.

7460. the 7459th method, wherein said osteogenic growth factor are selected from transforming growth factor, platelet-derived somatomedin, and fibroblast growth factor.

7461. the 7413rd method, wherein said filler comprise collagen protein or crosslinked collagen protein.

7462. the 7413rd method, wherein said filler comprises hydroxyapatite.

7463. the 7413rd method, wherein said filler comprise micronized allosome corium (alloderm) acellular matrix.

7464. the 7413rd method, wherein said filler comprises hyaluronic acid.

7465. the 7413rd method, wherein said filler is a hydrogel.

7466. the 7413rd method, wherein said filler comprises beta glucan.

7467. the 7413rd method, wherein said filler comprises the collagen protein fibril.

7468. the 7413rd method, wherein said filler comprises the hylan polymer.

7469. the 7413rd method, wherein said filler comprises microsphere.

7470. the 7413rd method, wherein said filler comprises polyacrylic acid or polyacrylate.

7471. the 7413rd method, wherein said filler comprise silicon or crosslinked silicon.

7472. the 7413rd method wherein forms agent and/or the combination of described filler with developing agent and described fibrous tissue.

7473. the 7413rd method wherein forms agent and/or the combination of described filler with coloring agent and described fibrous tissue.

7474. the 7413rd method is wherein handled so that aseptic compositions to be provided described compositions.

7475. the 7413rd method wherein is mixed with the urethra filler with described compositions.

7476. the 7413rd method wherein is mixed with the esophagus filler with described compositions.

7477. the 7413rd method wherein is mixed with the anus filler with described compositions.

7478. the 7413rd method, wherein said fibrous tissue form agent with about 0.005 μ g-10 μ g/mm ³Concentration be present in the described compositions.

7479. method for preparing medical apparatus, comprise i) rectificating surgery implant and ii) fibrous tissue form agent or comprise the compositions combination that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

7480. the 7479th method, wherein said fibrous tissue forms agent and promotes regeneration.

7481. forming agent, the 7479th method, wherein said fibrous tissue promote blood vessel to take place.

7482. the 7479th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

7483. the 7479th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

7484. the 7479th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

7485. the 7479th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

7486. the 7479th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

7487. the 7479th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

7488. the 7479th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

7489. the 7479th method, wherein said fibrous tissue formation agent is silk or comprises silk.

7490. the 7479th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

7491. the 7479th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

7492. the 7479th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

7493. the 7479th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

7494. the 7479th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

7495. the 7479th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

7496. the 7479th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

7497. the 7479th method, wherein said fibrous tissue form agent and exist with particulate form.

7498. the 7479th method, wherein said compositions also comprises inflammatory cytokine.

7499. the 7479th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

7500. the 7479th method, wherein said compositions exists with the form of gel or paste.

7501. the 7479th method, wherein said fibrous tissue form the form that agent is bunch.

7502. the 7479th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

7503. the 7479th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

7504. the 7479th method, wherein said implant and coating combination, and described coating comprises described fibrous tissue formation agent.

7505. the 7479th method, wherein said implant and coating combination, and described coating is placed on the surface of described device.

7506. the 7479th method, wherein said implant and coating combination, and described coating directly contacts described device.

7507. the 7479th method, wherein said implant and coating combination, and described coating contacts described device indirectly.

7508. the 7479th method, wherein said implant and coating combination, and described coating layer portion ground covers described device.

7509. the 7479th method, wherein said implant and coating combination, and described coating fully covers described device.

7510. the 7479th method, wherein said implant and coating combination, and described coating is uniform coating.

7511. the 7479th method, wherein said implant and coating combination, and described coating is uneven coating.

7512. the 7479th method, wherein said implant and coating combination, and described coating is a discontinuous coating.

7513. the 7479th method, wherein said implant and coating combination, and described coating is to form the coating of pattern.

7514. the 7479th method, wherein said implant and coating combination, and described coating has 100 μ m or littler thickness.

7515. the 7479th method, wherein said implant and coating combination, and described coating has 10 μ m or littler thickness.

7516. the 7479th method, wherein said implant and coating combination, and described coating is being disposed the surface adhesion that this installs later and this device.

7517. the 7479th method, the combination of wherein said implant and coating, and described coating in room temperature at least 1 year the time interim be stable.

7518. the 7479th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

7519. the 7479th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

7520. the 7479th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

7521. the 7479th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

7522. the 7479th method, wherein said implant and coating combination, and described coating also contains polymer.

7523. the 7479th method, wherein said device comprise first coating with first compositions and second coating with second compositions.

7524. the 7479th method, wherein said device comprise first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

7525. the 7479th method, wherein said device comprises polymer.

7526. the 7479th method, wherein said device comprises polymer, and described polymer is the component of described compositions.

7527. the 7479th method, wherein said implant and combination of polymers, and described polymer is a copolymer.

7528. the 7479th method, wherein said implant and combination of polymers, and described polymer is a block copolymer.

7529. the 7479th method, wherein said implant and combination of polymers, and described polymer is a random copolymer.

7530. the 7479th method, wherein said implant and combination of polymers, and described polymer is biodegradable polymer.

7531. the 7479th method, wherein said implant and combination of polymers, and described polymer is not biodegradable polymer.

7532. the 7479th method, wherein said implant and combination of polymers, and described polymer is a hydrophilic polymer.

7533. the 7479th method, wherein said implant and combination of polymers, and described polymer is a hydrophobic polymer.

7534. the 7479th method, wherein said implant and combination of polymers, and described polymer is the polymer with hydrophilic-structure territory.

7535. the 7479th method, wherein said implant and combination of polymers, and described polymer is the polymer with hydrophobic domains.

7536. the 7479th method, wherein said implant and combination of polymers, and described polymer is a non-conductive polymer.

7537. the 7479th method, wherein said implant and combination of polymers, and described polymer is an elastomer.

7538. the 7479th method, wherein said implant and combination of polymers, and described polymer is a hydrogel.

7539. the 7479th method, wherein said implant and combination of polymers, and described polymer is a siloxane polymer.

7540. the 7479th method, wherein said implant and combination of polymers, and described polymer is a hydrocarbon polymer.

7541. the 7479th method, wherein said implant and combination of polymers, and described polymer is the styrene derived polymers.

7542. the 7479th method, wherein said implant and combination of polymers, and described polymer is a butadiene polymer.

7543. the 7479th method, wherein said implant and combination of polymers, and described polymer is a macromonomer.

7544. the 7479th method, wherein said implant and combination of polymers, and described polymer is poly-(ethylene glycol) polymer.

7545. the 7479th method, wherein said implant and combination of polymers, and described polymer is an amorphous polymer.

7546. the 7479th method, wherein said implant and combination of polymers, and described polymer is a lubricant coating.

7547. the 7479th method, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

7548. the 7479th method, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

7549. the 7479th method, wherein said implant be combination second forms of pharmacologically active agents further.

7550. the 7479th method, wherein said implant further makes up antiinflammatory.

7551. the 7479th method, wherein said implant further make up the medicament that suppresses infection.

7552. the 7479th method, wherein said implant further makes up anthracycline.

7553. the 7479th method, wherein said implant further makes up doxorubicin.

7554. the 7479th method, wherein said implant further makes up mitoxantrone.

7555. the 7479th method, wherein said implant further makes up the fluorine pyrimidine.

7556. the 7479th method, wherein said implant further make up 5-fluorouracil (5-FU).

7557. the 7479th method, wherein said implant further makes up antifol.

7558. the 7479th method, wherein said implant further makes up methotrexate.

7559. the 7479th method, wherein said implant further makes up podophyllotoxin.

7560. the 7479th method, wherein said implant further makes up etoposide.

7561. the 7479th method, wherein said implant further makes up camptothecine.

7562. the 7479th method, wherein said implant further makes up hydroxyurea.

7563. the 7479th method, wherein said implant further makes up platinum complex.

7564. the 7479th method, wherein said implant further makes up cisplatin.

7565. the 7479th method, wherein said implant further makes up antithrombotic agent.

7566. the 7479th method, wherein said implant further makes up developing agent.

7567. the 7479th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

7568. the 7479th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

7569. the 7479th method, wherein said implant further makes up developing agent, and wherein said developing agent is a MRI response material.

7570. the 7479th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises gadolinium chelate compound.

7571. the 7479th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

7572. the 7479th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises iron oxide compound.

7573. the 7479th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

7574. the 7479th method, the material of the further combination results echo of wherein said implant.

7575. the 7479th method, the material of the further combination results echo of wherein said implant, the material of wherein said generation echo exists with the form of coating.

7576. the 7479th method, wherein said device is aseptic.

7577. the 7479th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

7578. the 7479th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

7579. the 7479th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

7580. the 7479th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

7581. the 7479th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

7582. the 7479th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

7583. the 7479th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

7584. the 7479th method, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

7585. the 7479th method, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

7586. the 7479th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

7587. the 7479th method, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

7588. the 7479th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

7589. the 7479th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

7590. the 7479th method, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

7591. the 7479th method, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

7592. the 7479th method, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

7593. the 7479th method, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

7594. the 7479th method, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

7595. the described fibrous tissue that the 7479th method, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

7596. the 7479th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7597. the 7479th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7598. the 7479th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7599. the 7479th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7600. the 7479th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7601. the 7479th method, wherein said rectificating surgery implant is used as the substitute of bone graft.

7602. the 7479th method, wherein said rectificating surgery implant are orthopedics's aciculiform implants.

7603. the 7479th method, wherein said rectificating surgery implant are orthopedics's nail shape implants.

7604. method for preparing medical apparatus, comprise i) orthopedics's prosthese and ii) fibrous tissue form agent or comprise the compositions combination that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

7605. the 7604th method, wherein said fibrous tissue forms agent and promotes regeneration.

7606. forming agent, the 7604th method, wherein said fibrous tissue promote blood vessel to take place.

7607. the 7604th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

7608. the 7604th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

7609. the 7604th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

7610. the 7604th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

7611. the 7604th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

7612. the 7604th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

7613. the 7604th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

7614. the 7604th method, wherein said fibrous tissue formation agent is silk or comprises silk.

7615. the 7604th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

7616. the 7604th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

7617. the 7604th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

7618. the 7604th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

7619. the 7604th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

7620. the 7604th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

7621. the 7604th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

7622. the 7604th method, wherein said fibrous tissue form agent and exist with particulate form.

7623. the 7604th method, wherein said compositions also comprises inflammatory cytokine.

7624. the 7604th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

7625. the 7604th method, wherein said compositions exists with the form of gel or paste.

7626. the 7604th method, wherein said fibrous tissue form the form that agent is bunch.

7627. the 7604th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

7628. the 7604th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

7629. the 7604th method, wherein said prosthese and coating combination, and described coating comprises described fibrous tissue formation agent.

7630. the 7604th method, wherein said prosthese and coating combination, and described coating is placed on the surface of described device.

7631. the 7604th method, wherein said prosthese and coating combination, and described coating directly contacts described device.

7632. the 7604th method, wherein said prosthese and coating combination, and described coating contacts described device indirectly.

7633. the 7604th method, wherein said prosthese and coating combination, and described coating layer portion ground covers described device.

7634. the 7604th method, wherein said prosthese and coating combination, and described coating fully covers described device.

7635. the 7604th method, wherein said prosthese and coating combination, and described coating is uniform coating.

7636. the 7604th method, wherein said prosthese and coating combination, and described coating is uneven coating.

7637. the 7604th method, wherein said prosthese and coating combination, and described coating is a discontinuous coating.

7638. the 7604th method, wherein said prosthese and coating combination, and described coating is to form the coating of pattern.

7639. the 7604th method, wherein said prosthese and coating combination, and described coating has 100 μ m or littler thickness.

7640. the 7604th method, wherein said prosthese and coating combination, and described coating has 10 μ m or littler thickness.

7641. the 7604th method, wherein said prosthese and coating combination, and described coating is being disposed the surface adhesion that this installs later and this device.

7642. the 7604th method, the combination of wherein said prosthese and coating, and described coating in room temperature at least 1 year the time interim be stable.

7643. the 7604th method, wherein said prosthese and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

7644. the 7604th method, wherein said prosthese and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

7645. the 7604th method, wherein said prosthese and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

7646. the 7604th method, wherein said prosthese and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

7647. the 7604th method, wherein said prosthese and coating combination, and described coating also contains polymer.

7648. the 7604th method, wherein said device comprise first coating with first compositions and second coating with second compositions.

7649. the 7604th method, wherein said device comprise first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

7650. the 7604th method, wherein said device comprises polymer.

7651. the 7604th method, wherein said device comprises polymer, and wherein said polymer is the component of described compositions.

7652. the 7604th method, wherein said prosthese and combination of polymers, and described polymer is a copolymer.

7653. the 7604th method, wherein said prosthese and combination of polymers, and described polymer is a block copolymer.

7654. the 7604th method, wherein said prosthese and combination of polymers, and described polymer is a random copolymer.

7655. the 7604th method, wherein said prosthese and combination of polymers, and described polymer is biodegradable polymer.

7656. the 7604th method, wherein said prosthese and combination of polymers, and described polymer is not biodegradable polymer.

7657. the 7604th method, wherein said prosthese and combination of polymers, and described polymer is a hydrophilic polymer.

7658. the 7604th method, wherein said prosthese and combination of polymers, and described polymer is a hydrophobic polymer.

7659. the 7604th method, wherein said prosthese and combination of polymers, and described polymer is the polymer with hydrophilic-structure territory.

7660. the 7604th method, wherein said prosthese and combination of polymers, and described polymer is the polymer with hydrophobic domains.

7661. the 7604th method, wherein said prosthese and combination of polymers, and described polymer is a non-conductive polymer.

7662. the 7604th method, wherein said prosthese and combination of polymers, and described polymer is an elastomer.

7663. the 7604th method, wherein said prosthese and combination of polymers, and described polymer is a hydrogel.

7664. the 7604th method, wherein said prosthese and combination of polymers, and described polymer is a siloxane polymer.

7665. the 7604th method, wherein said prosthese and combination of polymers, and described polymer is a hydrocarbon polymer.

7666. the 7604th method, wherein said prosthese and combination of polymers, and described polymer is the styrene derived polymers.

7667. the 7604th method, wherein said prosthese and combination of polymers, and described polymer is a butadiene polymer.

7668. the 7604th method, wherein said prosthese and combination of polymers, and described polymer is a macromonomer.

7669. the 7604th method, wherein said prosthese and combination of polymers, and described polymer is poly-(ethylene glycol) polymer.

7670. the 7604th method, wherein said prosthese and combination of polymers, and described polymer is an amorphous polymer.

7671. the 7604th method, wherein said prosthese and combination of polymers, and described polymer is a lubricant coating.

7672. the 7604th method, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

7673. the 7604th method, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

7674. the 7604th method, wherein said prosthese be combination second forms of pharmacologically active agents further.

7675. the 7604th method, wherein said prosthese further makes up antiinflammatory.

7676. the 7604th method, wherein said prosthese further makes up the inhibition infectious agent.

7677. the 7604th method, wherein said prosthese further makes up anthracycline.

7678. the 7604th method, wherein said prosthese further makes up doxorubicin.

7679. the 7604th method, wherein said prosthese further makes up mitoxantrone.

7680. the 7604th method, wherein said prosthese further makes up the fluorine pyrimidine.

7681. the 7604th method, wherein said prosthese further make up 5-fluorouracil (5-FU).

7682. the 7604th method, wherein said prosthese further makes up antifol.

7683. the 7604th method, wherein said prosthese further makes up methotrexate.

7684. the 7604th method, wherein said prosthese further makes up podophyllotoxin.

7685. the 7604th method, wherein said prosthese further makes up etoposide.

7686. the 7604th method, wherein said prosthese further makes up camptothecine.

7687. the 7604th method, wherein said prosthese further makes up hydroxyurea.

7688. the 7604th method, wherein said prosthese further makes up platinum complex.

7689. the 7604th method, wherein said prosthese further makes up cisplatin.

7690. the 7604th method, wherein said prosthese further makes up antithrombotic agent.

7691. the 7604th method, wherein said prosthese further makes up developing agent.

7692. the 7604th method, wherein said prosthese further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

7693. the 7604th method, wherein said prosthese further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

7694. the 7604th method, wherein said prosthese further makes up developing agent, and wherein said developing agent is a MRI response material.

7695. the 7604th method, wherein said prosthese further makes up developing agent, and wherein said developing agent comprises gadolinium chelate compound.

7696. the 7604th method, wherein said prosthese further makes up developing agent, and wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

7697. the 7604th method, wherein said prosthese further makes up developing agent, and wherein said developing agent comprises iron oxide compound.

7698. the 7604th method, wherein said prosthese further makes up developing agent, and wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

7699. the 7604th method, the material of the further combination results echo of wherein said prosthese.

7700. the 7604th method, the material of the further combination results echo of wherein said prosthese, the material of wherein said generation echo exists with the form of coating.

7701. the 7604th method, wherein said device is aseptic.

7702. the 7604th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

7703. the 7604th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

7704. the 7604th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

7705. the 7604th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

7706. the 7604th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

7707. the 7604th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

7708. the 7604th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

7709. the 7604th method, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

7710. the 7604th method, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

7711. the 7604th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

7712. the 7604th method, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

7713. the 7604th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

7714. the 7604th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

7715. the 7604th method, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

7716. the 7604th method, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

7717. the 7604th method, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

7718. the 7604th method, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

7719. the 7604th method, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

7720. the described fibrous tissue that the 7604th method, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

7721. the 7604th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7722. the 7604th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7723. the 7604th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7724. the 7604th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7725. the 7604th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7726. the 7604th method, wherein said rectificating surgery implant are the knee joint implants.

7727. the 7604th method, wherein said rectificating surgery implant are the hip implants.

7728. the 7604th method, wherein said rectificating surgery implant are the shoulder implants.

7729. the 7604th method, wherein said rectificating surgery implant are meant (toe) implant.

7730. method for preparing medical apparatus, comprise i) dental implant and ii) fibrous tissue form agent or comprise the compositions combination that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

7731. the 7730th method, wherein said fibrous tissue forms agent and promotes regeneration.

7732. forming agent, the 7730th method, wherein said fibrous tissue promote blood vessel to take place.

7733. the 7730th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

7734. the 7730th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

7735. the 7730th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

7736. the 7730th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

7737. the 7730th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

7738. the 7730th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

7739. the 7730th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

7740. the 7730th method, wherein said fibrous tissue formation agent is silk or comprises silk.

7741. the 7730th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

7742. the 7730th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

7743. the 7730th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

7744. the 7730th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

7745. the 7730th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

7746. the 7730th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

7747. the 7730th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

7748. the 7730th method, wherein said fibrous tissue form agent and exist with particulate form.

7749. the 7730th method, wherein said compositions also comprises inflammatory cytokine.

7750. the 7730th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

7751. the 7730th method, wherein said compositions exists with the form of gel or paste.

7752. the 7730th method, wherein said fibrous tissue form the form that agent is bunch.

7753. the 7730th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

7754. the 7730th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

7755. the 7730th method, wherein said implant and coating combination, and described coating comprises described fibrous tissue formation agent.

7756. the 7730th method, wherein said implant and coating combination, and described coating is placed on the surface of described device.

7757. the 7730th method, wherein said implant and coating combination, and described coating directly contacts described device.

7758. the 7730th method, wherein said implant and coating combination, and described coating contacts described device indirectly.

7759. the 7730th method, wherein said implant and coating combination, and described coating layer portion ground covers described device.

7760. the 7730th method, wherein said implant and coating combination, and described coating fully covers described device.

7761. the 7730th method, wherein said implant and coating combination, and described coating is uniform coating.

7762. the 7730th method, wherein said implant and coating combination, and described coating is uneven coating.

7763. the 7730th method, wherein said implant and coating combination, and described coating is a discontinuous coating.

7764. the 7730th method, wherein said implant and coating combination, and described coating is to form the coating of pattern.

7765. the 7730th method, wherein said implant and coating combination, and described coating has 100 μ m or littler thickness.

7766. the 7730th method, wherein said implant and coating combination, and described coating has 10 μ m or littler thickness.

7767. the 7730th method, wherein said implant and coating combination, and described coating is being disposed the surface adhesion that this installs later and this device.

7768. the 7730th method, the combination of wherein said implant and coating, and described coating in room temperature at least 1 year the time interim be stable.

7769. the 7730th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

7770. the 7730th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

7771. the 7730th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

7772. the 7730th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

7773. the 7730th method, wherein said implant and coating combination, and described coating also contains polymer.

7774. the 7730th method, wherein said device comprise first coating with first compositions and second coating with second compositions.

7775. the 7730th method, wherein said device comprise first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

7776. the 7730th method, wherein said device comprises polymer.

7777. the 7730th method, wherein said device comprises polymer, and wherein said polymer is the component of described compositions.

7778. the 7730th method, wherein said implant and combination of polymers, and described polymer is a copolymer.

7779. the 7730th method, wherein said implant and combination of polymers, and described polymer is a block copolymer.

7780. the 7730th method, wherein said implant and combination of polymers, and described polymer is a random copolymer.

7781. the 7730th method, wherein said implant and combination of polymers, and described polymer is biodegradable polymer.

7782. the 7730th method, wherein said implant and combination of polymers, and described polymer is not biodegradable polymer.

7783. the 7730th method, wherein said implant and combination of polymers, and described polymer is a hydrophilic polymer.

7784. the 7730th method, wherein said implant and combination of polymers, and described polymer is a hydrophobic polymer.

7785. the 7730th method, wherein said implant and combination of polymers, and described polymer is the polymer with hydrophilic-structure territory.

7786. the 7730th method, wherein said implant and combination of polymers, and described polymer is the polymer with hydrophobic domains.

7787. the 7730th method, wherein said implant and combination of polymers, and described polymer is a non-conductive polymer.

7788. the 7730th method, wherein said implant and combination of polymers, and described polymer is an elastomer.

7789. the 7730th method, wherein said implant and combination of polymers, and described polymer is a hydrogel.

7790. the 7730th method, wherein said implant and combination of polymers, and described polymer is a siloxane polymer.

7791. the 7730th method, wherein said implant and combination of polymers, and described polymer is a hydrocarbon polymer.

7792. the 7730th method, wherein said implant and combination of polymers, and described polymer is the styrene derived polymers.

7793. the 7730th method, wherein said implant and combination of polymers, and described polymer is a butadiene polymer.

7794. the 7730th method, wherein said implant and combination of polymers, and described polymer is a macromonomer.

7795. the 7730th method, wherein said implant and combination of polymers, and described polymer is poly-(ethylene glycol) polymer.

7796. the 7730th method, wherein said implant and combination of polymers, and described polymer is an amorphous polymer.

7797. the 7730th method, wherein said implant and combination of polymers, and described polymer is a lubricant coating.

7798. the 7730th method, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

7799. the 7730th method, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

7800. the 7730th method, wherein said implant be combination second forms of pharmacologically active agents further.

7801. the 7730th method, wherein said implant further makes up antiinflammatory.

7802. the 7730th method, wherein said implant further makes up the inhibition infectious agent.

7803. the 7730th method, wherein said implant further makes up anthracycline.

7804. the 7730th method, wherein said implant further makes up doxorubicin.

7805. the 7730th method, wherein said implant further makes up mitoxantrone.

7806. the 7730th method, wherein said implant further makes up the fluorine pyrimidine.

7807. the 7730th method, wherein said implant further make up 5-fluorouracil (5-FU).

7808. the 7730th method, wherein said implant further makes up antifol.

7809. the 7730th method, wherein said implant further makes up methotrexate.

7810. the 7730th method, wherein said implant further makes up podophyllotoxin.

7811. the 7730th method, wherein said implant further makes up etoposide.

7812. the 7730th method, wherein said implant further makes up camptothecine.

7813. the 7730th method, wherein said implant further makes up hydroxyurea.

7814. the 7730th method, wherein said implant further makes up platinum complex.

7815. the 7730th method, wherein said implant further makes up cisplatin.

7816. the 7730th method, wherein said implant further makes up antithrombotic agent.

7817. the 7730th method, wherein said implant further makes up developing agent.

7818. the 7730th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

7819. the 7730th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

7820. the 7730th method, wherein said implant further makes up developing agent, and wherein said developing agent is a MRI response material.

7821. the 7730th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises gadolinium chelate compound.

7822. the 7730th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

7823. the 7730th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises iron oxide compound.

7824. the 7730th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

7825. the 7730th method, the material of the further combination results echo of wherein said implant.

7826. the 7730th method, the material of the further combination results echo of wherein said implant, the material of wherein said generation echo exists with the form of coating.

7827. the 7730th method, wherein said device is aseptic.

7828. the 7730th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

7829. the 7730th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

7830. the 7730th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

7831. the 7730th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

7832. the 7730th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

7833. the 7730th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

7834. the 7730th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

7835. the 7730th method, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

7836. the 7730th method, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

7837. the 7730th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

7838. the 7730th method, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

7839. the 7730th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

7840. the 7730th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

7841. the 7730th method, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

7842. the 7730th method, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

7843. the 7730th method, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

7844. the 7730th method, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

7845. the 7730th method, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

7846. the described fibrous tissue that the 7730th method, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

7847. the 7730th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7848. the 7730th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7849. the 7730th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7850. the 7730th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7851. the 7730th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7852. the 7730th method, wherein said implant are the titanium fixtures that is used for replacing the root portion of the natural teeth that loses.

7853. the 7730th method, wherein said implant is an implant for into bones.

7854. the 7730th method, wherein said implant are the subperiosteum implants.

7855. the 7730th method, wherein said implant are guiding osteanagenesis (GBR) implants.

7856. the 7730th method, wherein said implant are the dental implants of the agglutination after the control periodontal.

7857. method for preparing medical apparatus, comprise i) the internal fixation implant and ii) fibrous tissue form agent or comprise the combination of compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

7858. the 7857th method, wherein said fibrous tissue forms agent and promotes regeneration.

7859. forming agent, the 7857th method, wherein said fibrous tissue promote blood vessel to take place.

7860. the 7857th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

7861. the 7857th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

7862. the 7857th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

7863. the 7857th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

7864. the 7857th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

7865. the 7857th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

7866. the 7857th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

7867. the 7857th method, wherein said fibrous tissue formation agent is silk or comprises silk.

7868. the 7857th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

7869. the 7857th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

7870. the 7857th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

7871. the 7857th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

7872. the 7857th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

7873. the 7857th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

7874. the 7857th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

7875. the 7857th method, wherein said fibrous tissue form agent and exist with particulate form.

7876. the 7857th method, wherein said compositions also comprises inflammatory cytokine.

7877. the 7857th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

7878. the 7857th method, wherein said compositions exists with the form of gel or paste.

7879. the 7857th method, wherein said fibrous tissue form the form that agent is bunch.

7880. the 7857th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

7881. the 7857th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

7882. the 7857th method, wherein said implant and coating combination, and described coating comprises described fibrous tissue formation agent.

7883. the 7857th method, wherein said implant and coating combination, and described coating is placed on the surface of described device.

7884. the 7857th method, wherein said implant and coating combination, and described coating directly contacts described device.

7885. the 7857th method, wherein said implant and coating combination, and described coating contacts described device indirectly.

7886. the 7857th method, wherein said implant and coating combination, and described coating layer portion ground covers described device.

7887. the 7857th method, wherein said implant and coating combination, and described coating fully covers described device.

7888. the 7857th method, wherein said implant and coating combination, and described coating is uniform coating.

7889. the 7857th method, wherein said implant and coating combination, and described coating is uneven coating.

7890. the 7857th method, wherein said implant and coating combination, and described coating is a discontinuous coating.

7891. the 7857th method, wherein said implant and coating combination, and described coating is to form the coating of pattern.

7892. the 7857th method, wherein said implant and coating combination, and described coating has 100 μ m or littler thickness.

7893. the 7857th method, wherein said implant and coating combination, and described coating has 10 μ m or littler thickness.

7894. the 7857th method, wherein said implant and coating combination, and described coating is being disposed the surface adhesion that this installs later and this device.

7895. the 7857th method, the combination of wherein said implant and coating, and described coating in room temperature at least 1 year the time interim be stable.

7896. the 7857th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

7897. the 7857th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

7898. the 7857th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

7899. the 7857th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

7900. the 7857th method, wherein said implant and coating combination, and described coating also contains polymer.

7901. the 7857th method, wherein said device comprise first coating with first compositions and second coating with second compositions.

7902. the 7857th method, wherein said device comprise first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

7903. the 7857th method, wherein said device comprises polymer.

7904. the 7857th method, wherein said device comprises polymer, and wherein said polymer is the component of described compositions.

7905. the 7857th method, wherein said implant and combination of polymers, and described polymer is a copolymer.

7906. the 7857th method, wherein said implant and combination of polymers, and described polymer is a block copolymer.

7907. the 7857th method, wherein said implant and combination of polymers, and described polymer is a random copolymer.

7908. the 7857th method, wherein said implant and combination of polymers, and described polymer is biodegradable polymer.

7909. the 7857th method, wherein said implant and combination of polymers, and described polymer is not biodegradable polymer.

7910. the 7857th method, wherein said implant and combination of polymers, and described polymer is a hydrophilic polymer.

7911. the 7857th method, wherein said implant and combination of polymers, and described polymer is a hydrophobic polymer.

7912. the 7857th method, wherein said implant and combination of polymers, and described polymer is the polymer with hydrophilic-structure territory.

7913. the 7857th method, wherein said implant and combination of polymers, and described polymer is the polymer with hydrophobic domains.

7914. the 7857th method, wherein said implant and combination of polymers, and described polymer is a non-conductive polymer.

7915. the 7857th method, wherein said implant and combination of polymers, and described polymer is an elastomer.

7916. the 7857th method, wherein said implant and combination of polymers, and described polymer is a hydrogel.

7917. the 7857th method, wherein said implant and combination of polymers, and described polymer is a siloxane polymer.

7918. the 7857th method, wherein said implant and combination of polymers, and described polymer is a hydrocarbon polymer.

7919. the 7857th method, wherein said implant and combination of polymers, and described polymer is the styrene derived polymers.

7920. the 7857th method, wherein said implant and combination of polymers, and described polymer is a butadiene polymer.

7921. the 7857th method, wherein said implant and combination of polymers, and described polymer is a macromonomer.

7922. the 7857th method, wherein said implant and combination of polymers, and described polymer is poly-(ethylene glycol) polymer.

7923. the 7857th method, wherein said implant and combination of polymers, and described polymer is an amorphous polymer.

7924. the 7857th method, wherein said implant and combination of polymers, and described polymer is a lubricant coating.

7925. the 7857th method, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

7926. the 7857th method, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

7927. the 7857th method, wherein said implant be combination second forms of pharmacologically active agents further.

7928. the 7857th method, wherein said implant further makes up antiinflammatory.

7929. the 7857th method, wherein said implant further makes up the inhibition infectious agent.

7930. the 7857th method, wherein said implant further makes up anthracycline.

7931. the 7857th method, wherein said implant further makes up doxorubicin.

7932. the 7857th method, wherein said implant further makes up mitoxantrone.

7933. the 7857th method, wherein said implant further makes up the fluorine pyrimidine.

7934. the 7857th method, wherein said implant further make up 5-fluorouracil (5-FU).

7935. the 7857th method, wherein said implant further makes up antifol.

7936. the 7857th method, wherein said implant further makes up methotrexate.

7937. the 7857th method, wherein said implant further makes up podophyllotoxin.

7938. the 7857th method, wherein said implant further makes up etoposide.

7939. the 7857th method, wherein said implant further makes up camptothecine.

7940. the 7857th method, wherein said implant further makes up hydroxyurea.

7941. the 7857th method, wherein said implant further makes up platinum complex.

7942. the 7857th method, wherein said implant further makes up cisplatin.

7943. the 7857th method, wherein said implant further makes up antithrombotic agent.

7944. the 7857th method, wherein said implant further makes up developing agent.

7945. the 7857th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

7946. the 7857th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

7947. the 7857th method, wherein said implant further makes up developing agent, and wherein said developing agent is a MRI response material.

7948. the 7857th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises gadolinium chelate compound.

7949. the 7857th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

7950. the 7857th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises iron oxide compound.

7951. the 7857th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

7952. the 7857th method, the material of the further combination results echo of wherein said implant.

7953. the 7857th method, the material of the further combination results echo of wherein said implant, the material of wherein said generation echo exists with the form of coating.

7954. the 7857th method, wherein said device is aseptic.

7955. the 7857th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

7956. the 7857th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

7957. the 7857th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

7958. the 7857th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

7959. the 7857th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

7960. the 7857th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

7961. the 7857th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

7962. the 7857th method, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

7963. the 7857th method, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

7964. the 7857th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

7965. the 7857th method, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

7966. the 7857th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

7967. the 7857th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

7968. the 7857th method, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

7969. the 7857th method, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

7970. the 7857th method, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

7971. the 7857th method, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

7972. the 7857th method, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

7973. the described fibrous tissue that the 7857th method, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

7974. the 7857th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7975. the 7857th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7976. the 7857th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7977. the 7857th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7978. the 7857th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

7979. the 7857th method, wherein said implant comprises screw.

7980. the 7857th method, wherein said implant are, or comprise hold-down screw.

7981. the 7857th method, wherein said implant are, or comprise the interference screw.

7982. the 7857th method, wherein said implant are, or comprise the rotor screw.

7983. the 7857th method, wherein said implant are, or comprise pin.

7984. the 7857th method, wherein said implant are, or comprise side plate.

7985. the 7857th method, wherein said implant are, or comprise intramedullary pin.

7986. the 7857th method, wherein said implant are, or comprise intramedullary needle.

7987. the 7857th method, wherein said implant is a hone lamella.

7988. the 7857th method, wherein said implant is a bone screw.

7989. the 7857th method, wherein said implant are level and smooth pins.

7990. the 7857th method, wherein said implant is a screw needle.

7991. the 7857th method, wherein said implant are tinsel (wire).

7992. the 7857th method, wherein said implant is a plate.

7993. method for preparing medical apparatus, comprise i) the external stability implant and ii) fibrous tissue form agent or comprise the combination of compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

7994. the 7993rd method, wherein said fibrous tissue forms agent and promotes regeneration.

7995. forming agent, the 7993rd method, wherein said fibrous tissue promote blood vessel to take place.

7996. the 7993rd method, wherein said fibrous tissue form agent and promote the fibroblast migration.

7997. the 7993rd method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

7998. the 7993rd method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

7999. the 7993rd method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

8000. the 7993rd method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

8001. the 7993rd method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

8002. the 7993rd method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

8003. the 7993rd method, wherein said fibrous tissue formation agent is silk or comprises silk.

8004. the 7993rd method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

8005. the 7993rd method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

8006. the 7993rd method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

8007. the 7993rd method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

8008. the 7993rd method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

8009. the 7993rd method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

8010. the 7993rd method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

8011. the 7993rd method, wherein said fibrous tissue form agent and exist with particulate form.

8012. the 7993rd method, wherein said compositions also comprises inflammatory cytokine.

8013. the 7993rd method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

8014. the 7993rd method, wherein said compositions exists with the form of gel or paste.

8015. the 7993rd method, wherein said fibrous tissue form the form that agent is bunch.

8016. the 7993rd method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

8017. the 7993rd method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

8018. the 7993rd method, wherein said implant and coating combination, and described coating comprises described fibrous tissue formation agent.

8019. the 7993rd method, wherein said implant and coating combination, and described coating is placed on the surface of described device.

8020. the 7993rd method, wherein said implant and coating combination, and described coating directly contacts described device.

8021. the 7993rd method, wherein said implant and coating combination, and described coating contacts described device indirectly.

8022. the 7993rd method, wherein said implant and coating combination, and described coating layer portion ground covers described device.

8023. the 7993rd method, wherein said implant and coating combination, and described coating fully covers described device.

8024. the 7993rd method, wherein said implant and coating combination, and described coating is uniform coating.

8025. the 7993rd method, wherein said implant and coating combination, and described coating is uneven coating.

8026. the 7993rd method, wherein said implant and coating combination, and described coating is a discontinuous coating.

8027. the 7993rd method, wherein said implant and coating combination, and described coating is to form the coating of pattern.

8028. the 7993rd method, wherein said implant and coating combination, and described coating has 100 μ m or littler thickness.

8029. the 7993rd method, wherein said implant and coating combination, and described coating has 10 μ m or littler thickness.

8030. the 7993rd method, wherein said implant and coating combination, and described coating is being disposed the surface adhesion that this installs later and this device.

8031. the 7993rd method, the combination of wherein said implant and coating, and described coating in room temperature at least 1 year the time interim be stable.

8032. the 7993rd method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

8033. the 7993rd method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

8034. the 7993rd method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

8035. the 7993rd method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

8036. the 7993rd method, wherein said implant and coating combination, and described coating also contains polymer.

8037. the 7993rd method, wherein said device comprise first coating with first compositions and second coating with second compositions.

8038. the 7993rd method, wherein said device comprise first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

8039. the 7993rd method, wherein said device comprises polymer.

8040. the 7993rd method, wherein said device comprises polymer, and wherein said polymer is the component of described compositions.

8041. the 7993rd method, wherein said implant and combination of polymers, and described polymer is a copolymer.

8042. the 7993rd method, wherein said implant and combination of polymers, and described polymer is a block copolymer.

8043. the 7993rd method, wherein said implant and combination of polymers, and described polymer is a random copolymer.

8044. the 7993rd method, wherein said implant and combination of polymers, and described polymer is biodegradable polymer.

8045. the 7993rd method, wherein said implant and combination of polymers, and described polymer is not biodegradable polymer.

8046. the 7993rd method, wherein said implant and combination of polymers, and described polymer is a hydrophilic polymer.

8047. the 7993rd method, wherein said implant and combination of polymers, and described polymer is a hydrophobic polymer.

8048. the 7993rd method, wherein said implant and combination of polymers, and described polymer is the polymer with hydrophilic-structure territory.

8049. the 7993rd method, wherein said implant and combination of polymers, and described polymer is the polymer with hydrophobic domains.

8050. the 7993rd method, wherein said implant and combination of polymers, and described polymer is a non-conductive polymer.

8051. the 7993rd method, wherein said implant and combination of polymers, and described polymer is an elastomer.

8052. the 7993rd method, wherein said implant and combination of polymers, and described polymer is a hydrogel.

8053. the 7993rd method, wherein said implant and combination of polymers, and described polymer is a siloxane polymer.

8054. the 7993rd method, wherein said implant and combination of polymers, and described polymer is a hydrocarbon polymer.

8055. the 7993rd method, wherein said implant and combination of polymers, and described polymer is the styrene derived polymers.

8056. the 7993rd method, wherein said implant and combination of polymers, and described polymer is a butadiene polymer.

8057. the 7993rd method, wherein said implant and combination of polymers, and described polymer is a macromonomer.

8058. the 7993rd method, wherein said implant and combination of polymers, and described polymer is poly-(ethylene glycol) polymer.

8059. the 7993rd method, wherein said implant and combination of polymers, and described polymer is an amorphous polymer.

8060. the 7993rd method, wherein said implant and combination of polymers, and described polymer is a lubricant coating.

8061. the 7993rd method, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

8062. the 7993rd method, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

8063. the 7993rd method, wherein said implant be combination second forms of pharmacologically active agents further.

8064. the 7993rd method, wherein said implant further makes up antiinflammatory.

8065. the 7993rd method, wherein said implant further makes up the inhibition infectious agent.

8066. the 7993rd method, wherein said implant further makes up anthracycline.

8067. the 7993rd method, wherein said implant further makes up doxorubicin.

8068. the 7993rd method, wherein said implant further makes up mitoxantrone.

8069. the 7993rd method, wherein said implant further makes up the fluorine pyrimidine.

8070. the 7993rd method, wherein said implant further make up 5-fluorouracil (5-FU).

8071. the 7993rd method, wherein said implant further makes up antifol.

8072. the 7993rd method, wherein said implant further makes up methotrexate.

8073. the 7993rd method, wherein said implant further makes up podophyllotoxin.

8074. the 7993rd method, wherein said implant further makes up etoposide.

8075. the 7993rd method, wherein said implant further makes up camptothecine.

8076. the 7993rd method, wherein said implant further makes up hydroxyurea.

8077. the 7993rd method, wherein said implant further makes up platinum complex.

8078. the 7993rd method, wherein said implant further makes up cisplatin.

8079. the 7993rd method, wherein said implant further makes up antithrombotic agent.

8080. the 7993rd method, wherein said implant further makes up developing agent.

8081. the 7993rd method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

8082. the 7993rd method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

8083. the 7993rd method, wherein said implant further makes up developing agent, and wherein said developing agent is a MRI response material.

8084. the 7993rd method, wherein said implant further makes up developing agent, and wherein said developing agent comprises gadolinium chelate compound.

8085. the 7993rd method, wherein said implant further makes up developing agent, and wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

8086. the 7993rd method, wherein said implant further makes up developing agent, and wherein said developing agent comprises iron oxide compound.

8087. the 7993rd method, wherein said implant further makes up developing agent, and wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

8088. the 7993rd method, the material of the further combination results echo of wherein said implant.

8089. the 7993rd method, the material of the further combination results echo of wherein said implant, the material of wherein said generation echo exists with the form of coating.

8090. the 7993rd method, wherein said device is aseptic.

8091. the 7993rd method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

8092. the 7993rd method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

8093. the 7993rd method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

8094. the 7993rd method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

8095. the 7993rd method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

8096. the 7993rd method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

8097. the 7993rd method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

8098. the 7993rd method, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

8099. the 7993rd method, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

8100. the 7993rd method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

8101. the 7993rd method, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

8102. forming agent, the 7993rd method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharge in the described device with valid density by being diffused in from disposing.

8103. forming agent, the 7993rd method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharging in the described device from disposing with valid density by corroding said composition.

8104. the 7993rd method, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

8105. the 7993rd method, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

8106. the 7993rd method, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

8107. the 7993rd method, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

8108. the 7993rd method, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

8109. the described fibrous tissue that the 7993rd method, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

8110. the 7993rd method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8111. the 7993rd method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8112. the 7993rd method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8113. the 7993rd method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8114. the 7993rd method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8115. the 7993rd method, wherein said implant are the forms of pin.

8116. the 7993rd method, wherein said implant are used to make laterally (transverse) fracture stabilization.

8117. the 7993rd method, wherein said implant comprises steel.

8118. method for preparing medical apparatus, comprise i) the collagen protein implant and ii) fibrous tissue form agent or comprise the combination of compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

8119. the 8118th method, wherein said fibrous tissue forms agent and promotes regeneration.

8120. forming agent, the 8118th method, wherein said fibrous tissue promote blood vessel to take place.

8121. the 8118th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

8122. the 8118th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

8123. the 8118th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

8124. the 8118th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

8125. the 8118th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

8126. the 8118th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

8127. the 8118th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

8128. the 8118th method, wherein said fibrous tissue formation agent is silk or comprises silk.

8129. the 8118th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

8130. the 8118th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

8131. the 8118th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

8132. the 8118th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

8133. the 8118th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

8134. the 8118th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

8135. the 8118th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

8136. the 8118th method, wherein said fibrous tissue form agent and exist with particulate form.

8137. the 8118th method, wherein said compositions also comprises inflammatory cytokine.

8138. the 8118th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

8139. the 8118th method, wherein said compositions exists with the form of gel or paste.

8140. the 8118th method, wherein said fibrous tissue form the form that agent is bunch.

8141. the 8118th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

8142. the 8118th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

8143. the 8118th method, wherein said implant and coating combination, and described coating comprises described fibrous tissue formation agent.

8144. the 8118th method, wherein said implant and coating combination, and described coating is placed on the surface of described device.

8145. the 8118th method, wherein said implant and coating combination, and described coating directly contacts described device.

8146. the 8118th method, wherein said implant and coating combination, and described coating contacts described device indirectly.

8147. the 8118th method, wherein said implant and coating combination, and described coating layer portion ground covers described device.

8148. the 8118th method, wherein said implant and coating combination, and described coating fully covers described device.

8149. the 8118th method, wherein said implant and coating combination, and described coating is uniform coating.

8150. the 8118th method, wherein said implant and coating combination, and described coating is uneven coating.

8151. the 8118th method, wherein said implant and coating combination, and described coating is a discontinuous coating.

8152. the 8118th method, wherein said implant and coating combination, and described coating is to form the coating of pattern.

8153. the 8118th method, wherein said implant and coating combination, and described coating has 100 μ m or littler thickness.

8154. the 8118th method, wherein said implant and coating combination, and described coating has 10 μ m or littler thickness.

8155. the 8118th method, wherein said implant and coating combination, and described coating is being disposed the surface adhesion that this installs later and this device.

8156. the 8118th method, the combination of wherein said implant and coating, and described coating in room temperature at least 1 year the time interim be stable.

8157. the 8118th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

8158. the 8118th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

8159. the 8118th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

8160. the 8118th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

8161. the 8118th method, wherein said implant and coating combination, and described coating also contains polymer.

8162. the 8118th method, wherein said device comprise first coating with first compositions and second coating with second compositions.

8163. the 8118th method, wherein said device comprise first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

8164. the 8118th method, wherein said device comprises polymer.

8165. the 8118th method, wherein said device comprises polymer, and wherein said polymer is the component of described compositions.

8166. the 8118th method, wherein said implant and combination of polymers, and described polymer is a copolymer.

8167. the 8118th method, wherein said implant and combination of polymers, and described polymer is a block copolymer.

8168. the 8118th method, wherein said implant and combination of polymers, and described polymer is a random copolymer.

8169. the 8118th method, wherein said implant and combination of polymers, and described polymer is biodegradable polymer.

8170. the 8118th method, wherein said implant and combination of polymers, and described polymer is not biodegradable polymer.

8171. the 8118th method, wherein said implant and combination of polymers, and described polymer is a hydrophilic polymer.

8172. the 8118th method, wherein said implant and combination of polymers, and described polymer is a hydrophobic polymer.

8173. the 8118th method, wherein said implant and combination of polymers, and described polymer is the polymer with hydrophilic-structure territory.

8174. the 8118th method, wherein said implant and combination of polymers, and described polymer is the polymer with hydrophobic domains.

8175. the 8118th method, wherein said implant and combination of polymers, and described polymer is a non-conductive polymer.

8176. the 8118th method, wherein said implant and combination of polymers, and described polymer is an elastomer.

8177. the 8118th method, wherein said implant and combination of polymers, and described polymer is a hydrogel.

8178. the 8118th method, wherein said implant and combination of polymers, and described polymer is a siloxane polymer.

8179. the 8118th method, wherein said implant and combination of polymers, and described polymer is a hydrocarbon polymer.

8180. the 8118th method, wherein said implant and combination of polymers, and described polymer is the styrene derived polymers.

8181. the 8118th method, wherein said implant and combination of polymers, and described polymer is a butadiene polymer.

8182. the 8118th method, wherein said implant and combination of polymers, and described polymer is a macromonomer.

8183. the 8118th method, wherein said implant and combination of polymers, and described polymer is poly-(ethylene glycol) polymer.

8184. the 8118th method, wherein said implant and combination of polymers, and described polymer is an amorphous polymer.

8185. the 8118th method, wherein said implant and combination of polymers, and described polymer is a lubricant coating.

8186. the 8118th method, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

8187. the 8118th method, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

8188. the 8118th method, wherein said implant be combination second forms of pharmacologically active agents further.

8189. the 8118th method, wherein said implant further makes up antiinflammatory.

8190. the 8118th method, wherein said implant further makes up the inhibition infectious agent.

8191. the 8118th method, wherein said implant further makes up anthracycline.

8192. the 8118th method, wherein said implant further makes up doxorubicin.

8193. the 8118th method, wherein said implant further makes up mitoxantrone.

8194. the 8118th method, wherein said implant further makes up the fluorine pyrimidine.

8195. the 8118th method, wherein said implant further make up 5-fluorouracil (5-FU).

8196. the 8118th method, wherein said implant further makes up antifol.

8197. the 8118th method, wherein said implant further makes up methotrexate.

8198. the 8118th method, wherein said implant further makes up podophyllotoxin.

8199. the 8118th method, wherein said implant further makes up etoposide.

8200. the 8118th method, wherein said implant further makes up camptothecine.

8201. the 8118th method, wherein said implant further makes up hydroxyurea.

8202. the 8118th method, wherein said implant further makes up platinum complex.

8203. the 8118th method, wherein said implant further makes up cisplatin.

8204. the 8118th method, wherein said implant further makes up antithrombotic agent.

8205. the 8118th method, wherein said implant further makes up developing agent.

8206. the 8118th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

8207. the 8118th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

8208. the 8118th method, wherein said implant further makes up developing agent, and wherein said developing agent is a MRI response material.

8209. the 8118th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises gadolinium chelate compound.

8210. the 8118th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

8211. the 8118th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises iron oxide compound.

8212. the 8118th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

8213. the 8118th method, the material of the further combination results echo of wherein said implant.

8214. the 8118th method, the material of the further combination results echo of wherein said implant, the material of wherein said generation echo exists with the form of coating.

8215. the 8118th method, wherein said device is aseptic.

8216. the 8118th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

8217. the 8118th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

8218. the 8118th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

8219. the 8118th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

8220. the 8118th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

8221. the 8118th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

8222. the 8118th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

8223. the 8118th method, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

8224. the 8118th method, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

8225. the 8118th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

8226. the 8118th method, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

8227. forming agent, the 8118th method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharge in the described device with valid density by being diffused in from disposing.

8228. forming agent, the 8118th method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharging in the described device from disposing with valid density by corroding said composition.

8229. the 8118th method, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

8230. the 8118th method, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

8231. the 8118th method, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

8232. the 8118th method, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

8233. the 8118th method, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

8234. the described fibrous tissue that the 8118th method, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

8235. the 8118th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8236. the 8118th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8237. the 8118th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8238. the 8118th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8239. the 8118th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8240. the 8118th method, wherein said implant is a dental implant.

8241. the 8118th method, wherein said implant is a rectificating surgery implant.

8242. the 8118th method, wherein said implant are the surgical operation meshes.

8243. the 8118th method, wherein said implant is all or part of to be made by crosslinked collagen protein.

8244. method for preparing medical apparatus, comprise i) the fallopian tube implant and ii) fibrous tissue form agent or comprise the combination of compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

8245. the 8244th method, wherein said fibrous tissue forms agent and promotes regeneration.

8246. forming agent, the 8244th method, wherein said fibrous tissue promote blood vessel to take place.

8247. the 8244th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

8248. the 8244th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

8249. the 8244th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

8250. the 8244th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

8251. the 8244th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

8252. the 8244th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

8253. the 8244th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

8254. the 8244th method, wherein said fibrous tissue formation agent is silk or comprises silk.

8255. the 8244th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

8256. the 8244th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

8257. the 8244th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

8258. the 8244th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

8259. the 8244th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

8260. the 8244th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

8261. the 8244th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

8262. the 8244th method, wherein said fibrous tissue form agent and exist with particulate form.

8263. the 8244th method, wherein said compositions also comprises inflammatory cytokine.

8264. the 8244th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

8265. the 8244th method, wherein said compositions exists with the form of gel or paste.

8266. the 8244th method, wherein said fibrous tissue form the form that agent is bunch.

8267. the 8244th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

8268. the 8244th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

8269. the 8244th method, wherein said implant and coating combination, and described coating comprises described fibrous tissue formation agent.

8270. the 8244th method, wherein said implant and coating combination, and described coating is placed on the surface of described device.

8271. the 8244th method, wherein said implant and coating combination, and described coating directly contacts described device.

8272. the 8244th method, wherein said implant and coating combination, and described coating contacts described device indirectly.

8273. the 8244th method, wherein said implant and coating combination, and described coating layer portion ground covers described device.

8274. the 8244th method, wherein said implant and coating combination, and described coating fully covers described device.

8275. the 8244th method, wherein said implant and coating combination, and described coating is uniform coating.

8276. the 8244th method, wherein said implant and coating combination, and described coating is uneven coating.

8277. the 8244th method, wherein said implant and coating combination, and described coating is a discontinuous coating.

8278. the 8244th method, wherein said implant and coating combination, and described coating is to form the coating of pattern.

8279. the 8244th method, wherein said implant and coating combination, and described coating has 100 μ m or littler thickness.

8280. the 8244th method, wherein said implant and coating combination, and described coating has 10 μ m or littler thickness.

8281. the 8244th method, wherein said implant and coating combination, and described coating is being disposed the surface adhesion that this installs later and this device.

8282. the 8244th method, the combination of wherein said implant and coating, and described coating in room temperature at least 1 year the time interim be stable.

8283. the 8244th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

8284. the 8244th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

8285. the 8244th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

8286. the 8244th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

8287. the 8244th method, wherein said implant and coating combination, and described coating also contains polymer.

8288. the 8244th method, wherein said device comprise first coating with first compositions and second coating with second compositions.

8289. the 8244th method, wherein said device comprise first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

8290. the 8244th method, wherein said device comprises polymer.

8291. the 8244th method, wherein said device comprises polymer, and wherein said polymer is the component of described compositions.

8292. the 8244th method, wherein said implant and combination of polymers, and described polymer is a copolymer.

8293. the 8244th method, wherein said implant and combination of polymers, and described polymer is a block copolymer.

8294. the 8244th method, wherein said implant and combination of polymers, and described polymer is a random copolymer.

8295. the 8244th method, wherein said implant and combination of polymers, and described polymer is biodegradable polymer.

8296. the 8244th method, wherein said implant and combination of polymers, and described polymer is not biodegradable polymer.

8297. the 8244th method, wherein said implant and combination of polymers, and described polymer is a hydrophilic polymer.

8298. the 8244th method, wherein said implant and combination of polymers, and described polymer is a hydrophobic polymer.

8299. the 8244th method, wherein said implant and combination of polymers, and described polymer has the hydrophilic-structure territory.

8300. the 8244th method, wherein said implant and combination of polymers, and described polymer has hydrophobic domains.

8301. the 8244th method, wherein said implant and combination of polymers, and described polymer is a non-conductive polymer.

8302. the 8244th method, wherein said implant and combination of polymers, and described polymer is an elastomer.

8303. the 8244th method, wherein said implant and combination of polymers, and described polymer is a hydrogel.

8304. the 8244th method, wherein said implant and combination of polymers, and described polymer is a siloxane polymer.

8305. the 8244th method, wherein said implant and combination of polymers, and described polymer is a hydrocarbon polymer.

8306. the 8244th method, wherein said implant and combination of polymers, and described polymer is the styrene derived polymers.

8307. the 8244th method, wherein said implant and combination of polymers, and described polymer is a butadiene polymer.

8308. the 8244th method, wherein said implant and combination of polymers, and described polymer is a macromonomer.

8309. the 8244th method, wherein said implant and combination of polymers, and described polymer is poly-(ethylene glycol) polymer.

8310. the 8244th method, wherein said implant and combination of polymers, and described polymer is an amorphous polymer.

8311. the 8244th method, wherein said implant and combination of polymers, and described polymer is a lubricant coating.

8312. the 8244th method, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

8313. the 8244th method, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

8314. the 8244th method, wherein said implant be combination second forms of pharmacologically active agents further.

8315. the 8244th method, wherein said implant further makes up antiinflammatory.

8316. the 8244th method, wherein said implant further makes up the inhibition infectious agent.

8317. the 8244th method, wherein said implant further makes up anthracycline.

8318. the 8244th method, wherein said implant further makes up doxorubicin.

8319. the 8244th method, wherein said implant further makes up mitoxantrone.

8320. the 8244th method, wherein said implant further makes up the fluorine pyrimidine.

8321. the 8244th method, wherein said implant further make up 5-fluorouracil (5-FU).

8322. the 8244th method, wherein said implant further makes up antifol.

8323. the 8244th method, wherein said implant further makes up methotrexate.

8324. the 8244th method, wherein said implant further makes up podophyllotoxin.

8325. the 8244th method, wherein said implant further makes up etoposide.

8326. the 8244th method, wherein said implant further makes up camptothecine.

8327. the 8244th method, wherein said implant further makes up hydroxyurea.

8328. the 8244th method, wherein said implant further makes up platinum complex.

8329. the 8244th method, wherein said implant further makes up cisplatin.

8330. the 8244th method, wherein said implant further makes up antithrombotic agent.

8331. the 8244th method, wherein said implant further makes up developing agent.

8332. the 8244th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

8333. the 8244th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

8334. the 8244th method, wherein said implant further makes up developing agent, and wherein said developing agent is a MRI response material.

8335. the 8244th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises gadolinium chelate compound.

8336. the 8244th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

8337. the 8244th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises iron oxide compound.

8338. the 8244th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

8339. the 8244th method, the material of the further combination results echo of wherein said implant.

8340. the 8244th method, the material of the further combination results echo of wherein said implant, the material of wherein said generation echo exists with the form of coating.

8341. the 8244th method, wherein said device is aseptic.

8342. the 8244th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

8343. the 8244th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

8344. the 8244th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

8345. the 8244th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

8346. the 8244th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

8347. the 8244th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

8348. the 8244th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

8349. the 8244th method, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

8350. the 8244th method, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

8351. the 8244th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

8352. the 8244th method, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

8353. forming agent, the 8244th method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharge in the described device with valid density by being diffused in from disposing.

8354. forming agent, the 8244th method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharging in the described device from disposing with valid density by corroding said composition.

8355. the 8244th method, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

8356. the 8244th method, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

8357. the 8244th method, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

8358. the 8244th method, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

8359. the 8244th method, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

8360. the described fibrous tissue that the 8244th method, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

8361. the 8244th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8362. the 8244th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8363. the 8244th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8364. the 8244th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8365. the 8244th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8366. the 8244th method, wherein said implant are vessel clamp (duct clamp).

8367. the 8244th method, wherein said implant are that lobe sterillization device is arranged.

8368. the 8244th method, wherein said implant are female sterilization devices in the transplantable fallopian tube.

8369. the 8244th device, wherein said implant are inaccessible tinsel or coil fallopian tube implant.

8370. the 8244th device, wherein said implant are through conduit occlusive implant.

8371. the 8244th device, wherein said implant are the fallopian tube stents.

8372. the 8244th device, wherein said implant are contraception temper palace implants.

8373. method for preparing medical apparatus, comprise i) the prosthese anal sphincter with ii) become fiber agent or comprise the combination of compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

8374. the 8373rd method, wherein said fibrous tissue forms agent and promotes regeneration.

8375. forming agent, the 8373rd method, wherein said fibrous tissue promote blood vessel to take place.

8376. the 8373rd method, wherein said fibrous tissue form agent and promote the fibroblast migration.

8377. the 8373rd method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

8378. the 8373rd method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

8379. the 8373rd method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

8380. the 8373rd method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

8381. the 8373rd method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

8382. the 8373rd method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

8383. the 8373rd method, wherein said fibrous tissue formation agent is silk or comprises silk.

8384. the 8373rd method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

8385. the 8373rd method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

8386. the 8373rd method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

8387. the 8373rd method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

8388. the 8373rd method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

8389. the 8373rd method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

8390. the 8373rd method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

8391. the 8373rd method, wherein said fibrous tissue form agent and exist with particulate form.

8392. the 8373rd method, wherein said compositions also comprises inflammatory cytokine.

8393. the 8373rd method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

8394. the 8373rd method, wherein said compositions exists with the form of gel or paste.

8395. the 8373rd method, wherein said fibrous tissue form the form that agent is bunch.

8396. the 8373rd method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

8397. the 8373rd method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

8398. the 8373rd method, wherein said implant and coating combination, and described coating comprises described fibrous tissue formation agent.

8399. the 8373rd method, wherein said implant and coating combination, and described coating is placed on the surface of described device.

8400. the 8373rd method, wherein said implant and coating combination, and described coating directly contacts described device.

8401. the 8373rd method, wherein said implant and coating combination, and described coating contacts described device indirectly.

8402. the 8373rd method, wherein said implant and coating combination, and described coating layer portion ground covers described device.

8403. the 8373rd method, wherein said implant and coating combination, and described coating fully covers described device.

8404. the 8373rd method, wherein said implant and coating combination, and described coating is uniform coating.

8405. the 8373rd method, wherein said implant and coating combination, and described coating is uneven coating.

8406. the 8373rd method, wherein said implant and coating combination, and described coating is a discontinuous coating.

8407. the 8373rd method, wherein said implant and coating combination, and described coating is to form the coating of pattern.

8408. the 8373rd method, wherein said implant and coating combination, and described coating has 100 μ m or littler thickness.

8409. the 8373rd method, wherein said implant and coating combination, and described coating has 10 μ m or littler thickness.

8410. the 8373rd method, wherein said implant and coating combination, and described coating is being disposed the surface adhesion that this installs later and this device.

8411. the 8373rd method, the combination of wherein said implant and coating, and described coating in room temperature at least 1 year the time interim be stable.

8412. the 8373rd method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

8413. the 8373rd method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

8414. the 8373rd method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

8415. the 8373rd method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

8416. the 8373rd method, wherein said implant and coating combination, and described coating also contains polymer.

8417. the 8373rd method, wherein said device comprise first coating with first compositions and second coating with second compositions.

8418. the 8373rd method, wherein said device comprise first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

8419. the 8373rd method, wherein said device comprises polymer.

8420. the 8373rd method, wherein said device comprises polymer, and wherein said polymer is the component of described compositions.

8421. the 8373rd method, wherein said implant and combination of polymers, and described polymer is a copolymer.

8422. the 8373rd method, wherein said implant and combination of polymers, and described polymer is a block copolymer.

8423. the 8373rd method, wherein said implant and combination of polymers, and described polymer is a random copolymer.

8424. the 8373rd method, wherein said implant and combination of polymers, and described polymer is biodegradable polymer.

8425. the 8373rd method, wherein said implant and combination of polymers, and described polymer is not biodegradable polymer.

8426. the 8373rd method, wherein said implant and combination of polymers, and described polymer is a hydrophilic polymer.

8427. the 8373rd method, wherein said implant and combination of polymers, and described polymer is a hydrophobic polymer.

8428. the 8373rd method, wherein said implant and combination of polymers, and described polymer has the hydrophilic-structure territory.

8429. the 8373rd method, wherein said implant and combination of polymers, and described polymer has hydrophobic domains.

8430. the 8373rd method, wherein said implant and combination of polymers, and described polymer is a non-conductive polymer.

8431. the 8373rd method, wherein said implant and combination of polymers, and described polymer is an elastomer.

8432. the 8373rd method, wherein said implant and combination of polymers, and described polymer is a hydrogel.

8433. the 8373rd method, wherein said implant and combination of polymers, and described polymer is a siloxane polymer.

8434. the 8373rd method, wherein said implant and combination of polymers, and described polymer is a hydrocarbon polymer.

8435. the 8373rd method, wherein said implant and combination of polymers, and described polymer is the styrene derived polymers.

8436. the 8373rd method, wherein said implant and combination of polymers, and described polymer is a butadiene polymer.

8437. the 8373rd method, wherein said implant and combination of polymers, and described polymer is a macromonomer.

8438. the 8373rd method, wherein said implant and combination of polymers, and described polymer is poly-(ethylene glycol) polymer.

8439. the 8373rd method, wherein said implant and combination of polymers, and described polymer is an amorphous polymer.

8440. the 8373rd method, wherein said implant and combination of polymers, and described polymer is a lubricant coating.

8441. the 8373rd method, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

8442. the 8373rd method, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

8443. the 8373rd method, wherein said implant be combination second forms of pharmacologically active agents further.

8444. the 8373rd method, wherein said implant further makes up antiinflammatory.

8445. the 8373rd method, wherein said implant further makes up the inhibition infectious agent.

8446. the 8373rd method, wherein said implant further makes up anthracycline.

8447. the 8373rd method, wherein said implant further makes up doxorubicin.

8448. the 8373rd method, wherein said implant further makes up mitoxantrone.

8449. the 8373rd method, wherein said implant further makes up the fluorine pyrimidine.

8450. the 8373rd method, wherein said implant further make up 5-fluorouracil (5-FU).

8451. the 8373rd method, wherein said implant further makes up antifol.

8452. the 8373rd method, wherein said implant further makes up methotrexate.

8453. the 8373rd method, wherein said implant further makes up podophyllotoxin.

8454. the 8373rd method, wherein said implant further makes up etoposide.

8455. the 8373rd method, wherein said implant further makes up camptothecine.

8456. the 8373rd method, wherein said implant further makes up hydroxyurea.

8457. the 8373rd method, wherein said implant further makes up platinum complex.

8458. the 8373rd method, wherein said implant further makes up cisplatin.

8459. the 8373rd method, wherein said implant further makes up antithrombotic agent.

8460. the 8373rd method, wherein said implant further makes up developing agent.

8461. the 8373rd method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

8462. the 8373rd method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

8463. the 8373rd method, wherein said implant further makes up developing agent, and wherein said developing agent is a MRI response material.

8464. the 8373rd method, wherein said implant further makes up developing agent, and wherein said developing agent comprises gadolinium chelate compound.

8465. the 8373rd method, wherein said implant further makes up developing agent, and wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

8466. the 8373rd method, wherein said implant further makes up developing agent, and wherein said developing agent comprises iron oxide compound.

8467. the 8373rd method, wherein said implant further makes up developing agent, and wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

8468. the 8373rd method, the material of the further combination results echo of wherein said implant.

8469. the 8373rd method, the material of the further combination results echo of wherein said implant, the material of wherein said generation echo exists with the form of coating.

8470. the 8373rd method, wherein said device is aseptic.

8471. the 8373rd method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

8472. the 8373rd method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

8473. the 8373rd method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

8474. the 8373rd method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

8475. the 8373rd method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

8476. the 8373rd method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

8477. the 8373rd method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

8478. the 8373rd method, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

8479. the 8373rd method, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

8480. the 8373rd method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

8481. the 8373rd method, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

8482. forming agent, the 8373rd method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharge in the described device with valid density by being diffused in from disposing.

8483. forming agent, the 8373rd method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharging in the described device from disposing with valid density by corroding said composition.

8484. the 8373rd method, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

8485. the 8373rd method, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

8486. the 8373rd method, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

8487. the 8373rd method, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

8488. the 8373rd method, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

8489. the described fibrous tissue that the 8373rd method, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

8490. the 8373rd method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8491. the 8373rd method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8492. the 8373rd method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8493. the 8373rd method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8494. the 8373rd method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8495. the 8373rd method, wherein said implant are perhaps to comprise and melt (ablation) device.

8496. the 8373rd method, wherein said implant are perhaps to comprise Dexedrine.

8497. the 8373rd method, wherein said implant are perhaps to comprise pump.

8498. the 8373rd method, wherein said implant are perhaps to comprise stitching (stapling) device.

8499. method for preparing medical apparatus, comprise i) transplantable male contraception device and ii) fibrous tissue form agent or comprise the combination of compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

8500. the 8499th method, wherein said fibrous tissue forms agent and promotes regeneration.

8501. forming agent, the 8499th method, wherein said fibrous tissue promote blood vessel to take place.

8502. the 8499th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

8503. the 8499th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

8504. the 8499th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

8505. the 8499th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

8506. the 8499th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

8507. the 8499th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

8508. the 8499th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

8509. the 8499th method, wherein said fibrous tissue formation agent is silk or comprises silk.

8510. the 8499th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

8511. the 8499th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

8512. the 8499th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

8513. the 8499th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

8514. the 8499th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

8515. the 8499th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

8516. the 8499th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

8517. the 8499th method, wherein said fibrous tissue form agent and exist with particulate form.

8518. the 8499th method, wherein said compositions also comprises inflammatory cytokine.

8519. the 8499th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

8520. the 8499th method, wherein said compositions exists with the form of gel or paste.

8521. the 8499th method, wherein said fibrous tissue form the form that agent is bunch.

8522. the 8499th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

8523. the 8499th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

8524. the 8499th method, wherein said implant and coating combination, and described coating comprises described fibrous tissue formation agent.

8525. the 8499th method, wherein said implant and coating combination, and described coating is placed on the surface of described device.

8526. the 8499th method, wherein said implant and coating combination, and described coating directly contacts described device.

8527. the 8499th method, wherein said implant and coating combination, and described coating contacts described device indirectly.

8528. the 8499th method, wherein said implant and coating combination, and described coating layer portion ground covers described device.

8529. the 8499th method, wherein said implant and coating combination, and described coating fully covers described device.

8530. the 8499th method, wherein said implant and coating combination, and described coating is uniform coating.

8531. the 8499th method, wherein said implant and coating combination, and described coating is uneven coating.

8532. the 8499th method, wherein said implant and coating combination, and described coating is a discontinuous coating.

8533. the 8499th method, wherein said implant and coating combination, and described coating is to form the coating of pattern.

8534. the 8499th method, wherein said implant and coating combination, and described coating has 100 μ m or littler thickness.

8535. the 8499th method, wherein said implant and coating combination, and described coating has 10 μ m or littler thickness.

8536. the 8499th method, wherein said implant and coating combination, and described coating is being disposed the surface adhesion that this installs later and this device.

8537. the 8499th method, the combination of wherein said implant and coating, and described coating in room temperature at least 1 year the time interim be stable.

8538. the 8499th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

8539. the 8499th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

8540. the 8499th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

8541. the 8499th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

8542. the 8499th method, wherein said implant and coating combination, and described coating also contains polymer.

8543. the 8499th method, wherein said device comprise first coating with first compositions and second coating with second compositions.

8544. the 8499th method, wherein said device comprise first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

8545. the 8499th method, wherein said device comprises polymer.

8546. the 8499th method, wherein said device comprises polymer, and wherein said polymer is the component of described compositions.

8547. the 8499th method, wherein said implant and combination of polymers, and described polymer is a copolymer.

8548. the 8499th method, wherein said implant and combination of polymers, and described polymer is a block copolymer.

8549. the 8499th method, wherein said implant and combination of polymers, and described polymer is a random copolymer.

8550. the 8499th method, wherein said implant and combination of polymers, and described polymer is biodegradable polymer.

8551. the 8499th method, wherein said implant and combination of polymers, and described polymer is not biodegradable polymer.

8552. the 8499th method, wherein said implant and combination of polymers, and described polymer is a hydrophilic polymer.

8553. the 8499th method, wherein said implant and combination of polymers, and described polymer is a hydrophobic polymer.

8554. the 8499th method, wherein said implant and combination of polymers, and described polymer has the hydrophilic-structure territory.

8555. the 8499th method, wherein said implant and combination of polymers, and described polymer has hydrophobic domains.

8556. the 8499th method, wherein said implant and combination of polymers, and described polymer is a non-conductive polymer.

8557. the 8499th method, wherein said implant and combination of polymers, and described polymer is an elastomer.

8558. the 8499th method, wherein said implant and combination of polymers, and described polymer is a hydrogel.

8559. the 8499th method, wherein said implant and combination of polymers, and described polymer is a siloxane polymer.

8560. the 8499th method, wherein said implant and combination of polymers, and described polymer is a hydrocarbon polymer.

8561. the 8499th method, wherein said implant and combination of polymers, and described polymer is the styrene derived polymers.

8562. the 8499th method, wherein said implant and combination of polymers, and described polymer is a butadiene polymer.

8563. the 8499th method, wherein said implant and combination of polymers, and described polymer is a macromonomer.

8564. the 8499th method, wherein said implant and combination of polymers, and described polymer is poly-(ethylene glycol) polymer.

8565. the 8499th method, wherein said implant and combination of polymers, and described polymer is an amorphous polymer.

8566. the 8499th method, wherein said implant and combination of polymers, and described polymer is a lubricant coating.

8567. the 8499th method, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

8568. the 8499th method, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

8569. the 8499th method, wherein said implant be combination second forms of pharmacologically active agents further.

8570. the 8499th method, wherein said implant further makes up antiinflammatory.

8571. the 8499th method, wherein said implant further makes up the inhibition infectious agent.

8572. the 8499th method, wherein said implant further makes up anthracycline.

8573. the 8499th method, wherein said implant further makes up doxorubicin.

8574. the 8499th method, wherein said implant further makes up mitoxantrone.

8575. the 8499th method, wherein said implant further makes up the fluorine pyrimidine.

8576. the 8499th method, wherein said implant further make up 5-fluorouracil (5-FU).

8577. the 8499th method, wherein said implant further makes up antifol.

8578. the 8499th method, wherein said implant further makes up methotrexate.

8579. the 8499th method, wherein said implant further makes up podophyllotoxin.

8580. the 8499th method, wherein said implant further makes up etoposide.

8581. the 8499th method, wherein said implant further makes up camptothecine.

8582. the 8499th method, wherein said implant further makes up hydroxyurea.

8583. the 8499th method, wherein said implant further makes up platinum complex.

8584. the 8499th method, wherein said implant further makes up cisplatin.

8585. the 8499th method, wherein said implant further makes up antithrombotic agent.

8586. the 8499th method, wherein said implant further makes up developing agent.

8587. the 8499th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

8588. the 8499th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

8589. the 8499th method, wherein said implant further makes up developing agent, and wherein said developing agent is a MRI response material.

8590. the 8499th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises gadolinium chelate compound.

8591. the 8499th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

8592. the 8499th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises iron oxide compound.

8593. the 8499th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

8594. the 8499th method, the material of the further combination results echo of wherein said implant.

8595. the 8499th method, the material of the further combination results echo of wherein said implant, the material of wherein said generation echo exists with the form of coating.

8596. the 8499th method, wherein said device is aseptic.

8597. the 8499th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

8598. the 8499th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

8599. the 8499th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

8600. the 8499th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

8601. the 8499th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

8602. the 8499th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

8603. the 8499th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

8604. the 8499th method, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

8605. the 8499th method, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

8606. the 8499th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

8607. the 8499th method, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

8608. forming agent, the 8499th method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharge in the described device with valid density by being diffused in from disposing.

8609. forming agent, the 8499th method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharging in the described device from disposing with valid density by corroding said composition.

8610. the 8499th method, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

8611. the 8499th method, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

8612. the 8499th method, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

8613. the 8499th method, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

8614. the 8499th method, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

8615. the described fibrous tissue that the 8499th method, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

8616. the 8499th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8617. the 8499th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8618. the 8499th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8619. the 8499th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8620. the 8499th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8621. the 8499th method, wherein said implant be, perhaps comprises to be used for surgical operation and to insert the deferential lobe sterillization device that has.

8622. the 8499th method, wherein said implant are perhaps to comprise reversible male sterilization device.

8623. the 8499th method, wherein said implant are perhaps to comprise the vasectomy folder.

8624. the 8499th method, wherein said implant are perhaps to comprise the vasectomy suture.

8625. the 8499th method is wherein implanted described implant in the deferent duct.

8626. method for preparing medical apparatus, comprise i) the gastric restriction implant and ii) fibrous tissue form agent or comprise the combination of compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

8627. the 8626th method, wherein said fibrous tissue forms agent and promotes regeneration.

8628. forming agent, the 8626th method, wherein said fibrous tissue promote blood vessel to take place.

8629. the 8626th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

8630. the 8626th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

8631. the 8626th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

8632. the 8626th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

8633. the 8626th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

8634. the 8626th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

8635. the 8626th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

8636. the 8626th method, wherein said fibrous tissue formation agent is silk or comprises silk.

8637. the 8626th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

8638. the 8626th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

8639. the 8626th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

8640. the 8626th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

8641. the 8626th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

8642. the 8626th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

8643. the 8626th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

8644. the 8626th method, wherein said fibrous tissue form agent and exist with particulate form.

8645. the 8626th method, wherein said compositions also comprises inflammatory cytokine.

8646. the 8626th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

8647. the 8626th method, wherein said compositions exists with the form of gel or paste.

8648. the 8626th method, wherein said fibrous tissue form the form that agent is bunch.

8649. the 8626th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

8650. the 8626th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

8651. the 8626th method, wherein said implant and coating combination, and described coating comprises described fibrous tissue formation agent.

8652. the 8626th method, wherein said implant and coating combination, and described coating is placed on the surface of described device.

8653. the 8626th method, wherein said implant and coating combination, and described coating directly contacts described device.

8654. the 8626th method, wherein said implant and coating combination, and described coating contacts described device indirectly.

8655. the 8626th method, wherein said implant and coating combination, and described coating layer portion ground covers described device.

8656. the 8626th method, wherein said implant and coating combination, and described coating fully covers described device.

8657. the 8626th method, wherein said implant and coating combination, and described coating is uniform coating.

8658. the 8626th method, wherein said implant and coating combination, and described coating is uneven coating.

8659. the 8626th method, wherein said implant and coating combination, and described coating is a discontinuous coating.

8660. the 8626th method, wherein said implant and coating combination, and described coating is to form the coating of pattern.

8661. the 8626th method, wherein said implant and coating combination, and described coating has 100 μ m or littler thickness.

8662. the 8626th method, wherein said implant and coating combination, and described coating has 10 μ m or littler thickness.

8663. the 8626th method, wherein said implant and coating combination, and described coating is being disposed the surface adhesion that this installs later and this device.

8664. the 8626th method, the combination of wherein said implant and coating, and described coating in room temperature at least 1 year the time interim be stable.

8665. the 8626th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

8666. the 8626th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

8667. the 8626th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

8668. the 8626th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

8669. the 8626th method, wherein said implant and coating combination, and described coating also contains polymer.

8670. the 8626th method, wherein said device comprise first coating with first compositions and second coating with second compositions.

8671. the 8626th method, wherein said device comprise first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

8672. the 8626th method, wherein said device comprises polymer.

8673. the 8626th method, wherein said device comprises polymer, and wherein said polymer is the component of described compositions.

8674. the 8626th method, wherein said implant and combination of polymers, and described polymer is a copolymer.

8675. the 8626th method, wherein said implant and combination of polymers, and described polymer is a block copolymer.

8676. the 8626th method, wherein said implant and combination of polymers, and described polymer is a random copolymer.

8677. the 8626th method, wherein said implant and combination of polymers, and described polymer is biodegradable polymer.

8678. the 8626th method, wherein said implant and combination of polymers, and described polymer is not biodegradable polymer.

8679. the 8626th method, wherein said implant and combination of polymers, and described polymer is a hydrophilic polymer.

8680. the 8626th method, wherein said implant and combination of polymers, and described polymer is a hydrophobic polymer.

8681. the 8626th method, wherein said implant and combination of polymers, and described polymer has the hydrophilic-structure territory.

8682. the 8626th method, wherein said implant and combination of polymers, and described polymer has hydrophobic domains.

8683. the 8626th method, wherein said implant and combination of polymers, and described polymer is a non-conductive polymer.

8684. the 8626th method, wherein said implant and combination of polymers, and described polymer is an elastomer.

8685. the 8626th method, wherein said implant and combination of polymers, and described polymer is a hydrogel.

8686. the 8626th method, wherein said implant and combination of polymers, and described polymer is a siloxane polymer.

8687. the 8626th method, wherein said implant and combination of polymers, and described polymer is a hydrocarbon polymer.

8688. the 8626th method, wherein said implant and combination of polymers, and described polymer is the styrene derived polymers.

8689. the 8626th method, wherein said implant and combination of polymers, and described polymer is a butadiene polymer.

8690. the 8626th method, wherein said implant and combination of polymers, and described polymer is a macromonomer.

8691. the 8626th method, wherein said implant and combination of polymers, and described polymer is poly-(ethylene glycol) polymer.

8692. the 8626th method, wherein said implant and combination of polymers, and described polymer is an amorphous polymer.

8693. the 8626th method, wherein said implant and combination of polymers, and described polymer is a lubricant coating.

8694. the 8626th method, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

8695. the 8626th method, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

8696. the 8626th method, wherein said implant be combination second forms of pharmacologically active agents further.

8697. the 8626th method, wherein said implant further makes up antiinflammatory.

8698. the 8626th method, wherein said implant further makes up the inhibition infectious agent.

8699. the 8626th method, wherein said implant further makes up anthracycline.

8700. the 8626th method, wherein said implant further makes up doxorubicin.

8701. the 8626th method, wherein said implant further makes up mitoxantrone.

8702. the 8626th method, wherein said implant further makes up the fluorine pyrimidine.

8703. the 8626th method, wherein said implant further make up 5-fluorouracil (5-FU).

8704. the 8626th method, wherein said implant further makes up antifol.

8705. the 8626th method, wherein said implant further makes up methotrexate.

8706. the 8626th method, wherein said implant further makes up podophyllotoxin.

8707. the 8626th method, wherein said implant further makes up etoposide.

8708. the 8626th method, wherein said implant further makes up camptothecine.

8709. the 8626th method, wherein said implant further makes up hydroxyurea.

8710. the 8626th method, wherein said implant further makes up platinum complex.

8711. the 8626th method, wherein said implant further makes up cisplatin.

8712. the 8626th method, wherein said implant further makes up antithrombotic agent.

8713. the 8626th method, wherein said implant further makes up developing agent.

8714. the 8626th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

8715. the 8626th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

8716. the 8626th method, wherein said implant further makes up developing agent, and wherein said developing agent is a MRI response material.

8717. the 8626th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises gadolinium chelate compound.

8718. the 8626th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

8719. the 8626th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises iron oxide compound.

8720. the 8626th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

8721. the 8626th method, the material of the further combination results echo of wherein said implant.

8722. the 8626th method, the material of the further combination results echo of wherein said implant, the material of wherein said generation echo exists with the form of coating.

8723. the 8626th method, wherein said device is aseptic.

8724. the 8626th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

8725. the 8626th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

8726. the 8626th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

8727. the 8626th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

8728. the 8626th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

8729. the 8626th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

8730. the 8626th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

8731. the 8626th method, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

8732. the 8626th method, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

8733. the 8626th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

8734. the 8626th method, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

8735. the 8626th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

8736. the 8626th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

8737. the 8626th method, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

8738. the 8626th method, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

8739. the 8626th method, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

8740. the 8626th method, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

8741. the 8626th method, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

8742. the described fibrous tissue that the 8626th method, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

8743. the 8626th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8744. the 8626th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8745. the 8626th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8746. the 8626th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8747. the 8626th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8748. the 8626th method, wherein said implant are perhaps to comprise expandable cover capsule (cuff).

8749. the 8626th method, wherein said implant are perhaps to comprise the occupancy device.

8750. method for preparing medical apparatus, comprise i) separate the inner chamber implant based on suture of stomach, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

8751. the 8750th method, wherein said fibrous tissue forms agent and promotes regeneration.

8752. forming agent, the 8750th method, wherein said fibrous tissue promote blood vessel to take place.

8753. the 8750th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

8754. the 8750th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

8755. the 8750th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

8756. the 8750th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

8757. the 8750th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

8758. the 8750th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

8759. the 8750th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

8760. the 8750th method, wherein said fibrous tissue formation agent is silk or comprises silk.

8761. the 8750th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

8762. the 8750th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

8763. the 8750th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

8764. the 8750th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

8765. the 8750th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

8766. the 8750th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

8767. the 8750th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

8768. the 8750th method, wherein said fibrous tissue form agent and exist with particulate form.

8769. the 8750th method, wherein said compositions also comprises inflammatory cytokine.

8770. the 8750th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

8771. the 8750th method, wherein said compositions exists with the form of gel or paste.

8772. the 8750th method, wherein said fibrous tissue form the form that agent is bunch.

8773. the 8750th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

8774. the 8750th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

8775. the 8750th method, wherein said implant and coating combination, and described coating comprises described fibrous tissue formation agent.

8776. the 8750th method, wherein said implant and coating combination, and described coating is placed on the surface of described device.

8777. the 8750th method, wherein said implant and coating combination, and described coating directly contacts described device.

8778. the 8750th method, wherein said implant and coating combination, and described coating contacts described device indirectly.

8779. the 8750th method, wherein said implant and coating combination, and described coating layer portion ground covers described device.

8780. the 8750th method, wherein said implant and coating combination, and described coating fully covers described device.

8781. the 8750th method, wherein said implant and coating combination, and described coating is uniform coating.

8782. the 8750th method, wherein said implant and coating combination, and described coating is uneven coating.

8783. the 8750th method, wherein said implant and coating combination, and described coating is a discontinuous coating.

8784. the 8750th method, wherein said implant and coating combination, and described coating is to form the coating of pattern.

8785. the 8750th method, wherein said implant and coating combination, and described coating has 100 μ m or littler thickness.

8786. the 8750th method, wherein said implant and coating combination, and described coating has 10 μ m or littler thickness.

8787. the 8750th method, wherein said implant and coating combination, and described coating is being disposed the surface adhesion that this installs later and this device.

8788. the 8750th method, the combination of wherein said implant and coating, and described coating in room temperature at least 1 year the time interim be stable.

8789. the 8750th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

8790. the 8750th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

8791. the 8750th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

8792. the 8750th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

8793. the 8750th method, wherein said implant and coating combination, and described coating also contains polymer.

8794. the 8750th method, wherein said device comprise first coating with first compositions and second coating with second compositions.

8795. the 8750th method, wherein said device comprise first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

8796. the 8750th method, wherein said device comprises polymer.

8797. the 8750th method, wherein said device comprises polymer, and wherein said polymer is the component of described compositions.

8798. the 8750th method, wherein said implant and combination of polymers, and described polymer is a copolymer.

8799. the 8750th method, wherein said implant and combination of polymers, and described polymer is a block copolymer.

8800. the 8750th method, wherein said implant and combination of polymers, and described polymer is a random copolymer.

8801. the 8750th method, wherein said implant and combination of polymers, and described polymer is biodegradable polymer.

8802. the 8750th method, wherein said implant and combination of polymers, and described polymer is not biodegradable polymer.

8803. the 8750th method, wherein said implant and combination of polymers, and described polymer is a hydrophilic polymer.

8804. the 8750th method, wherein said implant and combination of polymers, and described polymer is a hydrophobic polymer.

8805. the 8750th method, wherein said implant and combination of polymers, and described polymer has the hydrophilic-structure territory.

8806. the 8750th method, wherein said implant and combination of polymers, and described polymer has hydrophobic domains.

8807. the 8750th method, wherein said implant and combination of polymers, and described polymer is a non-conductive polymer.

8808. the 8750th method, wherein said implant and combination of polymers, and described polymer is an elastomer.

8809. the 8750th method, wherein said implant and combination of polymers, and described polymer is a hydrogel.

8810. the 8750th method, wherein said implant and combination of polymers, and described polymer is a siloxane polymer.

8811. the 8750th method, wherein said implant and combination of polymers, and described polymer is a hydrocarbon polymer.

8812. the 8750th method, wherein said implant and combination of polymers, and described polymer is the styrene derived polymers.

8813. the 8750th method, wherein said implant and combination of polymers, and described polymer is a butadiene polymer.

8814. the 8750th method, wherein said implant and combination of polymers, and described polymer is a macromonomer.

8815. the 8750th method, wherein said implant and combination of polymers, and described polymer is poly-(ethylene glycol) polymer.

8816. the 8750th method, wherein said implant and combination of polymers, and described polymer is an amorphous polymer.

8817. the 8750th method, wherein said implant and combination of polymers, and described polymer is a lubricant coating.

8818. the 8750th method, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

8819. the 8750th method, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

8820. the 8750th method, wherein said implant be combination second forms of pharmacologically active agents further.

8821. the 8750th method, wherein said implant further makes up antiinflammatory.

8822. the 8750th method, wherein said implant further makes up the inhibition infectious agent.

8823. the 8750th method, wherein said implant further makes up anthracycline.

8824. the 8750th method, wherein said implant further makes up doxorubicin.

8825. the 8750th method, wherein said implant further makes up mitoxantrone.

8826. the 8750th method, wherein said implant further makes up the fluorine pyrimidine.

8827. the 8750th method, wherein said implant further make up 5-fluorouracil (5-FU).

8828. the 8750th method, wherein said implant further makes up antifol.

8829. the 8750th method, wherein said implant further makes up methotrexate.

8830. the 8750th method, wherein said implant further makes up podophyllotoxin.

8831. the 8750th method, wherein said implant further makes up etoposide.

8832. the 8750th method, wherein said implant further makes up camptothecine.

8833. the 8750th method, wherein said implant further makes up hydroxyurea.

8834. the 8750th method, wherein said implant further makes up platinum complex.

8835. the 8750th method, wherein said implant further makes up cisplatin.

8836. the 8750th method, wherein said implant further makes up antithrombotic agent.

8837. the 8750th method, wherein said implant further makes up developing agent.

8838. the 8750th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

8839. the 8750th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

8840. the 8750th method, wherein said implant further makes up developing agent, and wherein said developing agent is a MRI response material.

8841. the 8750th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises gadolinium chelate compound.

8842. the 8750th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

8843. the 8750th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises iron oxide compound.

8844. the 8750th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

8845. the 8750th method, the material of the further combination results echo of wherein said implant.

8846. the 8750th method, the material of the further combination results echo of wherein said implant, the material of wherein said generation echo exists with the form of coating.

8847. the 8750th method, wherein said device is aseptic.

8848. the 8750th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

8849. the 8750th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

8850. the 8750th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

8851. the 8750th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

8852. the 8750th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

8853. the 8750th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

8854. the 8750th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

8855. the 8750th method, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

8856. the 8750th method, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

8857. the 8750th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

8858. the 8750th method, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

8859. forming agent, the 8750th method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharge in the described device with valid density by being diffused in from disposing.

8860. forming agent, the 8750th method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharging in the described device from disposing with valid density by corroding said composition.

8861. the 8750th method, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

8862. the 8750th method, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

8863. the 8750th method, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

8864. the 8750th method, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

8865. the 8750th method, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

8866. the described fibrous tissue that the 8750th method, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

8867. the 8750th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8868. the 8750th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8869. the 8750th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8870. the 8750th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8871. the 8750th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8872. method for preparing medical apparatus, comprise i) separate the electricity irritation implant of stomach, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

8873. the 8872nd method, wherein said fibrous tissue forms agent and promotes regeneration.

8874. forming agent, the 8872nd method, wherein said fibrous tissue promote blood vessel to take place.

8875. the 8872nd method, wherein said fibrous tissue form agent and promote the fibroblast migration.

8876. the 8872nd method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

8877. the 8872nd method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

8878. the 8872nd method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

8879. the 8872nd method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

8880. the 8872nd method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

8881. the 8872nd method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

8882. the 8872nd method, wherein said fibrous tissue formation agent is silk or comprises silk.

8883. the 8872nd method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

8884. the 8872nd method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

8885. the 8872nd method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

8886. the 8872nd method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

8887. the 8872nd method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

8888. the 8872nd method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

8889. the 8872nd method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

8890. the 8872nd method, wherein said fibrous tissue form agent and exist with particulate form.

8891. the 8872nd method, wherein said compositions also comprises inflammatory cytokine.

8892. the 8872nd method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

8893. the 8872nd method, wherein said compositions exists with the form of gel or paste.

8894. the 8872nd method, wherein said fibrous tissue form the form that agent is bunch.

8895. the 8872nd method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

8896. the 8872nd method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

8897. the 8872nd method, wherein said implant and coating combination, and described coating comprises described fibrous tissue formation agent.

8898. the 8872nd method, wherein said implant and coating combination, and described coating is placed on the surface of described device.

8899. the 8872nd method, wherein said implant and coating combination, and described coating directly contacts described device.

8900. the 8872nd method, wherein said implant and coating combination, and described coating contacts described device indirectly.

8901. the 8872nd method, wherein said implant and coating combination, and described coating layer portion ground covers described device.

8902. the 8872nd method, wherein said implant and coating combination, and described coating fully covers described device.

8903. the 8872nd method, wherein said implant and coating combination, and described coating is uniform coating.

8904. the 8872nd method, wherein said implant and coating combination, and described coating is uneven coating.

8905. the 8872nd method, wherein said implant and coating combination, and described coating is a discontinuous coating.

8906. the 8872nd method, wherein said implant and coating combination, and described coating is to form the coating of pattern.

8907. the 8872nd method, wherein said implant and coating combination, and described coating has 100 μ m or littler thickness.

8908. the 8872nd method, wherein said implant and coating combination, and described coating has 10 μ m or littler thickness.

8909. the 8872nd method, wherein said implant and coating combination, and described coating is being disposed the surface adhesion that this installs later and this device.

8910. the 8872nd method, the combination of wherein said implant and coating, and described coating in room temperature at least 1 year the time interim be stable.

8911. the 8872nd method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

8912. the 8872nd method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

8913. the 8872nd method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

8914. the 8872nd method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

8915. the 8872nd method, wherein said implant and coating combination, and described coating also contains polymer.

8916. the 8872nd method, wherein said device comprise first coating with first compositions and second coating with second compositions.

8917. the 8872nd method, wherein said device comprise first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

8918. the 8872nd method, wherein said device comprises polymer.

8919. the 8872nd method, wherein said device comprises polymer, and wherein said polymer is the component of described compositions.

8920. the 8872nd method, wherein said implant and combination of polymers, and described polymer is a copolymer.

8921. the 8872nd method, wherein said implant and combination of polymers, and described polymer is a block copolymer.

8922. the 8872nd method, wherein said implant and combination of polymers, and described polymer is a random copolymer.

8923. the 8872nd method, wherein said implant and combination of polymers, and described polymer is biodegradable polymer.

8924. the 8872nd method, wherein said implant and combination of polymers, and described polymer is not biodegradable polymer.

8925. the 8872nd method, wherein said implant and combination of polymers, and described polymer is a hydrophilic polymer.

8926. the 8872nd method, wherein said implant and combination of polymers, and described polymer is a hydrophobic polymer.

8927. the 8872nd method, wherein said implant and combination of polymers, and described polymer has the hydrophilic-structure territory.

8928. the 8872nd method, wherein said implant and combination of polymers, and described polymer has hydrophobic domains.

8929. the 8872nd method, wherein said implant and combination of polymers, and described polymer is a non-conductive polymer.

8930. the 8872nd method, wherein said implant and combination of polymers, and described polymer is an elastomer.

8931. the 8872nd method, wherein said implant and combination of polymers, and described polymer is a hydrogel.

8932. the 8872nd method, wherein said implant and combination of polymers, and described polymer is a siloxane polymer.

8933. the 8872nd method, wherein said implant and combination of polymers, and described polymer is a hydrocarbon polymer.

8934. the 8872nd method, wherein said implant and combination of polymers, and described polymer is the styrene derived polymers.

8935. the 8872nd method, wherein said implant and combination of polymers, and described polymer is a butadiene polymer.

8936. the 8872nd method, wherein said implant and combination of polymers, and described polymer is a macromonomer.

8937. the 8872nd method, wherein said implant and combination of polymers, and described polymer is poly-(ethylene glycol) polymer.

8938. the 8872nd method, wherein said implant and combination of polymers, and described polymer is an amorphous polymer.

8939. the 8872nd method, wherein said implant and combination of polymers, and described polymer is a lubricant coating.

8940. the 8872nd method, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

8941. the 8872nd method, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

8942. the 8872nd method, wherein said implant be combination second forms of pharmacologically active agents further.

8943. the 8872nd method, wherein said implant further makes up antiinflammatory.

8944. the 8872nd method, wherein said implant further makes up the inhibition infectious agent.

8945. the 8872nd method, wherein said implant further makes up anthracycline.

8946. the 8872nd method, wherein said implant further makes up doxorubicin.

8947. the 8872nd method, wherein said implant further makes up mitoxantrone.

8948. the 8872nd method, wherein said implant further makes up the fluorine pyrimidine.

8949. the 8872nd method, wherein said implant further make up 5-fluorouracil (5-FU).

8950. the 8872nd method, wherein said implant further makes up antifol.

8951. the 8872nd method, wherein said implant further makes up methotrexate.

8952. the 8872nd method, wherein said implant further makes up podophyllotoxin.

8953. the 8872nd method, wherein said implant further makes up etoposide.

8954. the 8872nd method, wherein said implant further makes up camptothecine.

8955. the 8872nd method, wherein said implant further makes up hydroxyurea.

8956. the 8872nd method, wherein said implant further makes up platinum complex.

8957. the 8872nd method, wherein said implant further makes up cisplatin.

8958. the 8872nd method, wherein said implant further makes up antithrombotic agent.

8959. the 8872nd method, wherein said implant further makes up developing agent.

8960. the 8872nd method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

8961. the 8872nd method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

8962. the 8872nd method, wherein said implant further makes up developing agent, and wherein said developing agent is a MRI response material.

8963. the 8872nd method, wherein said implant further makes up developing agent, and wherein said developing agent comprises gadolinium chelate compound.

8964. the 8872nd method, wherein said implant further makes up developing agent, and wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

8965. the 8872nd method, wherein said implant further makes up developing agent, and wherein said developing agent comprises iron oxide compound.

8966. the 8872nd method, wherein said implant further makes up developing agent, and wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

8967. the 8872nd method, the material of the further combination results echo of wherein said implant.

8968. the 8872nd method, the material of the further combination results echo of wherein said implant, the material of wherein said generation echo exists with the form of coating.

8969. the 8872nd method, wherein said device is aseptic.

8970. the 8872nd method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

8971. the 8872nd method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

8972. the 8872nd method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

8973. the 8872nd method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

8974. the 8872nd method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

8975. the 8872nd method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

8976. the 8872nd method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

8977. the 8872nd method, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

8978. the 8872nd method, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

8979. the 8872nd method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

8980. the 8872nd method, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

8981. forming agent, the 8872nd method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharge in the described device with valid density by being diffused in from disposing.

8982. forming agent, the 8872nd method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharging in the described device from disposing with valid density by corroding said composition.

8983. the 8872nd method, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

8984. the 8872nd method, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

8985. the 8872nd method, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

8986. the 8872nd method, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

8987. the 8872nd method, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

8988. the described fibrous tissue that the 8872nd method, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

8989. the 8872nd method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8990. the 8872nd method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8991. the 8872nd method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8992. the 8872nd method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8993. the 8872nd method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

8994. the 8872nd method, wherein said implant are the nerve electric stimulation implants.

8995. the 8872nd method, wherein said implant are non-nerve electric stimulation implants.

8996. method for preparing medical apparatus, comprise i) the soft palate implant, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

8997. the 8996th method, wherein said fibrous tissue forms agent and promotes regeneration.

8998. forming agent, the 8996th method, wherein said fibrous tissue promote blood vessel to take place.

8999. the 8996th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

9000. the 8996th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

9001. the 8996th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

9002. the 8996th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

9003. the 8996th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

9004. the 8996th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

9005. the 8996th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

9006. the 8996th method, wherein said fibrous tissue formation agent is silk or comprises silk.

9007. the 8996th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

9008. the 8996th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

9009. the 8996th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

9010. the 8996th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

9011. the 8996th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

9012. the 8996th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

9013. the 8996th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

9014. the 8996th method, wherein said fibrous tissue form agent and exist with particulate form.

9015. the 8996th method, wherein said compositions also comprises inflammatory cytokine.

9016. the 8996th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

9017. the 8996th method, wherein said compositions exists with the form of gel or paste.

9018. the 8996th method, wherein said fibrous tissue form the form that agent is bunch.

9019. the 8996th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

9020. the 8996th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

9021. the 8996th method, wherein said implant and coating combination, and described coating comprises described fibrous tissue formation agent.

9022. the 8996th method, wherein said implant and coating combination, and described coating is placed on the surface of described device.

9023. the 8996th method, wherein said implant and coating combination, and described coating directly contacts described device.

9024. the 8996th method, wherein said implant and coating combination, and described coating contacts described device indirectly.

9025. the 8996th method, wherein said implant and coating combination, and described coating layer portion ground covers described device.

9026. the 8996th method, wherein said implant and coating combination, and described coating fully covers described device.

9027. the 8996th method, wherein said implant and coating combination, and described coating is uniform coating.

9028. the 8996th method, wherein said implant and coating combination, and described coating is uneven coating.

9029. the 8996th method, wherein said implant and coating combination, and described coating is a discontinuous coating.

9030. the 8996th method, wherein said implant and coating combination, and described coating is to form the coating of pattern.

9031. the 8996th method, wherein said implant and coating combination, and described coating has 100 μ m or littler thickness.

9032. the 8996th method, wherein said implant and coating combination, and described coating has 10 μ m or littler thickness.

9033. the 8996th method, wherein said implant and coating combination, and described coating is being disposed the surface adhesion that this installs later and this device.

9034. the 8996th method, the combination of wherein said implant and coating, and described coating in room temperature at least 1 year the time interim be stable.

9035. the 8996th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

9036. the 8996th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

9037. the 8996th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

9038. the 8996th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

9039. the 8996th method, wherein said implant and coating combination, and described coating also contains polymer.

9040. the 8996th method, wherein said device comprise first coating with first compositions and second coating with second compositions.

9041. the 8996th method, wherein said device comprise first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

9042. the 8996th method, wherein said device comprises polymer.

9043. the 8996th method, wherein said device comprises polymer, and wherein said polymer is the component of described compositions.

9044. the 8996th method, wherein said implant and combination of polymers, and described polymer is a copolymer.

9045. the 8996th method, wherein said implant and combination of polymers, and described polymer is a block copolymer.

9046. the 8996th method, wherein said implant and combination of polymers, and described polymer is a random copolymer.

9047. the 8996th method, wherein said implant and combination of polymers, and described polymer is biodegradable polymer.

9048. the 8996th method, wherein said implant and combination of polymers, and described polymer is not biodegradable polymer.

9049. the 8996th method, wherein said implant and combination of polymers, and described polymer is a hydrophilic polymer.

9050. the 8996th method, wherein said implant and combination of polymers, and described polymer is a hydrophobic polymer.

9051. the 8996th method, wherein said implant and combination of polymers, and described polymer has the hydrophilic-structure territory.

9052. the 8996th method, wherein said implant and combination of polymers, and described polymer has hydrophobic domains.

9053. the 8996th method, wherein said implant and combination of polymers, and described polymer is a non-conductive polymer.

9054. the 8996th method, wherein said implant and combination of polymers, and described polymer is an elastomer.

9055. the 8996th method, wherein said implant and combination of polymers, and described polymer is a hydrogel.

9056. the 8996th method, wherein said implant and combination of polymers, and described polymer is a siloxane polymer.

9057. the 8996th method, wherein said implant and combination of polymers, and described polymer is a hydrocarbon polymer.

9058. the 8996th method, wherein said implant and combination of polymers, and described polymer is the styrene derived polymers.

9059. the 8996th method, wherein said implant and combination of polymers, and described polymer is a butadiene polymer.

9060. the 8996th method, wherein said implant and combination of polymers, and described polymer is a macromonomer.

9061. the 8996th method, wherein said implant and combination of polymers, and described polymer is poly-(ethylene glycol) polymer.

9062. the 8996th method, wherein said implant and combination of polymers, and described polymer is an amorphous polymer.

9063. the 8996th method, wherein said implant and combination of polymers, and described polymer is a lubricant coating.

9064. the 8996th method, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

9065. the 8996th method, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

9066. the 8996th method, wherein said implant be combination second forms of pharmacologically active agents further.

9067. the 8996th method, wherein said implant further makes up antiinflammatory.

9068. the 8996th method, wherein said implant further makes up the inhibition infectious agent.

9069. the 8996th method, wherein said implant further makes up anthracycline.

9070. the 8996th method, wherein said implant further makes up doxorubicin.

9071. the 8996th method, wherein said implant further makes up mitoxantrone.

9072. the 8996th method, wherein said implant further makes up the fluorine pyrimidine.

9073. the 8996th method, wherein said implant further make up 5-fluorouracil (5-FU).

9074. the 8996th method, wherein said implant further makes up antifol.

9075. the 8996th method, wherein said implant further makes up methotrexate.

9076. the 8996th method, wherein said implant further makes up podophyllotoxin.

9077. the 8996th method, wherein said implant further makes up etoposide.

9078. the 8996th method, wherein said implant further makes up camptothecine.

9079. the 8996th method, wherein said implant further makes up hydroxyurea.

9080. the 8996th method, wherein said implant further makes up platinum complex.

9081. the 8996th method, wherein said implant further makes up cisplatin.

9082. the 8996th method, wherein said implant further makes up antithrombotic agent.

9083. the 8996th method, wherein said implant further makes up developing agent.

9084. the 8996th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

9085. the 8996th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

9086. the 8996th method, wherein said implant further makes up developing agent, and wherein said developing agent is a MRI response material.

9087. the 8996th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises gadolinium chelate compound.

9088. the 8996th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

9089. the 8996th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises iron oxide compound.

9090. the 8996th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

9091. the 8996th method, the material of the further combination results echo of wherein said implant.

9092. the 8996th method, the material of the further combination results echo of wherein said implant, the material of wherein said generation echo exists with the form of coating.

9093. the 8996th method, wherein said device is aseptic.

9094. the 8996th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

9095. the 8996th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

9096. the 8996th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

9097. the 8996th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

9098. the 8996th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

9099. the 8996th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

9100. the 8996th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

9101. the 8996th method, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

9102. the 8996th method, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

9103. the 8996th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

9104. the 8996th method, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

9105. the 8996th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

9106. the 8996th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

9107. the 8996th method, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

9108. the 8996th method, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

9109. the 8996th method, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

9110. the 8996th method, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

9111. the 8996th method, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

9112. the described fibrous tissue that the 8996th method, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

9113. the 8996th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9114. the 8996th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9115. the 8996th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9116. the 8996th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9117. the 8996th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9118. method for preparing medical apparatus, comprise i) blood vessel coil implant, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

9119. the 9118th method, wherein said fibrous tissue forms agent and promotes regeneration.

9120. forming agent, the 9118th method, wherein said fibrous tissue promote blood vessel to take place.

9121. the 9118th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

9122. the 9118th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

9123. the 9118th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

9124. the 9118th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

9125. the 9118th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

9126. the 9118th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

9127. the 9118th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

9128. the 9118th method, wherein said fibrous tissue formation agent is silk or comprises silk.

9129. the 9118th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

9130. the 9118th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

9131. the 9118th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

9132. the 9118th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

9133. the 9118th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

9134. the 9118th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

9135. the 9118th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

9136. the 9118th method, wherein said fibrous tissue form agent and exist with particulate form.

9137. the 9118th method, wherein said compositions also comprises inflammatory cytokine.

9138. the 9118th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

9139. the 9118th method, wherein said compositions exists with the form of gel or paste.

9140. the 9118th method, wherein said fibrous tissue form the form that agent is bunch.

9141. the 9118th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

9142. the 9118th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

9143. the 9118th method, wherein said implant and coating combination, and described coating comprises described fibrous tissue formation agent.

9144. the 9118th method, wherein said implant and coating combination, and described coating is placed on the surface of described device.

9145. the 9118th method, wherein said implant and coating combination, and described coating directly contacts described device.

9146. the 9118th method, wherein said implant and coating combination, and described coating contacts described device indirectly.

9147. the 9118th method, wherein said implant and coating combination, and described coating layer portion ground covers described device.

9148. the 9118th method, wherein said implant and coating combination, and described coating fully covers described device.

9149. the 9118th method, wherein said implant and coating combination, and described coating is uniform coating.

9150. the 9118th method, wherein said implant and coating combination, and described coating is uneven coating.

9151. the 9118th method, wherein said implant and coating combination, and described coating is a discontinuous coating.

9152. the 9118th method, wherein said implant and coating combination, and described coating is to form the coating of pattern.

9153. the 9118th method, wherein said implant and coating combination, and described coating has 100 μ m or littler thickness.

9154. the 9118th method, wherein said implant and coating combination, and described coating has 10 μ m or littler thickness.

9155. the 9118th method, wherein said implant and coating combination, and described coating is being disposed the surface adhesion that this installs later and this device.

9156. the 9118th method, the combination of wherein said implant and coating, and described coating in room temperature at least 1 year the time interim be stable.

9157. the 9118th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

9158. the 9118th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

9159. the 9118th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

9160. the 9118th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

9161. the 9118th method, wherein said implant and coating combination, and described coating also contains polymer.

9162. the 9118th method, wherein said device comprise first coating with first compositions and second coating with second compositions.

9163. the 9118th method, wherein said device comprise first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

9164. the 9118th method, wherein said device comprises polymer.

9165. the 9118th method, wherein said device comprises polymer, and wherein said polymer is the component of described compositions.

9166. the 9118th method, wherein said implant and combination of polymers, and described polymer is a copolymer.

9167. the 9118th method, wherein said implant and combination of polymers, and described polymer is a block copolymer.

9168. the 9118th method, wherein said implant and combination of polymers, and described polymer is a random copolymer.

9169. the 9118th method, wherein said implant and combination of polymers, and described polymer is biodegradable polymer.

9170. the 9118th method, wherein said implant and combination of polymers, and described polymer is not biodegradable polymer.

9171. the 9118th method, wherein said implant and combination of polymers, and described polymer is a hydrophilic polymer.

9172. the 9118th method, wherein said implant and combination of polymers, and described polymer is a hydrophobic polymer.

9173. the 9118th method, wherein said implant and combination of polymers, and described polymer has the hydrophilic-structure territory.

9174. the 9118th method, wherein said implant and combination of polymers, and described polymer has hydrophobic domains.

9175. the 9118th method, wherein said implant and combination of polymers, and described polymer is a non-conductive polymer.

9176. the 9118th method, wherein said implant and combination of polymers, and described polymer is an elastomer.

9177. the 9118th method, wherein said implant and combination of polymers, and described polymer is a hydrogel.

9178. the 9118th method, wherein said implant and combination of polymers, and described polymer is a siloxane polymer.

9179. the 9118th method, wherein said implant and combination of polymers, and described polymer is a hydrocarbon polymer.

9180. the 9118th method, wherein said implant and combination of polymers, and described polymer is the styrene derived polymers.

9181. the 9118th method, wherein said implant and combination of polymers, and described polymer is a butadiene polymer.

9182. the 9118th method, wherein said implant and combination of polymers, and described polymer is a macromonomer.

9183. the 9118th method, wherein said implant and combination of polymers, and described polymer is poly-(ethylene glycol) polymer.

9184. the 9118th method, wherein said implant and combination of polymers, and described polymer is an amorphous polymer.

9185. the 9118th method, wherein said implant and combination of polymers, and described polymer is a lubricant coating.

9186. the 9118th method, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

9187. the 9118th method, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

9188. the 9118th method, wherein said implant be combination second forms of pharmacologically active agents further.

9189. the 9118th method, wherein said implant further makes up antiinflammatory.

9190. the 9118th method, wherein said implant further makes up the inhibition infectious agent.

9191. the 9118th method, wherein said implant further makes up anthracycline.

9192. the 9118th method, wherein said implant further makes up doxorubicin.

9193. the 9118th method, wherein said implant further makes up mitoxantrone.

9194. the 9118th method, wherein said implant further makes up the fluorine pyrimidine.

9195. the 9118th method, wherein said implant further make up 5-fluorouracil (5-FU).

9196. the 9118th method, wherein said implant further makes up antifol.

9197. the 9118th method, wherein said implant further makes up methotrexate.

9198. the 9118th method, wherein said implant further makes up podophyllotoxin.

9199. the 9118th method, wherein said implant further makes up etoposide.

9200. the 9118th method, wherein said implant further makes up camptothecine.

9201. the 9118th method, wherein said implant further makes up hydroxyurea.

9202. the 9118th method, wherein said implant further makes up platinum complex.

9203. the 9118th method, wherein said implant further makes up cisplatin.

9204. the 9118th method, wherein said implant further makes up antithrombotic agent.

9205. the 9118th method, wherein said implant further makes up developing agent.

9206. the 9118th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

9207. the 9118th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

9208. the 9118th method, wherein said implant further makes up developing agent, and wherein said developing agent is a MRI response material.

9209. the 9118th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises gadolinium chelate compound.

9210. the 9118th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

9211. the 9118th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises iron oxide compound.

9212. the 9118th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

9213. the 9118th method, the material of the further combination results echo of wherein said implant.

9214. the 9118th method, the material of the further combination results echo of wherein said implant, the material of wherein said generation echo exists with the form of coating.

9215. the 9118th method, wherein said device is aseptic.

9216. the 9118th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

9217. the 9118th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

9218. the 9118th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

9219. the 9118th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

9220. the 9118th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

9221. the 9118th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

9222. the 9118th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

9223. the 9118th method, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

9224. the 9118th method, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

9225. the 9118th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

9226. the 9118th method, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

9227. the 9118th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by being diffused in from about 90 days period, discharging in the administration with valid density.

9228. the 9118th method, wherein said fibrous tissue form agent from the compositions that contains fibrous tissue and form agent by corroding said composition from about 90 days period, discharging in the administration with valid density.

9229. the 9118th method, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

9230. the 9118th method, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

9231. the 9118th method, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

9232. the 9118th method, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

9233. the 9118th method, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

9234. the described fibrous tissue that the 9118th method, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

9235. the 9118th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9236. the 9118th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9237. the 9118th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9238. the 9118th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9239. the 9118th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9240. the 9118th method, wherein said blood vessel coil implant comprises fluorinated polymer.

9241. the 9118th method, wherein said blood vessel coil implant is porous.

9242. the 9118th method, wherein said blood vessel coil implant comprises biological active agents.

9243. the 9118th method, wherein said blood vessel coil implant is an any biological inert.

9244. the 9118th method, wherein said blood vessel coil implant have second state after inserting the first preceding state and inserting.

9245. method for preparing medical apparatus, comprise i) vascular occlusion coil implant, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

9246. the 9245th method, wherein said fibrous tissue forms agent and promotes regeneration.

9247. forming agent, the 9245th method, wherein said fibrous tissue promote blood vessel to take place.

9248. the 9245th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

9249. the 9245th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

9250. the 9245th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

9251. the 9245th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

9252. the 9245th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

9253. the 9245th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

9254. the 9245th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

9255. the 9245th method, wherein said fibrous tissue formation agent is silk or comprises silk.

9256. the 9245th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

9257. the 9245th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

9258. the 9245th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

9259. the 9245th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

9260. the 9245th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

9261. the 9245th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

9262. the 9245th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

9263. the 9245th method, wherein said fibrous tissue form agent and exist with particulate form.

9264. the 9245th method, wherein said compositions also comprises inflammatory cytokine.

9265. the 9245th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

9266. the 9245th method, wherein said compositions exists with the form of gel or paste.

9267. the 9245th method, wherein said fibrous tissue form the form that agent is bunch.

9268. the 9245th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

9269. the 9245th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

9270. the 9245th method, wherein said implant and coating combination, and described coating comprises described fibrous tissue formation agent.

9271. the 9245th method, wherein said implant and coating combination, and described coating is placed on the surface of described device.

9272. the 9245th method, wherein said implant and coating combination, and described coating directly contacts described device.

9273. the 9245th method, wherein said implant and coating combination, and described coating contacts described device indirectly.

9274. the 9245th method, wherein said implant and coating combination, and described coating layer portion ground covers described device.

9275. the 9245th method, wherein said implant and coating combination, and described coating fully covers described device.

9276. the 9245th method, wherein said implant and coating combination, and described coating is uniform coating.

9277. the 9245th method, wherein said implant and coating combination, and described coating is uneven coating.

9278. the 9245th method, wherein said implant and coating combination, and described coating is a discontinuous coating.

9279. the 9245th method, wherein said implant and coating combination, and described coating is to form the coating of pattern.

9280. the 9245th method, wherein said implant and coating combination, and described coating has 100 μ m or littler thickness.

9281. the 9245th method, wherein said implant and coating combination, and described coating has 10 μ m or littler thickness.

9282. the 9245th method, wherein said implant and coating combination, and described coating is being disposed the surface adhesion that this installs later and this device.

9283. the 9245th method, the combination of wherein said implant and coating, and described coating in room temperature at least 1 year the time interim be stable.

9284. the 9245th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

9285. the 9245th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

9286. the 9245th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

9287. the 9245th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

9288. the 9245th method, wherein said implant and coating combination, and described coating also contains polymer.

9289. the 9245th method, wherein said device comprise first coating with first compositions and second coating with second compositions.

9290. the 9245th method, wherein said device comprise first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

9291. the 9245th method, wherein said device comprises polymer.

9292. the 9245th method, wherein said device comprises polymer, and wherein said polymer is the component of described compositions.

9293. the 9245th method, wherein said implant and combination of polymers, and described polymer is a copolymer.

9294. the 9245th method, wherein said implant and combination of polymers, and described polymer is a block copolymer.

9295. the 9245th method, wherein said implant and combination of polymers, and described polymer is a random copolymer.

9296. the 9245th method, wherein said implant and combination of polymers, and described polymer is biodegradable polymer.

9297. the 9245th method, wherein said implant and combination of polymers, and described polymer is not biodegradable polymer.

9298. the 9245th method, wherein said implant and combination of polymers, and described polymer is a hydrophilic polymer.

9299. the 9245th method, wherein said implant and combination of polymers, and described polymer is a hydrophobic polymer.

9300. the 9245th method, wherein said implant and combination of polymers, and described polymer has the hydrophilic-structure territory.

9301. the 9245th method, wherein said implant and combination of polymers, and described polymer has hydrophobic domains.

9302. the 9245th method, wherein said implant and combination of polymers, and described polymer is a non-conductive polymer.

9303. the 9245th method, wherein said implant and combination of polymers, and described polymer is an elastomer.

9304. the 9245th method, wherein said implant and combination of polymers, and described polymer is a hydrogel.

9305. the 9245th method, wherein said implant and combination of polymers, and described polymer is a siloxane polymer.

9306. the 9245th method, wherein said implant and combination of polymers, and described polymer is a hydrocarbon polymer.

9307. the 9245th method, wherein said implant and combination of polymers, and described polymer is the styrene derived polymers.

9308. the 9245th method, wherein said implant and combination of polymers, and described polymer is a butadiene polymer.

9309. the 9245th method, wherein said implant and combination of polymers, and described polymer is a macromonomer.

9310. the 9245th method, wherein said implant and combination of polymers, and described polymer is poly-(ethylene glycol) polymer.

9311. the 9245th method, wherein said implant and combination of polymers, and described polymer is an amorphous polymer.

9312. the 9245th method, wherein said implant and combination of polymers, and described polymer is a lubricant coating.

9313. the 9245th method, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

9314. the 9245th method, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

9315. the 9245th method, wherein said implant be combination second forms of pharmacologically active agents further.

9316. the 9245th method, wherein said implant further makes up antiinflammatory.

9317. the 9245th method, wherein said implant further makes up the inhibition infectious agent.

9318. the 9245th method, wherein said implant further makes up anthracycline.

9319. the 9245th method, wherein said implant further makes up doxorubicin.

9320. the 9245th method, wherein said implant further makes up mitoxantrone.

9321. the 9245th method, wherein said implant further makes up the fluorine pyrimidine.

9322. the 9245th method, wherein said implant further make up 5-fluorouracil (5-FU).

9323. the 9245th method, wherein said implant further makes up antifol.

9324. the 9245th method, wherein said implant further makes up methotrexate.

9325. the 9245th method, wherein said implant further makes up podophyllotoxin.

9326. the 9245th method, wherein said implant further makes up etoposide.

9327. the 9245th method, wherein said implant further makes up camptothecine.

9328. the 9245th method, wherein said implant further makes up hydroxyurea.

9329. the 9245th method, wherein said implant further makes up platinum complex.

9330. the 9245th method, wherein said implant further makes up cisplatin.

9331. the 9245th method, wherein said implant further makes up antithrombotic agent.

9332. the 9245th method, wherein said implant further makes up developing agent.

9333. the 9245th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

9334. the 9245th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

9335. the 9245th method, wherein said implant further makes up developing agent, and wherein said developing agent is a MRI response material.

9336. the 9245th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises gadolinium chelate compound.

9337. the 9245th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

9338. the 9245th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises iron oxide compound.

9339. the 9245th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

9340. the 9245th method, the material of the further combination results echo of wherein said implant.

9341. the 9245th method, the material of the further combination results echo of wherein said implant, the material of wherein said generation echo exists with the form of coating.

9342. the 9245th method, wherein said device is aseptic.

9343. the 9245th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

9344. the 9245th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

9345. the 9245th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

9346. the 9245th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

9347. the 9245th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

9348. the 9245th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

9349. the 9245th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

9350. the 9245th method, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

9351. the 9245th method, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

9352. the 9245th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

9353. the 9245th method, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

9354. forming agent, the 9245th method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharge in the described device with valid density by being diffused in from disposing.

9355. forming agent, the 9245th method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharging in the described device from disposing with valid density by corroding said composition.

9356. the 9245th method, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

9357. the 9245th method, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

9358. the 9245th method, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

9359. the 9245th method, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

9360. the 9245th method, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

9361. the described fibrous tissue that the 9245th method, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

9362. the 9245th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9363. the 9245th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9364. the 9245th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9365. the 9245th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9366. the 9245th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9367. method for preparing medical apparatus, comprise i) the vascular occlusion implant, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

9368. the 9367th method, wherein said fibrous tissue forms agent and promotes regeneration.

9369. forming agent, the 9367th method, wherein said fibrous tissue promote blood vessel to take place.

9370. the 9367th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

9371. the 9367th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

9372. the 9367th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

9373. the 9367th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

9374. the 9367th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

9375. the 9367th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

9376. the 9367th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

9377. the 9367th method, wherein said fibrous tissue formation agent is silk or comprises silk.

9378. the 9367th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

9379. the 9367th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

9380. the 9367th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

9381. the 9367th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

9382. the 9367th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

9383. the 9367th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

9384. the 9367th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

9385. the 9367th method, wherein said fibrous tissue form agent and exist with particulate form.

9386. the 9367th method, wherein said compositions also comprises inflammatory cytokine.

9387. the 9367th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

9388. the 9367th method, wherein said compositions exists with the form of gel or paste.

9389. the 9367th method, wherein said fibrous tissue form the form that agent is bunch.

9390. the 9367th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

9391. the 9367th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

9392. the 9367th method, wherein said implant and coating combination, and described coating comprises described fibrous tissue formation agent.

9393. the 9367th method, wherein said implant and coating combination, and described coating is placed on the surface of described device.

9394. the 9367th method, wherein said implant and coating combination, and described coating directly contacts described device.

9395. the 9367th method, wherein said implant and coating combination, and described coating contacts described device indirectly.

9396. the 9367th method, wherein said implant and coating combination, and described coating layer portion ground covers described device.

9397. the 9367th method, wherein said implant and coating combination, and described coating fully covers described device.

9398. the 9367th method, wherein said implant and coating combination, and described coating is uniform coating.

9399. the 9367th method, wherein said implant and coating combination, and described coating is uneven coating.

9400. the 9367th method, wherein said implant and coating combination, and described coating is a discontinuous coating.

9401. the 9367th method, wherein said implant and coating combination, and described coating is to form the coating of pattern.

9402. the 9367th method, wherein said implant and coating combination, and described coating has 100 μ m or littler thickness.

9403. the 9367th method, wherein said implant and coating combination, and described coating has 10 μ m or littler thickness.

9404. the 9367th method, wherein said implant and coating combination, and described coating is being disposed the surface adhesion that this installs later and this device.

9405. the 9367th method, the combination of wherein said implant and coating, and described coating in room temperature at least 1 year the time interim be stable.

9406. the 9367th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

9407. the 9367th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

9408. the 9367th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

9409. the 9367th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

9410. the 9367th method, wherein said implant and coating combination, and described coating also contains polymer.

9411. the 9367th method, wherein said device comprise first coating with first compositions and second coating with second compositions.

9412. the 9367th method, wherein said device comprise first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

9413. the 9367th method, wherein said device comprises polymer.

9414. the 9367th method, wherein said device comprises polymer, and wherein said polymer is the component of described compositions.

9415. the 9367th method, wherein said implant and combination of polymers, and described polymer is a copolymer.

9416. the 9367th method, wherein said implant and combination of polymers, and described polymer is a block copolymer.

9417. the 9367th method, wherein said implant and combination of polymers, and described polymer is a random copolymer.

9418. the 9367th method, wherein said implant and combination of polymers, and described polymer is biodegradable polymer.

9419. the 9367th method, wherein said implant and combination of polymers, and described polymer is not biodegradable polymer.

9420. the 9367th method, wherein said implant and combination of polymers, and described polymer is a hydrophilic polymer.

9421. the 9367th method, wherein said implant and combination of polymers, and described polymer is a hydrophobic polymer.

9422. the 9367th method, wherein said implant and combination of polymers, and described polymer has the hydrophilic-structure territory.

9423. the 9367th method, wherein said implant and combination of polymers, and described polymer has hydrophobic domains.

9424. the 9367th method, wherein said implant and combination of polymers, and described polymer is a non-conductive polymer.

9425. the 9367th method, wherein said implant and combination of polymers, and described polymer is an elastomer.

9426. the 9367th method, wherein said implant and combination of polymers, and described polymer is a hydrogel.

9427. the 9367th method, wherein said implant and combination of polymers, and described polymer is a siloxane polymer.

9428. the 9367th method, wherein said implant and combination of polymers, and described polymer is a hydrocarbon polymer.

9429. the 9367th method, wherein said implant and combination of polymers, and described polymer is the styrene derived polymers.

9430. the 9367th method, wherein said implant and combination of polymers, and described polymer is a butadiene polymer.

9431. the 9367th method, wherein said implant and combination of polymers, and described polymer is a macromonomer.

9432. the 9367th method, wherein said implant and combination of polymers, and described polymer is poly-(ethylene glycol) polymer.

9433. the 9367th method, wherein said implant and combination of polymers, and described polymer is an amorphous polymer.

9434. the 9367th method, wherein said implant and combination of polymers, and described polymer is a lubricant coating.

9435. the 9367th method, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

9436. the 9367th method, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

9437. the 9367th method, wherein said implant be combination second forms of pharmacologically active agents further.

9438. the 9367th method, wherein said implant further makes up antiinflammatory.

9439. the 9367th method, wherein said implant further makes up the inhibition infectious agent.

9440. the 9367th method, wherein said implant further makes up anthracycline.

9441. the 9367th method, wherein said implant further makes up doxorubicin.

9442. the 9367th method, wherein said implant further makes up mitoxantrone.

9443. the 9367th method, wherein said implant further makes up the fluorine pyrimidine.

9444. the 9367th method, wherein said implant further make up 5-fluorouracil (5-FU).

9445. the 9367th method, wherein said implant further makes up antifol.

9446. the 9367th method, wherein said implant further makes up methotrexate.

9447. the 9367th method, wherein said implant further makes up podophyllotoxin.

9448. the 9367th method, wherein said implant further makes up etoposide.

9449. the 9367th method, wherein said implant further makes up camptothecine.

9450. the 9367th method, wherein said implant further makes up hydroxyurea.

9451. the 9367th method, wherein said implant further makes up platinum complex.

9452. the 9367th method, wherein said implant further makes up cisplatin.

9453. the 9367th method, wherein said implant further makes up antithrombotic agent.

9454. the 9367th method, wherein said implant further makes up developing agent.

9455. the 9367th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

9456. the 9367th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

9457. the 9367th method, wherein said implant further makes up developing agent, and wherein said developing agent is a MRI response material.

9458. the 9367th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises gadolinium chelate compound.

9459. the 9367th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

9460. the 9367th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises iron oxide compound.

9461. the 9367th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

9462. the 9367th method, the material of the further combination results echo of wherein said implant.

9463. the 9367th method, the material of the further combination results echo of wherein said implant, the material of wherein said generation echo exists with the form of coating.

9464. the 9367th method, wherein said device is aseptic.

9465. the 9367th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

9466. the 9367th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

9467. the 9367th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

9468. the 9367th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

9469. the 9367th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

9470. the 9367th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

9471. the 9367th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

9472. the 9367th method, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

9473. the 9367th method, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

9474. the 9367th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

9475. the 9367th method, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

9476. forming agent, the 9367th method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharge in the described device with valid density by being diffused in from disposing.

9477. forming agent, the 9367th method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharging in the described device from disposing with valid density by corroding said composition.

9478. the 9367th method, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

9479. the 9367th method, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

9480. the 9367th method, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

9481. the 9367th method, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

9482. the 9367th method, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

9483. the described fibrous tissue that the 9367th method, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

9484. the 9367th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9485. the 9367th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9486. the 9367th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9487. the 9367th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9488. the 9367th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9489. method for preparing medical apparatus, comprise i) the vascular occlusion implant of non-coiling, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

9490. the 9489th method, wherein said fibrous tissue forms agent and promotes regeneration.

9491. forming agent, the 9489th method, wherein said fibrous tissue promote blood vessel to take place.

9492. the 9489th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

9493. the 9489th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

9494. the 9489th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

9495. the 9489th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

9496. the 9489th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

9497. the 9489th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

9498. the 9489th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

9499. the 9489th method, wherein said fibrous tissue formation agent is silk or comprises silk.

9500. the 9489th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

9501. the 9489th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

9502. the 9489th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

9503. the 9489th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

9504. the 9489th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

9505. the 9489th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

9506. the 9489th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

9507. the 9489th method, wherein said fibrous tissue form agent and exist with particulate form.

9508. the 9489th method, wherein said compositions also comprises inflammatory cytokine.

9509. the 9489th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

9510. the 9489th method, wherein said compositions exists with the form of gel or paste.

9511. the 9489th method, wherein said fibrous tissue form the form that agent is bunch.

9512. the 9489th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

9513. the 9489th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

9514. the 9489th method, wherein said implant and coating combination, and described coating comprises described fibrous tissue formation agent.

9515. the 9489th method, wherein said implant and coating combination, and described coating is placed on the surface of described device.

9516. the 9489th method, wherein said implant and coating combination, and described coating directly contacts described device.

9517. the 9489th method, wherein said implant and coating combination, and described coating contacts described device indirectly.

9518. the 9489th method, wherein said implant and coating combination, and described coating layer portion ground covers described device.

9519. the 9489th method, wherein said implant and coating combination, and described coating fully covers described device.

9520. the 9489th method, wherein said implant and coating combination, and described coating is uniform coating.

9521. the 9489th method, wherein said implant and coating combination, and described coating is uneven coating.

9522. the 9489th method, wherein said implant and coating combination, and described coating is a discontinuous coating.

9523. the 9489th method, wherein said implant and coating combination, and described coating is to form the coating of pattern.

9524. the 9489th method, wherein said implant and coating combination, and described coating has 100 μ m or littler thickness.

9525. the 9489th method, wherein said implant and coating combination, and described coating has 10 μ m or littler thickness.

9526. the 9489th method, wherein said implant and coating combination, and described coating is being disposed the surface adhesion that this installs later and this device.

9527. the 9489th method, the combination of wherein said implant and coating, and described coating in room temperature at least 1 year the time interim be stable.

9528. the 9489th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

9529. the 9489th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

9530. the 9489th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

9531. the 9489th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

9532. the 9489th method, wherein said implant and coating combination, and described coating also contains polymer.

9533. the 9489th method, wherein said device comprise first coating with first compositions and second coating with second compositions.

9534. the 9489th method, wherein said device comprise first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

9535. the 9489th method, wherein said device comprises polymer.

9536. the 9489th method, wherein said device comprises polymer, and wherein said polymer is the component of described compositions.

9537. the 9489th method, wherein said implant and combination of polymers, and described polymer is a copolymer.

9538. the 9489th method, wherein said implant and combination of polymers, and described polymer is a block copolymer.

9539. the 9489th method, wherein said implant and combination of polymers, and described polymer is a random copolymer.

9540. the 9489th method, wherein said implant and combination of polymers, and described polymer is biodegradable polymer.

9541. the 9489th method, wherein said implant and combination of polymers, and described polymer is not biodegradable polymer.

9542. the 9489th method, wherein said implant and combination of polymers, and described polymer is a hydrophilic polymer.

9543. the 9489th method, wherein said implant and combination of polymers, and described polymer is a hydrophobic polymer.

9544. the 9489th method, wherein said implant and combination of polymers, and described polymer has the hydrophilic-structure territory.

9545. the 9489th method, wherein said implant and combination of polymers, and described polymer has hydrophobic domains.

9546. the 9489th method, wherein said implant and combination of polymers, and described polymer is a non-conductive polymer.

9547. the 9489th method, wherein said implant and combination of polymers, and described polymer is an elastomer.

9548. the 9489th method, wherein said implant and combination of polymers, and described polymer is a hydrogel.

9549. the 9489th method, wherein said implant and combination of polymers, and described polymer is a siloxane polymer.

9550. the 9489th method, wherein said implant and combination of polymers, and described polymer is a hydrocarbon polymer.

9551. the 9489th method, wherein said implant and combination of polymers, and described polymer is the styrene derived polymers.

9552. the 9489th method, wherein said implant and combination of polymers, and described polymer is a butadiene polymer.

9553. the 9489th method, wherein said implant and combination of polymers, and described polymer is a macromonomer.

9554. the 9489th method, wherein said implant and combination of polymers, and described polymer is poly-(ethylene glycol) polymer.

9555. the 9489th method, wherein said implant and combination of polymers, and described polymer is an amorphous polymer.

9556. the 9489th method, wherein said implant and combination of polymers, and described polymer is a lubricant coating.

9557. the 9489th method, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

9558. the 9489th method, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

9559. the 9489th method, wherein said implant be combination second forms of pharmacologically active agents further.

9560. the 9489th method, wherein said implant further makes up antiinflammatory.

9561. the 9489th method, wherein said implant further makes up the inhibition infectious agent.

9562. the 9489th method, wherein said implant further makes up anthracycline.

9563. the 9489th method, wherein said implant further makes up doxorubicin.

9564. the 9489th method, wherein said implant further makes up mitoxantrone.

9565. the 9489th method, wherein said implant further makes up the fluorine pyrimidine.

9566. the 9489th method, wherein said implant further make up 5-fluorouracil (5-FU).

9567. the 9489th method, wherein said implant further makes up antifol.

9568. the 9489th method, wherein said implant further makes up methotrexate.

9569. the 9489th method, wherein said implant further makes up podophyllotoxin.

9570. the 9489th method, wherein said implant further makes up etoposide.

9571. the 9489th method, wherein said implant further makes up camptothecine.

9572. the 9489th method, wherein said implant further makes up hydroxyurea.

9573. the 9489th method, wherein said implant further makes up platinum complex.

9574. the 9489th method, wherein said implant further makes up cisplatin.

9575. the 9489th method, wherein said implant further makes up antithrombotic agent.

9576. the 9489th method, wherein said implant further makes up developing agent.

9577. the 9489th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

9578. the 9489th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

9579. the 9489th method, wherein said implant further makes up developing agent, and wherein said developing agent is a MRI response material.

9580. the 9489th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises gadolinium chelate compound.

9581. the 9489th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

9582. the 9489th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises iron oxide compound.

9583. the 9489th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

9584. the 9489th method, the material of the further combination results echo of wherein said implant.

9585. the 9489th method, the material of the further combination results echo of wherein said implant, the material of wherein said generation echo exists with the form of coating.

9586. the 9489th method, wherein said device is aseptic.

9587. the 9489th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

9588. the 9489th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

9589. the 9489th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

9590. the 9489th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

9591. the 9489th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

9592. the 9489th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

9593. the 9489th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

9594. the 9489th method, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

9595. the 9489th method, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

9596. the 9489th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

9597. the 9489th method, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

9598. forming agent, the 9489th method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharge in the described device with valid density by being diffused in from disposing.

9599. forming agent, the 9489th method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharging in the described device from disposing with valid density by corroding said composition.

9600. the 9489th method, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

9601. the 9489th method, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

9602. the 9489th method, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

9603. the 9489th method, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

9604. the 9489th method, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

9605. the described fibrous tissue that the 9489th method, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

9606. the 9489th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9607. the 9489th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9608. the 9489th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9609. the 9489th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9610. the 9489th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9611. the 9489th method, wherein said implant is extendible.

9612. method for preparing medical apparatus, comprise i) hernia mesh implant, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

9613. the 9612nd method, wherein said fibrous tissue forms agent and promotes regeneration.

9614. forming agent, the 9612nd method, wherein said fibrous tissue promote blood vessel to take place.

9615. the 9612nd method, wherein said fibrous tissue form agent and promote the fibroblast migration.

9616. the 9612nd method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

9617. the 9612nd method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

9618. the 9612nd method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

9619. the 9612nd method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

9620. the 9612nd method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

9621. the 9612nd method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

9622. the 9612nd method, wherein said fibrous tissue formation agent is silk or comprises silk.

9623. the 9612nd method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

9624. the 9612nd method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

9625. the 9612nd method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

9626. the 9612nd method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

9627. the 9612nd method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

9628. the 9612nd method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

9629. the 9612nd method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

9630. the 9612nd method, wherein said fibrous tissue form agent and exist with particulate form.

9631. the 9612nd method, wherein said compositions also comprises inflammatory cytokine.

9632. the 9612nd method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

9633. the 9612nd method, wherein said compositions exists with the form of gel or paste.

9634. the 9612nd method, wherein said fibrous tissue form the form that agent is bunch.

9635. the 9612nd method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

9636. the 9612nd method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

9637. the 9612nd method, wherein said implant and coating combination, and described coating comprises described fibrous tissue formation agent.

9638. the 9612nd method, wherein said implant and coating combination, and described coating is placed on the surface of described device.

9639. the 9612nd method, wherein said implant and coating combination, and described coating directly contacts described device.

9640. the 9612nd method, wherein said implant and coating combination, and described coating contacts described device indirectly.

9641. the 9612nd method, wherein said implant and coating combination, and described coating layer portion ground covers described device.

9642. the 9612nd method, wherein said implant and coating combination, and described coating fully covers described device.

9643. the 9612nd method, wherein said implant and coating combination, and described coating is uniform coating.

9644. the 9612nd method, wherein said implant and coating combination, and described coating is uneven coating.

9645. the 9612nd method, wherein said implant and coating combination, and described coating is a discontinuous coating.

9646. the 9612nd method, wherein said implant and coating combination, and described coating is to form the coating of pattern.

9647. the 9612nd method, wherein said implant and coating combination, and described coating has 100 μ m or littler thickness.

9648. the 9612nd method, wherein said implant and coating combination, and described coating has 10 μ m or littler thickness.

9649. the 9612nd method, wherein said implant and coating combination, and described coating is being disposed the surface adhesion that this installs later and this device.

9650. the 9612nd method, the combination of wherein said implant and coating, and described coating in room temperature at least 1 year the time interim be stable.

9651. the 9612nd method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

9652. the 9612nd method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

9653. the 9612nd method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

9654. the 9612nd method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

9655. the 9612nd method, wherein said implant and coating combination, and described coating also contains polymer.

9656. the 9612nd method, wherein said device comprise first coating with first compositions and second coating with second compositions.

9657. the 9612nd method, wherein said device comprise first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

9658. the 9612nd method, wherein said device comprises polymer.

9659. the 9612nd method, wherein said device comprises polymer, and wherein said polymer is the component of described compositions.

9660. the 9612nd method, wherein said implant and combination of polymers, and described polymer is a copolymer.

9661. the 9612nd method, wherein said implant and combination of polymers, and described polymer is a block copolymer.

9662. the 9612nd method, wherein said implant and combination of polymers, and described polymer is a random copolymer.

9663. the 9612nd method, wherein said implant and combination of polymers, and described polymer is biodegradable polymer.

9664. the 9612nd method, wherein said implant and combination of polymers, and described polymer is not biodegradable polymer.

9665. the 9612nd method, wherein said implant and combination of polymers, and described polymer is a hydrophilic polymer.

9666. the 9612nd method, wherein said implant and combination of polymers, and described polymer is a hydrophobic polymer.

9667. the 9612nd method, wherein said implant and combination of polymers, and described polymer has the hydrophilic-structure territory.

9668. the 9612nd method, wherein said implant and combination of polymers, and described polymer has hydrophobic domains.

9669. the 9612nd method, wherein said implant and combination of polymers, and described polymer is a non-conductive polymer.

9670. the 9612nd method, wherein said implant and combination of polymers, and described polymer is an elastomer.

9671. the 9612nd method, wherein said implant and combination of polymers, and described polymer is a hydrogel.

9672. the 9612nd method, wherein said implant and combination of polymers, and described polymer is a siloxane polymer.

9673. the 9612nd method, wherein said implant and combination of polymers, and described polymer is a hydrocarbon polymer.

9674. the 9612nd method, wherein said implant and combination of polymers, and described polymer is the styrene derived polymers.

9675. the 9612nd method, wherein said implant and combination of polymers, and described polymer is a butadiene polymer.

9676. the 9612nd method, wherein said implant and combination of polymers, and described polymer is a macromonomer.

9677. the 9612nd method, wherein said implant and combination of polymers, and described polymer is poly-(ethylene glycol) polymer.

9678. the 9612nd method, wherein said implant and combination of polymers, and described polymer is an amorphous polymer.

9679. the 9612nd method, wherein said implant and combination of polymers, and described polymer is a lubricant coating.

9680. the 9612nd method, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

9681. the 9612nd method, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

9682. the 9612nd method, wherein said implant be combination second forms of pharmacologically active agents further.

9683. the 9612nd method, wherein said implant further makes up antiinflammatory.

9684. the 9612nd method, wherein said implant further makes up the inhibition infectious agent.

9685. the 9612nd method, wherein said implant further makes up anthracycline.

9686. the 9612nd method, wherein said implant further makes up doxorubicin.

9687. the 9612nd method, wherein said implant further makes up mitoxantrone.

9688. the 9612nd method, wherein said implant further makes up the fluorine pyrimidine.

9689. the 9612nd method, wherein said implant further make up 5-fluorouracil (5-FU).

9690. the 9612nd method, wherein said implant further makes up antifol.

9691. the 9612nd method, wherein said implant further makes up methotrexate.

9692. the 9612nd method, wherein said implant further makes up podophyllotoxin.

9693. the 9612nd method, wherein said implant further makes up etoposide.

9694. the 9612nd method, wherein said implant further makes up camptothecine.

9695. the 9612nd method, wherein said implant further makes up hydroxyurea.

9696. the 9612nd method, wherein said implant further makes up platinum complex.

9697. the 9612nd method, wherein said implant further makes up cisplatin.

9698. the 9612nd method, wherein said implant further makes up antithrombotic agent.

9699. the 9612nd method, wherein said implant further makes up developing agent.

9700. the 9612nd method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

9701. the 9612nd method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

9702. the 9612nd method, wherein said implant further makes up developing agent, and wherein said developing agent is a MRI response material.

9703. the 9612nd method, wherein said implant further makes up developing agent, and wherein said developing agent comprises gadolinium chelate compound.

9704. the 9612nd method, wherein said implant further makes up developing agent, and wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

9705. the 9612nd method, wherein said implant further makes up developing agent, and wherein said developing agent comprises iron oxide compound.

9706. the 9612nd method, wherein said implant further makes up developing agent, and wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

9707. the 9612nd method, the material of the further combination results echo of wherein said implant.

9708. the 9612nd method, the material of the further combination results echo of wherein said implant, the material of wherein said generation echo exists with the form of coating.

9709. the 9612nd method, wherein said device is aseptic.

9710. the 9612nd method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

9711. the 9612nd method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

9712. the 9612nd method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

9713. the 9612nd method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

9714. the 9612nd method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

9715. the 9612nd method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

9716. the 9612nd method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

9717. the 9612nd method, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

9718. the 9612nd method, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

9719. the 9612nd method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

9720. the 9612nd method, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

9721. forming agent, the 9612nd method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharge in the described device with valid density by being diffused in from disposing.

9722. forming agent, the 9612nd method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharging in the described device from disposing with valid density by corroding said composition.

9723. the 9612nd method, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

9724. the 9612nd method, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

9725. the 9612nd method, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

9726. the 9612nd method, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

9727. the 9612nd method, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

9728. the described fibrous tissue that the 9612nd method, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

9729. the 9612nd method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9730. the 9612nd method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9731. the 9612nd method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9732. the 9612nd method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9733. the 9612nd method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9734. the 9612nd method, wherein said hernia net is all or part of to be made by synthetic fibers.

9735. the 9612nd method, wherein said hernia net comprises polypropylene.

9736. method for preparing medical apparatus, comprise i) surgical operation film implant, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

9737. the 9736th method, wherein said fibrous tissue forms agent and promotes regeneration.

9738. forming agent, the 9736th method, wherein said fibrous tissue promote blood vessel to take place.

9739. the 9736th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

9740. the 9736th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

9741. the 9736th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

9742. the 9736th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

9743. the 9736th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

9744. the 9736th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

9745. the 9736th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

9746. the 9736th method, wherein said fibrous tissue formation agent is silk or comprises silk.

9747. the 9736th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

9748. the 9736th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

9749. the 9736th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

9750. the 9736th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

9751. the 9736th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

9752. the 9736th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

9753. the 9736th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

9754. the 9736th method, wherein said fibrous tissue form agent and exist with particulate form.

9755. the 9736th method, wherein said compositions also comprises inflammatory cytokine.

9756. the 9736th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

9757. the 9736th method, wherein said compositions exists with the form of gel or paste.

9758. the 9736th method, wherein said fibrous tissue form the form that agent is bunch.

9759. the 9736th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

9760. the 9736th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

9761. the 9736th method, wherein said implant and coating combination, and described coating comprises described fibrous tissue formation agent.

9762. the 9736th method, wherein said implant and coating combination, and described coating is placed on the surface of described device.

9763. the 9736th method, wherein said implant and coating combination, and described coating directly contacts described device.

9764. the 9736th method, wherein said implant and coating combination, and described coating contacts described device indirectly.

9765. the 9736th method, wherein said implant and coating combination, and described coating layer portion ground covers described device.

9766. the 9736th method, wherein said implant and coating combination, and described coating fully covers described device.

9767. the 9736th method, wherein said implant and coating combination, and described coating is uniform coating.

9768. the 9736th method, wherein said implant and coating combination, and described coating is uneven coating.

9769. the 9736th method, wherein said implant and coating combination, and described coating is a discontinuous coating.

9770. the 9736th method, wherein said implant and coating combination, and described coating is to form the coating of pattern.

9771. the 9736th method, wherein said implant and coating combination, and described coating has 100 μ m or littler thickness.

9772. the 9736th method, wherein said implant and coating combination, and described coating has 10 μ m or littler thickness.

9773. the 9736th method, wherein said implant and coating combination, and described coating is being disposed the surface adhesion that this installs later and this device.

9774. the 9736th method, the combination of wherein said implant and coating, and described coating in room temperature at least 1 year the time interim be stable.

9775. the 9736th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

9776. the 9736th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

9777. the 9736th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

9778. the 9736th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

9779. the 9736th method, wherein said implant and coating combination, and described coating also contains polymer.

9780. the 9736th method, wherein said device comprise first coating with first compositions and second coating with second compositions.

9781. the 9736th method, wherein said device comprise first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

9782. the 9736th method, wherein said device comprises polymer.

9783. the 9736th method, wherein said device comprises polymer, and wherein said polymer is the component of described compositions.

9784. the 9736th method, wherein said implant and combination of polymers, and described polymer is a copolymer.

9785. the 9736th method, wherein said implant and combination of polymers, and described polymer is a block copolymer.

9786. the 9736th method, wherein said implant and combination of polymers, and described polymer is a random copolymer.

9787. the 9736th method, wherein said implant and combination of polymers, and described polymer is biodegradable polymer.

9788. the 9736th method, wherein said implant and combination of polymers, and described polymer is not biodegradable polymer.

9789. the 9736th method, wherein said implant and combination of polymers, and described polymer is a hydrophilic polymer.

9790. the 9736th method, wherein said implant and combination of polymers, and described polymer is a hydrophobic polymer.

9791. the 9736th method, wherein said implant and combination of polymers, and described polymer has the hydrophilic-structure territory.

9792. the 9736th method, wherein said implant and combination of polymers, and described polymer has hydrophobic domains.

9793. the 9736th method, wherein said implant and combination of polymers, and described polymer is a non-conductive polymer.

9794. the 9736th method, wherein said implant and combination of polymers, and described polymer is an elastomer.

9795. the 9736th method, wherein said implant and combination of polymers, and described polymer is a hydrogel.

9796. the 9736th method, wherein said implant and combination of polymers, and described polymer is a siloxane polymer.

9797. the 9736th method, wherein said implant and combination of polymers, and described polymer is a hydrocarbon polymer.

9798. the 9736th method, wherein said implant and combination of polymers, and described polymer is the styrene derived polymers.

9799. the 9736th method, wherein said implant and combination of polymers, and described polymer is a butadiene polymer.

9800. the 9736th method, wherein said implant and combination of polymers, and described polymer is a macromonomer.

9801. the 9736th method, wherein said implant and combination of polymers, and described polymer is poly-(ethylene glycol) polymer.

9802. the 9736th method, wherein said implant and combination of polymers, and described polymer is an amorphous polymer.

9803. the 9736th method, wherein said implant and combination of polymers, and described polymer is a lubricant coating.

9804. the 9736th method, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

9805. the 9736th method, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

9806. the 9736th method, wherein said implant be combination second forms of pharmacologically active agents further.

9807. the 9736th method, wherein said implant further makes up antiinflammatory.

9808. the 9736th method, wherein said implant further makes up the inhibition infectious agent.

9809. the 9736th method, wherein said implant further makes up anthracycline.

9810. the 9736th method, wherein said implant further makes up doxorubicin.

9811. the 9736th method, wherein said implant further makes up mitoxantrone.

9812. the 9736th method, wherein said implant further makes up the fluorine pyrimidine.

9813. the 9736th method, wherein said implant further make up 5-fluorouracil (5-FU).

9814. the 9736th method, wherein said implant further makes up antifol.

9815. the 9736th method, wherein said implant further makes up methotrexate.

9816. the 9736th method, wherein said implant further makes up podophyllotoxin.

9817. the 9736th method, wherein said implant further makes up etoposide.

9818. the 9736th method, wherein said implant further makes up camptothecine.

9819. the 9736th method, wherein said implant further makes up hydroxyurea.

9820. the 9736th method, wherein said implant further makes up platinum complex.

9821. the 9736th method, wherein said implant further makes up cisplatin.

9822. the 9736th method, wherein said implant further makes up antithrombotic agent.

9823. the 9736th method, wherein said implant further makes up developing agent.

9824. the 9736th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

9825. the 9736th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

9826. the 9736th method, wherein said implant further makes up developing agent, and wherein said developing agent is a MRI response material.

9827. the 9736th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises gadolinium chelate compound.

9828. the 9736th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

9829. the 9736th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises iron oxide compound.

9830. the 9736th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

9831. the 9736th method, the material of the further combination results echo of wherein said implant.

9832. the 9736th method, the material of the further combination results echo of wherein said implant, the material of wherein said generation echo exists with the form of coating.

9833. the 9736th method, wherein said device is aseptic.

9834. the 9736th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

9835. the 9736th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

9836. the 9736th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

9837. the 9736th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

9838. the 9736th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

9839. the 9736th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

9840. the 9736th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

9841. the 9736th method, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

9842. the 9736th method, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

9843. the 9736th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

9844. the 9736th method, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

9845. forming agent, the 9736th method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharge in the described device with valid density by being diffused in from disposing.

9846. forming agent, the 9736th method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharging in the described device from disposing with valid density by corroding said composition.

9847. the 9736th method, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

9848. the 9736th method, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

9849. the 9736th method, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

9850. the 9736th method, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

9851. the 9736th method, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

9852. the described fibrous tissue that the 9736th method, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

9853. the 9736th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9854. the 9736th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9855. the 9736th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9856. the 9736th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9857. the 9736th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9858. the 9736th method, wherein said surgical operation thin film implant comprises cellulose or cellulose derivative.

9859. the 9736th method, wherein said surgical operation thin film implant is porous.

9860. the 9736th method, wherein said surgical operation thin film implant is biodegradable.

9861. method for preparing medical apparatus, comprise i) the spinal fusion implant, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

9862. the 9861st method, wherein said fibrous tissue forms agent and promotes regeneration.

9863. forming agent, the 9861st method, wherein said fibrous tissue promote blood vessel to take place.

9864. the 9861st method, wherein said fibrous tissue form agent and promote the fibroblast migration.

9865. the 9861st method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

9866. the 9861st method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

9867. the 9861st method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

9868. the 9861st method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

9869. the 9861st method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

9870. the 9861st method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

9871. the 9861st method, wherein said fibrous tissue formation agent is silk or comprises silk.

9872. the 9861st method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

9873. the 9861st method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

9874. the 9861st method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

9875. the 9861st method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

9876. the 9861st method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

9877. the 9861st method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

9878. the 9861st method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

9879. the 9861st method, wherein said fibrous tissue form agent and exist with particulate form.

9880. the 9861st method, wherein said compositions also comprises inflammatory cytokine.

9881. the 9861st method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

9882. the 9861st method, wherein said compositions exists with the form of gel or paste.

9883. the 9861st method, wherein said fibrous tissue form the form that agent is bunch.

9884. the 9861st method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

9885. the 9861st method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

9886. the 9861st method, wherein said implant and coating combination, and described coating comprises described fibrous tissue formation agent.

9887. the 9861st method, wherein said implant and coating combination, and described coating is placed on the surface of described device.

9888. the 9861st method, wherein said implant and coating combination, and described coating directly contacts described device.

9889. the 9861st method, wherein said implant and coating combination, and described coating contacts described device indirectly.

9890. the 9861st method, wherein said implant and coating combination, and described coating layer portion ground covers described device.

9891. the 9861st method, wherein said implant and coating combination, and described coating fully covers described device.

9892. the 9861st method, wherein said implant and coating combination, and described coating is uniform coating.

9893. the 9861st method, wherein said implant and coating combination, and described coating is uneven coating.

9894. the 9861st method, wherein said implant and coating combination, and described coating is a discontinuous coating.

9895. the 9861st method, wherein said implant and coating combination, and described coating is to form the coating of pattern.

9896. the 9861st method, wherein said implant and coating combination, and described coating has 100 μ m or littler thickness.

9897. the 9861st method, wherein said implant and coating combination, and described coating has 10 μ m or littler thickness.

9898. the 9861st method, wherein said implant and coating combination, and described coating is being disposed the surface adhesion that this installs later and this device.

9899. the 9861st method, the combination of wherein said implant and coating, and described coating in room temperature at least 1 year the time interim be stable.

9900. the 9861st method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

9901. the 9861st method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

9902. the 9861st method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

9903. the 9861st method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

9904. the 9861st method, wherein said implant and coating combination, and described coating also contains polymer.

9905. the 9861st method, wherein said device comprise first coating with first compositions and second coating with second compositions.

9906. the 9861st method, wherein said device comprise first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

9907. the 9861st method, wherein said device comprises polymer.

9908. the 9861st method, wherein said device comprises polymer, and wherein said polymer is the component of described compositions.

9909. the 9861st method, wherein said implant and combination of polymers, and described polymer is a copolymer.

9910. the 9861st method, wherein said implant and combination of polymers, and described polymer is a block copolymer.

9911. the 9861st method, wherein said implant and combination of polymers, and described polymer is a random copolymer.

9912. the 9861st method, wherein said implant and combination of polymers, and described polymer is biodegradable polymer.

9913. the 9861st method, wherein said implant and combination of polymers, and described polymer is not biodegradable polymer.

9914. the 9861st method, wherein said implant and combination of polymers, and described polymer is a hydrophilic polymer.

9915. the 9861st method, wherein said implant and combination of polymers, and described polymer is a hydrophobic polymer.

9916. the 9861st method, wherein said implant and combination of polymers, and described polymer has the hydrophilic-structure territory.

9917. the 9861st method, wherein said implant and combination of polymers, and described polymer has hydrophobic domains.

9918. the 9861st method, wherein said implant and combination of polymers, and described polymer is a non-conductive polymer.

9919. the 9861st method, wherein said implant and combination of polymers, and described polymer is an elastomer.

9920. the 9861st method, wherein said implant and combination of polymers, and described polymer is a hydrogel.

9921. the 9861st method, wherein said implant and combination of polymers, and described polymer is a siloxane polymer.

9922. the 9861st method, wherein said implant and combination of polymers, and described polymer is a hydrocarbon polymer.

9923. the 9861st method, wherein said implant and combination of polymers, and described polymer is the styrene derived polymers.

9924. the 9861st method, wherein said implant and combination of polymers, and described polymer is a butadiene polymer.

9925. the 9861st method, wherein said implant and combination of polymers, and described polymer is a macromonomer.

9926. the 9861st method, wherein said implant and combination of polymers, and described polymer is poly-(ethylene glycol) polymer.

9927. the 9861st method, wherein said implant and combination of polymers, and described polymer is an amorphous polymer.

9928. the 9861st method, wherein said implant and combination of polymers, and described polymer is a lubricant coating.

9929. the 9861st method, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

9930. the 9861st method, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

9931. the 9861st method, wherein said implant be combination second forms of pharmacologically active agents further.

9932. the 9861st method, wherein said implant further makes up antiinflammatory.

9933. the 9861st method, wherein said implant further makes up the inhibition infectious agent.

9934. the 9861st method, wherein said implant further makes up anthracycline.

9935. the 9861st method, wherein said implant further makes up doxorubicin.

9936. the 9861st method, wherein said implant further makes up mitoxantrone.

9937. the 9861st method, wherein said implant further makes up the fluorine pyrimidine.

9938. the 9861st method, wherein said implant further make up 5-fluorouracil (5-FU).

9939. the 9861st method, wherein said implant further makes up antifol.

9940. the 9861st method, wherein said implant further makes up methotrexate.

9941. the 9861st method, wherein said implant further makes up podophyllotoxin.

9942. the 9861st method, wherein said implant further makes up etoposide.

9943. the 9861st method, wherein said implant further makes up camptothecine.

9944. the 9861st method, wherein said implant further makes up hydroxyurea.

9945. the 9861st method, wherein said implant further makes up platinum complex.

9946. the 9861st method, wherein said implant further makes up cisplatin.

9947. the 9861st method, wherein said implant further makes up antithrombotic agent.

9948. the 9861st method, wherein said implant further makes up developing agent.

9949. the 9861st method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

9950. the 9861st method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

9951. the 9861st method, wherein said implant further makes up developing agent, and wherein said developing agent is a MRI response material.

9952. the 9861st method, wherein said implant further makes up developing agent, and wherein said developing agent comprises gadolinium chelate compound.

9953. the 9861st method, wherein said implant further makes up developing agent, and wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

9954. the 9861st method, wherein said implant further makes up developing agent, and wherein said developing agent comprises iron oxide compound.

9955. the 9861st method, wherein said implant further makes up developing agent, and wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

9956. the 9861st method, the material of the further combination results echo of wherein said implant.

9957. the 9861st method, the material of the further combination results echo of wherein said implant, the material of wherein said generation echo exists with the form of coating.

9958. the 9861st method, wherein said device is aseptic.

9959. the 9861st method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

9960. the 9861st method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

9961. the 9861st method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

9962. the 9861st method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

9963. the 9861st method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

9964. the 9861st method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

9965. the 9861st method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

9966. the 9861st method, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

9967. the 9861st method, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

9968. the 9861st method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

9969. the 9861st method, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

9970. forming agent, the 9861st method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharge in the described device with valid density by being diffused in from disposing.

9971. forming agent, the 9861st method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharging in the described device from disposing with valid density by corroding said composition.

9972. the 9861st method, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

9973. the 9861st method, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

9974. the 9861st method, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

9975. the 9861st method, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

9976. the 9861st method, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

9977. the described fibrous tissue that the 9861st method, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

9978. the 9861st method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9979. the 9861st method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9980. the 9861st method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9981. the 9861st method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9982. the 9861st method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

9983. the 9861st method, wherein said spinal fusion device are to merge basket (fusion basket).

9984. the 9861st method, wherein said spinal fusion device are fusion cage (fusion cage) devices.

9985. the 9861st method, wherein said spinal fusion device are the amboceptor boxes.

9986. the 9861st method, wherein said spinal fusion device are the amboceptor implants.

9987. the 9861st method, wherein said spinal fusion device are the fusion cage fixtures.

9988. the 9861st method, wherein said spinal fusion device are to merge equalization chamber.

9989. the 9861st method, wherein said spinal fusion device are the fusion cage fixing heads.

9990. the 9861st method, wherein said spinal fusion device is a bone anchoring device.

9991. the 9861st method, wherein said spinal fusion device are the stationarity hone lamellas.

9992. the 9861st method, wherein said spinal fusion device are the stationarity bone screw.

9993. the 9861st method, wherein said spinal fusion device is a tissue filler.

9994. the 9861st method, wherein said spinal fusion device is a bone cement.

9995. the 9861st method, wherein said spinal fusion device are allograft's materials.

9996. the 9861st method, wherein said spinal fusion device are the autograft materials.

9997. the 9861st method, wherein said spinal fusion device are the collagen protein implants.

9998. the 9861st method, wherein said spinal fusion device is injectable.

9999. method for preparing medical apparatus, comprise i) in every inaccessible sticking patch implant, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

10000. the 9999th method, wherein said fibrous tissue forms agent and promotes regeneration.

10001. forming agent, the 9999th method, wherein said fibrous tissue promote blood vessel to take place.

10002. the 9999th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

10003. the 9999th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

10004. the 9999th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

10005. the 9999th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

10006. the 9999th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

10007. the 9999th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

10008. the 9999th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

10009. the 9999th method, wherein said fibrous tissue formation agent is silk or comprises silk.

10010. the 9999th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

10011. the 9999th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

10012. the 9999th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

10013. the 9999th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

10014. the 9999th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

10015. the 9999th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

10016. the 9999th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

10017. the 9999th method, wherein said fibrous tissue form agent and exist with particulate form.

10018. the 9999th method, wherein said compositions also comprises inflammatory cytokine.

10019. the 9999th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

10020. the 9999th method, wherein said compositions exists with the form of gel or paste.

10021. the 9999th method, wherein said fibrous tissue form the form that agent is bunch.

10022. the 9999th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

10023. the 9999th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

10024. the 9999th method, wherein said implant and coating combination, and described coating comprises described fibrous tissue formation agent.

10025. the 9999th method, wherein said implant and coating combination, and described coating is placed on the surface of described device.

10026. the 9999th method, wherein said implant and coating combination, and described coating directly contacts described device.

10027. the 9999th method, wherein said implant and coating combination, and described coating contacts described device indirectly.

10028. the 9999th method, wherein said implant and coating combination, and described coating layer portion ground covers described device.

10029. the 9999th method, wherein said implant and coating combination, and described coating fully covers described device.

10030. the 9999th method, wherein said implant and coating combination, and described coating is uniform coating.

10031. the 9999th method, wherein said implant and coating combination, and described coating is uneven coating.

10032. the 9999th method, wherein said implant and coating combination, and described coating is a discontinuous coating.

10033. the 9999th method, wherein said implant and coating combination, and described coating is to form the coating of pattern.

10034. the 9999th method, wherein said implant and coating combination, and described coating has 100 μ m or littler thickness.

10035. the 9999th method, wherein said implant and coating combination, and described coating has 10 μ m or littler thickness.

10036. the 9999th method, wherein said implant and coating combination, and described coating is being disposed the surface adhesion that this installs later and this device.

10037. the 9999th method, the combination of wherein said implant and coating, and described coating in room temperature at least 1 year the time interim be stable.

10038. the 9999th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

10039. the 9999th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

10040. the 9999th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

10041. the 9999th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

10042. the 9999th method, wherein said implant and coating combination, and described coating also contains polymer.

10043. the 9999th method, wherein said device comprise first coating with first compositions and second coating with second compositions.

10044. the 9999th method, wherein said device comprise first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

10045. the 9999th method, wherein said device comprises polymer.

10046. the 9999th method, wherein said device comprises polymer, and wherein said polymer is the component of described compositions.

10047. the 9999th method, wherein said implant and combination of polymers, and described polymer is a copolymer.

10048. the 9999th method, wherein said implant and combination of polymers, and described polymer is a block copolymer.

10049. the 9999th method, wherein said implant and combination of polymers, and described polymer is a random copolymer.

10050. the 9999th method, wherein said implant and combination of polymers, and described polymer is biodegradable polymer.

10051. the 9999th method, wherein said implant and combination of polymers, and described polymer is not biodegradable polymer.

10052. the 9999th method, wherein said implant and combination of polymers, and described polymer is a hydrophilic polymer.

10053. the 9999th method, wherein said implant and combination of polymers, and described polymer is a hydrophobic polymer.

10054. the 9999th method, wherein said implant and combination of polymers, and described polymer has the hydrophilic-structure territory.

10055. the 9999th method, wherein said implant and combination of polymers, and described polymer has hydrophobic domains.

10056. the 9999th method, wherein said implant and combination of polymers, and described polymer is a non-conductive polymer.

10057. the 9999th method, wherein said implant and combination of polymers, and described polymer is an elastomer.

10058. the 9999th method, wherein said implant and combination of polymers, and described polymer is a hydrogel.

10059. the 9999th method, wherein said implant and combination of polymers, and described polymer is a siloxane polymer.

10060. the 9999th method, wherein said implant and combination of polymers, and described polymer is a hydrocarbon polymer.

10061. the 9999th method, wherein said implant and combination of polymers, and described polymer is the styrene derived polymers.

10062. the 9999th method, wherein said implant and combination of polymers, and described polymer is a butadiene polymer.

10063. the 9999th method, wherein said implant and combination of polymers, and described polymer is a macromonomer.

10064. the 9999th method, wherein said implant and combination of polymers, and described polymer is poly-(ethylene glycol) polymer.

10065. the 9999th method, wherein said implant and combination of polymers, and described polymer is an amorphous polymer.

10066. the 9999th method, wherein said implant and combination of polymers, and described polymer is a lubricant coating.

10067. the 9999th method, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

10068. the 9999th method, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

10069. the 9999th method, wherein said implant be combination second forms of pharmacologically active agents further.

10070. the 9999th method, wherein said implant further makes up antiinflammatory.

10071. the 9999th method, wherein said implant further makes up the inhibition infectious agent.

10072. the 9999th method, wherein said implant further makes up anthracycline.

10073. the 9999th method, wherein said implant further makes up doxorubicin.

10074. the 9999th method, wherein said implant further makes up mitoxantrone.

10075. the 9999th method, wherein said implant further makes up the fluorine pyrimidine.

10076. the 9999th method, wherein said implant further make up 5-fluorouracil (5-FU).

10077. the 9999th method, wherein said implant further makes up antifol.

10078. the 9999th method, wherein said implant further makes up methotrexate.

10079. the 9999th method, wherein said implant further makes up podophyllotoxin.

10080. the 9999th method, wherein said implant further makes up etoposide.

10081. the 9999th method, wherein said implant further makes up camptothecine.

10082. the 9999th method, wherein said implant further makes up hydroxyurea.

10083. the 9999th method, wherein said implant further makes up platinum complex.

10084. the 9999th method, wherein said implant further makes up cisplatin.

10085. the 9999th method, wherein said implant further makes up antithrombotic agent.

10086. the 9999th method, wherein said implant further makes up developing agent.

10087. the 9999th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

10088. the 9999th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

10089. the 9999th method, wherein said implant further makes up developing agent, and wherein said developing agent is a MRI response material.

10090. the 9999th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises gadolinium chelate compound.

10091. the 9999th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

10092. the 9999th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises iron oxide compound.

10093. the 9999th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

10094. the 9999th method, the material of the further combination results echo of wherein said implant.

10095. the 9999th method, the material of the further combination results echo of wherein said implant, the material of wherein said generation echo exists with the form of coating.

10096. the 9999th method, wherein said device is aseptic.

10097. the 9999th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

10098. the 9999th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

10099. the 9999th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

10100. the 9999th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

10101. the 9999th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

10102. the 9999th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

10103. the 9999th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

10104. the 9999th method, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

10105. the 9999th method, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

10106. the 9999th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

10107. the 9999th method, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

10108. forming agent, the 9999th method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharge in the described device with valid density by being diffused in from disposing.

10109. forming agent, the 9999th method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharging in the described device from disposing with valid density by corroding said composition.

10110. the 9999th method, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

10111. the 9999th method, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

10112. the 9999th method, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

10113. the 9999th method, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

10114. the 9999th method, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

10115. the described fibrous tissue that the 9999th method, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

10116. the 9999th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

10117. the 9999th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

10118. the 9999th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

10119. the 9999th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

10120. the 9999th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

10121. the 9999th method, wherein said in inaccessible sticking patch is every closing device.

10122. the 9999th method, wherein said in every inaccessible sticking patch be the shunting closing device.

10123. the 9999th method is intracardiac closer every inaccessible sticking patch in wherein said.

10124. the 9999th method is a damaged closure system every inaccessible sticking patch in wherein said.

10125. the 9999th method is a branch apparatus in the blood vessel every inaccessible sticking patch in wherein said.

10126. method for preparing medical apparatus, comprise i) inner chamber fastener implant, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

10127. the 10126th method, wherein said fibrous tissue forms agent and promotes regeneration.

10128. forming agent, the 10126th method, wherein said fibrous tissue promote blood vessel to take place.

10129. the 10126th method, wherein said fibrous tissue form agent and promote the fibroblast migration.

10130. the 10126th method, wherein said fibrous tissue forms agent and promotes fibroblast proliferation.

10131. the 10126th method, wherein said fibrous tissue forms the deposition that agent promotes extracellular matrix (ECM).

10132. the 10126th method, wherein said fibrous tissue forms agent and promotes tissue reconstruction.

10133. the 10126th method, it is the ductus arteriosus wall stimulant that wherein said fibrous tissue forms agent.

10134. the 10126th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

10135. the 10126th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

10136. the 10126th method, wherein said fibrous tissue formation agent is silk or comprises silk.

10137. the 10126th method, wherein said fibrous tissue form agent and are mineral particles or comprise mineral particle.

10138. the 10126th method, wherein said fibrous tissue form agent and are chitosans or comprise chitosan.

10139. the 10126th method, wherein said fibrous tissue form agent and are polylysines or comprise polylysine.

10140. the 10126th method, wherein said fibrous tissue form agent and are fibronectins or comprise fibronectin.

10141. the 10126th method, wherein said fibrous tissue form agent and are bleomycin or comprise bleomycin.

10142. the 10126th method, wherein said fibrous tissue form agent and are CTGF or comprise CTGF.

10143. the 10126th method, wherein said fibrous tissue formation agent exists with the form of line, or contacts with line.

10144. the 10126th method, wherein said fibrous tissue form agent and exist with particulate form.

10145. the 10126th method, wherein said compositions also comprises inflammatory cytokine.

10146. the 10126th method, wherein said compositions also comprises the medicament that stimulates cellular proliferation.

10147. the 10126th method, wherein said compositions exists with the form of gel or paste.

10148. the 10126th method, wherein said fibrous tissue form the form that agent is bunch.

10149. the 10126th method, wherein said fibrous tissue form the adhesion between the host that agent promotes described device and implanted described device.

10150. the 10126th method, wherein said device forms agent with described fibrous tissue and is delivered locally in the tissue of described device.

10151. the 10126th method, wherein said implant and coating combination, and described coating comprises described fibrous tissue formation agent.

10152. the 10126th method, wherein said implant and coating combination, and described coating is placed on the surface of described device.

10153. the 10126th method, wherein said implant and coating combination, and described coating directly contacts described device.

10154. the 10126th method, wherein said implant and coating combination, and described coating contacts described device indirectly.

10155. the 10126th method, wherein said implant and coating combination, and described coating layer portion ground covers described device.

10156. the 10126th method, wherein said implant and coating combination, and described coating fully covers described device.

10157. the 10126th method, wherein said implant and coating combination, and described coating is uniform coating.

10158. the 10126th method, wherein said implant and coating combination, and described coating is uneven coating.

10159. the 10126th method, wherein said implant and coating combination, and described coating is a discontinuous coating.

10160. the 10126th method, wherein said implant and coating combination, and described coating is to form the coating of pattern.

10161. the 10126th method, wherein said implant and coating combination, and described coating has 100 μ m or littler thickness.

10162. the 10126th method, wherein said implant and coating combination, and described coating has 10 μ m or littler thickness.

10163. the 10126th method, wherein said implant and coating combination, and described coating is being disposed the surface adhesion that this installs later and this device.

10164. the 10126th method, the combination of wherein said implant and coating, and described coating in room temperature at least 1 year the time interim be stable.

10165. the 10126th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 1 weight % between about 0.0001 weight %.

10166. the 10126th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 10 weight % between about 1 weight %.

10167. the 10126th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 25 weight % between about 10 weight %.

10168. the 10126th method, wherein said implant and coating combination, and described fibrous tissue forms agent to be present in the described coating to the amount of scope between about 70 weight % between about 25 weight %.

10169. the 10126th method, wherein said implant and coating combination, and described coating also contains polymer.

10170. the 10126th method, wherein said device comprise first coating with first compositions and second coating with second compositions.

10171. the 10126th method, wherein said device comprise first coating with first compositions and second coating with second compositions, wherein said first compositions is different with second compositions.

10172. the 10126th method, wherein said device comprises polymer.

10173. the 10126th method, wherein said device comprises polymer, and wherein said polymer is the component of described compositions.

10174. the 10126th method, wherein said implant and combination of polymers, and described polymer is a copolymer.

10175. the 10126th method, wherein said implant and combination of polymers, and described polymer is a block copolymer.

10176. the 10126th method, wherein said implant and combination of polymers, and described polymer is a random copolymer.

10177. the 10126th method, wherein said implant and combination of polymers, and described polymer is biodegradable polymer.

10178. the 10126th method, wherein said implant and combination of polymers, and described polymer is not biodegradable polymer.

10179. the 10126th method, wherein said implant and combination of polymers, and described polymer is a hydrophilic polymer.

10180. the 10126th method, wherein said implant and combination of polymers, and described polymer is a hydrophobic polymer.

10181. the 10126th method, wherein said implant and combination of polymers, and described polymer has the hydrophilic-structure territory.

10182. the 10126th method, wherein said implant and combination of polymers, and described polymer has hydrophobic domains.

10183. the 10126th method, wherein said implant and combination of polymers, and described polymer is a non-conductive polymer.

10184. the 10126th method, wherein said implant and combination of polymers, and described polymer is an elastomer.

10185. the 10126th method, wherein said implant and combination of polymers, and described polymer is a hydrogel.

10186. the 10126th method, wherein said implant and combination of polymers, and described polymer is a siloxane polymer.

10187. the 10126th method, wherein said implant and combination of polymers, and described polymer is a hydrocarbon polymer.

10188. the 10126th method, wherein said implant and combination of polymers, and described polymer is the styrene derived polymers.

10189. the 10126th method, wherein said implant and combination of polymers, and described polymer is a butadiene polymer.

10190. the 10126th method, wherein said implant and combination of polymers, and described polymer is a macromonomer.

10191. the 10126th method, wherein said implant and combination of polymers, and described polymer is poly-(ethylene glycol) polymer.

10192. the 10126th method, wherein said implant and combination of polymers, and described polymer is an amorphous polymer.

10193. the 10126th method, wherein said implant and combination of polymers, and described polymer is a lubricant coating.

10194. the 10126th method, wherein said fibrous tissue forms hole or the hole that agent is arranged in described device.

10195. the 10126th method, wherein said fibrous tissue forms passage, chamber or the divet that agent is arranged in described device.

10196. the 10126th method, wherein said implant be combination second forms of pharmacologically active agents further.

10197. the 10126th method, wherein said implant further makes up antiinflammatory.

10198. the 10126th method, wherein said implant further makes up the inhibition infectious agent.

10199. the 10126th method, wherein said implant further makes up anthracycline.

10200. the 10126th method, wherein said implant further makes up doxorubicin.

10201. the 10126th method, wherein said implant further makes up mitoxantrone.

10202. the 10126th method, wherein said implant further makes up the fluorine pyrimidine.

10203. the 10126th method, wherein said implant further make up 5-fluorouracil (5-FU).

10204. the 10126th method, wherein said implant further makes up antifol.

10205. the 10126th method, wherein said implant further makes up methotrexate.

10206. the 10126th method, wherein said implant further makes up podophyllotoxin.

10207. the 10126th method, wherein said implant further makes up etoposide.

10208. the 10126th method, wherein said implant further makes up camptothecine.

10209. the 10126th method, wherein said implant further makes up hydroxyurea.

10210. the 10126th method, wherein said implant further makes up platinum complex.

10211. the 10126th method, wherein said implant further makes up cisplatin.

10212. the 10126th method, wherein said implant further makes up antithrombotic agent.

10213. the 10126th method, wherein said implant further makes up developing agent.

10214. the 10126th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises metal, halogenated compound, or containing barium compound.

10215. the 10126th method, wherein said implant further makes up developing agent, and wherein said developing agent is radiopaque material, and wherein said radiopaque material comprises barium, tantalum or technetium.

10216. the 10126th method, wherein said implant further makes up developing agent, and wherein said developing agent is a MRI response material.

10217. the 10126th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises gadolinium chelate compound.

10218. the 10126th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises ferrum, magnesium, manganese, copper, or chromium.

10219. the 10126th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises iron oxide compound.

10220. the 10126th method, wherein said implant further makes up developing agent, and wherein said developing agent comprises, dyestuff, pigment, or coloring agent.

10221. the 10126th method, the material of the further combination results echo of wherein said implant.

10222. the 10126th method, the material of the further combination results echo of wherein said implant, the material of wherein said generation echo exists with the form of coating.

10223. the 10126th method, wherein said device is aseptic.

10224. the 10126th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device.

10225. the 10126th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a connective tissue.

10226. the 10126th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a muscular tissue.

10227. the 10126th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is a nervous tissue.

10228. the 10126th method, wherein after disposing this device, described fibrous tissue forms agent and is released near the tissue of described device, and wherein said tissue is an epithelial tissue.

10229. the 10126th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 year period in disposing described device.

10230. the 10126th method, wherein said fibrous tissue form agent and are discharging with valid density from described device in about 1 month to 6 months period.

10231. the 10126th method, wherein said fibrous tissue form agent and discharge with valid density from described device in about 1-90 days period.

10232. the 10126th method, wherein said fibrous tissue form agent and discharge with valid density from described device with constant speed.

10233. the 10126th method, wherein said fibrous tissue form agent and discharge with valid density from described device with cumulative speed.

10234. the 10126th method, wherein said fibrous tissue formation agent discharges with valid density from described device with speed decrescence.

10235. forming agent, the 10126th method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharge in the described device with valid density by being diffused in from disposing.

10236. forming agent, the 10126th method, wherein said fibrous tissue from the compositions that contains fibrous tissue and form agent, in about 90 days period, discharging in the described device from disposing with valid density by corroding said composition.

10237. the 10126th method, wherein said device comprise the described fibrous tissue formation agent of about 0.01 μ g to about 10 μ g.

10238. the 10126th method, wherein said device comprise the described fibrous tissue formation agent of about 10 μ g to about 10mg.

10239. the 10126th method, wherein said device comprise the described fibrous tissue formation agent of about 10mg to about 250mg.

10240. the 10126th method, wherein said device comprise the described fibrous tissue formation agent of about 250mg to about 1000mg.

10241. the 10126th method, wherein said device comprise the described fibrous tissue formation agent of about 1000mg to about 2500mg.

10242. the described fibrous tissue that the 10126th method, the surface of wherein said device comprise less than 0.01 μ g forms agent/mm ²Use the apparatus surface that described fibrous tissue forms agent.

10243. the 10126th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 0.01 μ g to about 1 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

10244. the 10126th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1 μ g to about 10 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

10245. the 10126th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 10 μ g to about 250 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

10246. the 10126th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 250 μ g to about 1000 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

10247. the 10126th method, the surface of wherein said device comprise the described fibrous tissue formation agent/mm of about 1000 μ g to about 2500 μ g ²Use the apparatus surface that described fibrous tissue forms agent.

By the mode of illustration, but not provide the following example by the mode of restriction.

Embodiment

Embodiment 1

With fibronectin coating medical science graft

Apparatus for coating is made up of the suspension type agitator (Fisher Scientific) of horizontal location.Conical stainless steel tap is invested on the rotation chuck of agitator.One end of aneurysm coil is moved on the swivel head up to fixation.The other end invested described medical science graft is remained on folder-rotary head device on the horizontal level, but allow of the axle rotation of described medical implant along it.Thereby subsequently agitator is set in 30rpm go up rotation make whole medical science graft with this speed along horizontal rotational shaft.1% (w/w) fibronectin (Calbiochem, San Diego, CA) solution in the preparation sterilized water.When described medical implant rotated, in 2 minutes time this solution of two hectolambdas slowly being drawn was the wide ring of 3mm, and it is arranged in apart from the medical implant end 5mm that is fixed to conical steel toe at a distance.Then along with described medical implant continues to be rotated under the nitrogen current with described fibronectin drying.When drying, remove described medical implant, revolution (turn around) and be coated with the other end of described medical implant in an identical manner.Utilize this method that flexible fibronectin ring is placed the two ends of described medical implant, and can not diminish the physical characteristic of described medical implant.Other example of the medical implant that can be coated with similar fashion comprises blood vessel (vaso-) occlusive coil and the inaccessible implant of blood vessel (vaso-).

Embodiment 2

Be coated with medical implant with poly-L-Lysine

Utilize the method coating medical implant described in the embodiment 1.1% (w/w) poly-L-Lysine (Sigma, St.Louis, MO) solution in the preparation sterilized water.When described medical implant rotated, in 2 minutes time this solution of two hectolambdas slowly being drawn was the wide ring of 3mm, and it is arranged in apart from the medical implant end 5mm that is fixed to conical steel toe at a distance.Then along with described medical implant continues to be rotated under the nitrogen current with described poly-L-Lysine drying.When drying, remove described medical implant, turn round and be coated with in an identical manner the other end of described medical implant.Utilize this method that flexible poly-L-Lysine ring is placed the two ends of described medical implant, and can not diminish the physical characteristic of described medical implant.

Embodiment 3

With the chitosan-coated medical implant of N-carboxylic butyl

Utilize the method coating medical implant described in the embodiment 1.1% (w/w) N-carboxylic butyl chitosan (Carbomer, Westborough, MA) solution in the preparation sterilized water.When described medical implant rotated, in 2 minutes time this solution of two hectolambdas slowly being drawn was the wide ring of 3mm, and it is arranged in apart from the medical implant end 5mm that is fixed to conical steel toe at a distance.Along with described medical implant continues to be rotated under the nitrogen current with described N-carboxylic butyl chitosan drying.When drying, remove described medical implant, turn round and be coated with in an identical manner the other end.Utilize this method that flexible N-carboxylic butyl chitosan ring is placed the two ends of described medical implant, and can not diminish the physical characteristic of described medical implant.

Embodiment 4

With the coating of the bromocriptine in poly-(ethylene-vinyl acetas) medical implant

Utilize the method coating medical implant described in the embodiment 1.The EVA solution (ratio of ethylene and vinylacetate is 60/40) (Polysciences USA) that in dichloromethane, prepares 4.5% (w/w).(Sigma, St.Louis MO) dissolve/are suspended in this solution with 5mg/ml with bromocriptine methanesulfonates (Bromocriptine mesylate).When described medical implant rotated, in 2 minutes time this solution of two hectolambdas slowly being drawn was the wide ring of 3mm, and it is arranged in apart from the medical implant end 5mm that is fixed to conical steel toe at a distance.Along with described medical implant continues to be rotated under the nitrogen current with EVA/ bromocriptine drying.When drying, remove described medical implant, turn round and be coated with in an identical manner the other end of described medical implant.Utilize this method that flexible EVA/ bromocriptine ring is placed the two ends of described medical implant, and can not diminish the physical characteristic of described medical implant.

Embodiment 5

The preparation of inflammatory microcrystal (a hydration monosodium urate and two hydration calcium pyrophosphates)

Hydration monosodium urate (MSUM) microcrystal of growing.The solution of uric acid and sodium hydroxide is placed in ambient temperature overnight with pH 8.9 in 55 ℃.With cold (4 ℃) distilled water rinsing crystal several times and circulating air oven (Fisher, Isotemp) in 60 ℃ of dryings 12 hours.

Be prepared as follows three oblique brilliant two hydration calcium pyrophosphate (CPPD) crystal.The 250ml beaker that will contain the 103ml distilled water is heated to 60 ℃ in water-bath, and constantly stirs with the stirring rod of TEFLON coating.Slow down and stir and the concentrated hydrochloric acid of adding 0.71ml and the glacial acetic acid of 0.32ml, add the 0.6g calcium acetate subsequently.The 150ml beaker that will contain the 20ml distilled water is heated to 60 ℃ in water-bath, and adds the 0.6g calcium acetate.In the 250ml beaker, improve stir speed (S.S.), and add 2g acid calcium pyrophosphate rapidly.Work as CaH ₂P ₂O ₇When almost all dissolving, reduce stir speed (S.S.) and continue 5 minutes, in 15 seconds time, be accompanied by vigorous stirring the content in the small beaker is poured in the large beaker subsequently.In preparation subsequently batch, three oblique brilliant CPPD crystal of trace are added in the large beakers as the crystal seed material.Stop to stir, form white gels.Make this in the water-bath of freezing but, keep static.The pH of supernatant is always less than 3.0.Along with formed the CPPD crystal in 24 hours, described gel is disintegrated (collapse).Described crystal is washed in distilled water 3 times, wash in ethanol, wash in acetone subsequently, the sector-style of going forward side by side is done.

Embodiment 6

With inflammatory microcrystal (a hydration monosodium urate or two hydration calcium pyrophosphates) coating medical implant

According to the coating of the method described in the embodiment 1 medical implant.The EVA solution (ratio of ethylene and vinylacetate is 60/40) for preparing 4.5% (w/w) in dichloromethane (Polysciences).In pestle and mortar, inflammatory microcrystal (MSUM or CPPD) is milled to the granular size of 10-50 micron and is suspended in the described solution with 5mg/ml.When described medical implant rotated, in 2 minutes time this suspension of two hectolambdas slowly being drawn was the wide ring of 3mm, and it is arranged in apart from the medical implant end 5mm that is fixed to conical steel toe at a distance.Then along with described medical implant continues to be rotated under the nitrogen current with EVA/ microcrystal coating drying.When drying, remove described medical implant, turn round and be coated with in an identical manner the other end of described medical implant.Utilize this method that flexible EVA/ microcrystal ring is placed the two ends of described medical implant, and can not diminish the physical characteristic of described medical implant.

Embodiment 7

With inflammatory microcrystal (a hydration monosodium urate or two hydration calcium pyrophosphates) coating medical implant

Preparation 1% other polyurethane of w/w medical grade (PU) solution in dichloromethane (Thermomedics, Woburn, MA).In pestle and mortar, inflammatory microcrystal (MSUM or CPPD) is milled to the granular size of 10-50 micron and is suspended in the described solution with 2mg/ml.Insert tight front in operation, inserting in the suspension that shakes each end of medical implant (for example, aneurysm coil or hernia mesh) approximately, 5mm continues 2 seconds deeply.Described medical implant is carried out air-dry (rotating 3 minutes by have gentle hands is light).Utilize this method that flexible EVA/ microcrystal coating ring is placed the two ends of described medical implant, and can not diminish the physical characteristic of described medical implant.

Embodiment 8

With the coating of the bromocriptine in polyurethane medical implant

Preparation 1% other polyurethane of w/w medical grade (PU) solution (Thermomedics) in dichloromethane.5%w/w with PU dissolves/is suspended in this solution with bromocriptine methanesulfonates (Sigma).Described solution is placed 5ml Fisher TLC aerosol apparatus (Fisher Scientific).Before operation, described medical implant vertically is suspended from the bottom 1cm that also the solution spray (utilizing the nitrogen propellant) of 1ml is arrived described medical implant in the fume hood by the 360 degree described medical implants of rotation.With dry 2 minutes of described medical implant, in a similar manner the other end of described medical implant is sprayed subsequently.Subsequently with described medical implant further air-dry (rotating 3 minutes) by have gentle hands is light.Utilize this method that flexible bromocriptine/PU ring is placed the two ends of described medical implant, and can not diminish the physical characteristic of described medical implant.Bromocriptine/PU solution among the imagination DCM finally may offer the doctor and be used for above operation with the form of little aerosol.

Embodiment 9

With inflammatory microcrystal (a hydration monosodium urate or two hydration calcium pyrophosphates) coating medical implant

According to the coating of the method described in the embodiment 1 medical implant.Preparation and methoxy poly (ethylene glycol) 350 (MePEG 350) (Union Carbide in dichloromethane, Danbury, CT) with poly-(lactide-co-glycolide) of the mixed of 80:20w/w (PLGA:MePEG) (85:15) (IV0.61) (Birmingham Polymers, Birmingham, 4.5% (w/w) solution AL).The inflammatory microcrystal is suspended in the described solution with 5mg/ml.When described medical implant rotated, in 2 minutes time this suspension of two hectolambdas slowly being drawn was the wide ring of 3mm, and it is arranged in apart from the medical implant end 5mm that is fixed to conical steel toe at a distance.Then along with described medical implant continues to be rotated under the nitrogen current with PLGA/MePEG/ inflammatory crystal drying.When drying, remove described medical implant, turn round and be coated with in an identical manner the other end of described medical implant.Utilize this method that flexible PLGA/MePEG/ microcrystal ring is placed the two ends of described medical implant, and can not diminish the physical characteristic of described medical implant.

Embodiment 10

With the hypertensin 2 coating medical implant that is packaged in the Polyethylene Glycol (PEG)

The Polyethylene Glycol (PEG 1475) (Union Carbide) of 1.8 grams is placed flat 20ml glass scintillation bottle and is heated to 50 ℃ to melt PEG in water-bath, add the glycerol (Fisher Scientific) of 200mg.The hypertensin 2 (Sigma) of 2mg is weighed in the bottle and in 50 ℃ of PEG that mix/be dissolved into thawing.By using clamp that described bottle is tilted in the water-bath with 10 degree.(for example, aneurysm coil or hernia mesh) each end is rotating in the goods that immerse fusing, thereby the ring of described material coating is placed on the bottom 5mm of described medical implant outer surface with medical implant.With the described medical implant of postcooling and stand-by in 4 ℃ of preservations.Perhaps, in order to immerse, that PEG/ angiotensin mixture is stand-by in 4 ℃ of preservations in the tight front of operation.In the tight front of operation, the bottle of PEG/ angiotensin is heated to 50 ℃ melted and as mentioned above medical implant was coated with in 2 minutes.

Embodiment 11

With the transforming growth factor in the crosslinked hyaluronic acid 9 (TGF-9) coating medical implant

According to the coating of the method described in the embodiment 1 medical implant.Dissolve 1% hyaluronic acid (HA) (Sodium salt, Sigma) solution for preparing in the water that comprises 30% glycerol (for the w/w of HA) (Fisher Scientific) and 8mM 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide (EDAC) by spending the night.(Calbiochem, San Diego CA) are dissolved in this solution with 0.01mg/ml with TGF-9.When described medical implant rotated, in 2 minutes time this solution of two hectolambdas slowly being drawn was the wide ring of 3mm, and it is arranged in apart from the medical implant end 5mm that is fixed to conical steel toe at a distance.Along with described medical implant continues to be rotated under the nitrogen current with HA/ glycerol/TGF-9 solution drying.When drying, remove described medical implant, turn round and be coated with in an identical manner the other end.Utilize this method that flexible HA/ glycerol/TGF-9 ring is placed the two ends of described medical implant, and can not diminish the physical characteristic of described medical implant.

Embodiment 12

With the fibroblast growth factor in the crosslinked chitosan (FGF) coating medical implant

According to the coating of the method described in the embodiment 1 medical implant.The dissolving preparation comprises 30% glycerol (for the w/w of chitosan) (Fisher Scientific) and 0.5% glutaraldehyde (Sigma by spending the night, St.Louis, 1% chitosan (medical rank, Carbomer in acetic acid,diluted MO) (pH5), Westborough, MA) solution.(Calbiochem, San Diego CA) are dissolved in this solution with 0.01mg/ml with FGF.When described medical implant rotated, in 2 minutes time this solution of two hectolambdas slowly being drawn was the wide ring of 3mm, and it is arranged in apart from the medical implant end 5mm that is fixed to conical steel toe at a distance.Along with described medical implant continues to be rotated under the nitrogen current with chitosan/glycerol/FGF solution drying.When drying, remove described medical implant, turn round and be coated with in an identical manner the other end.Utilize this method that flexible chitosan/glycerol/FGF ring is placed the two ends of described medical implant, and can not diminish the physical characteristic of described medical implant.

Embodiment 13

Transplant the screening technique of (Perigraft) reaction assessment for periphery

Describe all models of a kind of Sanguis Leporis seu oryctolagi pipe and identified arterial blood tube wall stimulus object.Big rabbit is placed generalized anesthetic state.Utilize aseptic preventive measure, expose infrarenal abdominal aorta and thereon face and below clamp.Implement vertical arterial wall arteriotomy and in aorta, insert 2 mm dias, thereby the PTFE graft fragment of 1 centimeter length is also sewed up the nearside of described graft and distal face and is made whole aortic flows by graft, in the mode of people's open surgical ventral aorta reparation described graft is included in the ventral aorta (not to be present in this model except there being aneurysm).Pass through the surgical operation mode subsequently with described aorta cut closure and with the abdominal wound closure, animal is restored.

Select animals received standard P TFE graft or graft at random, the middle part 1cm of described graft is coated with on every side without anything (contrast) or with reagent separately, adhesion between the independent induction of vascular wall reaction of described reagent or stent graft and the blood vessel wall, or be contained in polymer in the slow release, as polycaprolactone or polylactic acid.

Putting to death animal between 1 week and 6 weeks after the operation, Removing All aorta and adhesive reaction is detected in the zone relevant with described graft roughly.Attention from the tremulous pulse part that does not comprise graft, comprise the part of no coating graft and comprise the morphology of part of graft and any difference on the histology with coating.

Embodiment 14

Animal abdominal aortic aneurysm model

Described a kind of animal model and determined whether the stent graft that comprises biologic activity or pungent stimulates the fibre modification reaction.Pig or sheep are placed generalized anesthetic state.Utilize aseptic preventive measure, expose ventral aorta.Use heparin and carrying out the intersection clamp of tremulous pulse under the renal artery and on the bifurcated to animal.With vascular ring or the temporary transient control of folder collateral line, behind complete operation with its removal.Cause vertical arteriotomy in aortal tremulous pulse direction, will be sewn into from the oval rectus sheath sticking patch of same animals in the aortotomy to generate aneurysm.Remove the aorta clamp and the closed abdominal cavity of lumbar arteries and collateral line.After 30 days, described animal is anaesthetized and opens once more stomach wall again.On iliac artery, implement venesection, and by this, the stent graft is passed the infrarenal abdominal aorta aneurysm to be placed, the normal infrarenal abdominal aorta of described graft above the aneurysm that operation generates extends to the normal infrarenal abdominal aorta below the aneurysm that generates of performing the operation, and described device discharges in a conventional manner.

Animal is randomized into 5 windings is subjected to uncoated stent graft, the stent graft that comprises independent release polymer, with the stent graft that contains biologic activity or pungent, its as previously mentioned screening inspection determine.After arteriotomy and abdominal wound closure, allow animal restore.Insert the back during 6 weeks and 3 months at the stent graft, put to death animal and Remove All aorta.Infrarenal abdominal aorta is checked the evidence of histologic reaction and periphery graft seepage.

Embodiment 15

The Screening test method of the effect of assessment Ciclosporin A on cell proliferation

Described a kind of external test method and determined whether irritation cell (fibroblast) propagation (is seen In Vitro Toxicol. (1990) 3:219 to a kind of material; Biotech.Histochem. (1993) 68:29; Anal.Biochem. (1993) 213:426).The smooth muscle cell that 70-90% is converged carries out trypsinization, carries out renewed vaccination with 600 cells/well in culture medium and allow its attaching of spending the night in 96 orifice plates.Preparation concentration 10 in DMSO ^-2The Ciclosporin A of M also dilutes 10 times to provide a mother liquid concentration scope (10 ^-8M-10 ^-2M).In culture medium with drug dilution liquid dilution 1/1000 and join in the cell to provide the cumulative volume in 200 μ L/ holes.Every kind of drug level is all tested in three repeated holes.The plate that will comprise smooth muscle cell and Ciclosporin A was in 37 ℃ of incubations 72 hours.

Go culture medium to stop measuring by light absorption.With CYQUANT 400X GR dye indicator (Molecular Probes; Eugene, 1/400 diluent OR) is added in the 1X cell lysis buffer solution, and the mixture of 200 μ L is added in the hole of described plate.In room temperature with plate lucifuge incubation 3-5 minute.In～480nm excitation wavelength and～the 520nm emission maximum reads fluorescence in fluorescence micro plate reader.Meansigma methods by utilizing three repeated holes is also compared (see figure 1) with average relative fluorescence unit and DMSO contrast and is determined the activation of breeding.

Repeat described mensuration for following proliferative therapeutic agent: dexamethasone (Fig. 2), all-trans retinoic acid (Fig. 3), isotretinoin (Fig. 4), 17-(Fig. 5) and 1 α, 25-dihydroxy-vitamin D ₃(Fig. 6).

Embodiment 16

Assessment PDGF is to the Screening test method of the effect of smooth muscle cell migration

Described a kind of external test method and determined whether irritation cell (fibroblast) moves a kind of material.Before the test human smooth muscular cells was originally carried out serum starvation 16 hours in the smooth muscle cell minimal medium that contains insulin and human alkaline fibroblast growth factor (bFGF).In order to move mensuration, pair cell carries out trypsinization so that remove cell from bottle, is diluted to 2-2.5 X 10 with the washing of migration culture medium and in the migration culture medium ⁵The concentration of cell/ml.The migration culture medium is made up of no phenol red Dulbecco ' the s Modified Eagle culture medium (DMEM) that contains 0.35% human serum albumin.The smooth muscle cell of 100 μ L volumes (about 20,000-25,000 cell) is joined the top of Boyden chamber (Boyden chamber) composite set (assembly) (Chemicon QCMCHEMOTAXIS 96-hole migration plate).Cumulative volume with the concentration 150 μ L of 10ng/ml adds chemotaxis reagent, the somatomedin of regenerated human blood-platelet derivative (rhPDGF-BB) to bottom outlet.Preparation concentration 10 in DMSO ^-210 times of the paclitaxel of M and serial dilutions are to provide a mother liquid concentration scope (10 ^-8M-10 ^-2M).Add the paclitaxel DMSO mother solution of previous preparation and in cell, add paclitaxel with 1/1000 dilution by direct cell in upper chambers.With plate incubation 4 hours so that carry out cell migration.

After 4 hours, the smooth muscle cell that discards the cell in the upper chambers and will be attached to the filter downside separated 30 minutes in 37 ℃ in (Chemicon) at cell separation solution (Cell Detachment Solution).With the cracking and in room temperature incubation 15 minutes in the lysis buffer that contains DNA associativity CYQUANT GR dyestuff of isolated cell.In～480nm excitation wavelength and～the 520nm emission maximum reads fluorescence in fluorescence micro plate reader.Removing background fluorescence (the contrast chamber of no chemical inhibitor) back on average from the relative fluorescence unit of three repeated holes and by the smooth muscle cell standard curve acquisition cell migration average number that is diluted to 98 cells/well continuously from 25,000 cells/well.The cell migration average is recently determined 50% inhibition concentration (IC mutually with positive control (reacting on the smooth muscle cell chemotaxis of rhPDGF-BB) by will have paclitaxel the time ₅₀).See Fig. 7.List of references: Biotechniques (2000) 29:81; J.Immunol Methods (2001) 254:85.

Embodiment 17

The all PU films of blood vessel of assessment silk coating in the body are with the evaluation cicatrization

Described a kind of rat carotid artery model and determined whether a kind of material stimulates the fibre modification reaction.To weigh the Wistar rat anesthesia of 300g-400g with halothane.Skin on the shaving neck region is also sterilized described skin.On trachea, implement the cutting perpendicularly art and expose left neck artery.Be rolled in around the common carotid artery tip part covering the polyurethane film of silk thread or PU film that quilt is not wrapped in contrast.Closure of wound also restores animal.After 28 days, put to death rat and carry out pressure injection in 100mmHg with 10% buffering formaldehyde with carbon dioxide.Collect two carotid artery and carry out histology's processing.Can downcut successive transverse section every 2mm at the left neck artery of handling with on untreated right carotid respective horizontal.Use H﹠amp; E and Movat ' s stain dye with the tissue growth around the assessment carotid artery to section.Quantize by the area of area of computer aided morphometric analysis all granulation tissuies of blood vessel.Wrapped apparently higher than contrast by the granulation tissue area in organizing at the silk bag by the area in the group.See Fig. 8.

Embodiment 18

The all PU films of blood vessel of the different silk suture material coatings of assessment in the body are with the evaluation cicatrization

Described a kind of rat carotid artery model and determined whether a kind of material stimulates the fibre modification reaction.To weigh the Wistar rat anesthesia of 300g-400g with halothane.Skin on the shaving neck region is also sterilized described skin.On trachea, make vertical incision and expose left neck artery.Will be from three different manufacturers (3-0Silk-Black Braided (Davis; Geck), 3-0 SOFSILK (U.S.Surgical/Davis ﹠amp; Geck) and 3-0 Silk-Black Braided (LIGAPAK) (Ethicon, Inc.) polyurethane film of one of coating silk suture is rolled in around the common carotid artery tip part.(described polyurethane film can also be coated with other reagent to induce the fibre modification reaction).Closure of wound also restores animal.

After 28 days, put to death rat and carry out pressure injection in 100mmHg with 10% buffering formaldehyde with carbon dioxide.Collect two carotid artery and carry out histology's processing.Can downcut successive transverse section every 2mm at the left neck artery of handling with on untreated right carotid respective horizontal.Use H﹠amp; E and Movat ' s stain dye with the tissue growth around the assessment carotid artery to section.Quantize by the area of area of computer aided morphometric analysis all granulation tissuies of blood vessel.Hamartoplasia in three groups around the identical demonstration silk suture of the thickness of granulation tissue does not rely on production method.See Fig. 9.

Embodiment 19

Assessment blood vessel week silk powder is with the evaluation cicatrization in the body

Described a kind of rat carotid artery model and determined whether a kind of material stimulates the fibre modification reaction.To weigh the Wistar rat anesthesia of 300g-400g with halothane.Skin on the shaving neck region is also sterilized described skin.On trachea, make vertical incision and expose left neck artery.The silk powder is spread on the tremulous pulse of exposure, described tremulous pulse wraps up with the PU film subsequently.In on the same group animal not, use the silk powder (pollution-free protein) of natural silk powder or purification.The carotid artery of wrapping up in the PU film is used as matched group.Closure of wound also restores animal.After 28 days, put to death rat and carry out pressure injection in 100mmHg with 10% buffering formaldehyde with carbon dioxide.Collect two carotid artery and carry out histology's processing.Can downcut successive transverse section every 2mm at the left neck artery of handling with on untreated right carotid respective horizontal.Use H﹠amp; E and Movat ' s stain dye with the tissue growth around the assessment carotid artery to section.Quantize by the area of area of computer aided morphometric analysis all granulation tissuies of film and blood vessel in tunicle inner membrance, the tunicle.

Natural silk has caused serious cellular inflammation, mainly is made up of neutrophil cell and lymphocytic infiltration in the fibrin network of no any extracellular matrix or blood vessel.In addition, treated tremulous pulse is by the elastic sheet of hypocellular medium, fragmentation and thick neointimal hyperplasia grievous injury.Neointimal hyperplasia comprises many inflammatory cells and is occlusive under 2/6 situation.This serious immunoreation is inspired by the antigenic protein of fibroin by bag in this dosage form.At the other end, regenerated silk powder has only inspired slight foreign body reaction around treated tremulous pulse.This tissue reaction feature is inflammatory cell, giant cell and the blood vessel in the extracellular matrix.Treated tremulous pulse is intact.These results show that removing coating protein from natural silk stops immunoreation and promote the benign tissue growth.The degraded display organization reaction of carrying out the regenerated silk powder in some tissue slices may the ripe and healing along with the time.See Figure 10.

Embodiment 20

Assessment blood vessel week Pulvis Talci is with the evaluation cicatrization in the body

Described a kind of rat carotid artery model and determined whether a kind of material stimulates the fibre modification reaction.To weigh the Wistar rat anesthesia of 300g-400g with halothane.Skin on the shaving neck region is also sterilized described skin.On trachea, make vertical incision and expose left neck artery.Pulvis Talci is spread on the tremulous pulse of exposure, described tremulous pulse wraps up with the PU film subsequently.The carotid artery of only wrapping up in the PU film is used as matched group.Closure of wound also restores animal.1 or after 3 months, put to death rat and cushion formaldehyde with 10% and carry out pressure injection with carbon dioxide in 100mmHg.Collect two carotid artery and carry out histology's processing.Can downcut successive cross section every 2mm at the left neck artery of handling with on untreated right carotid respective horizontal.Use H﹠amp; E and Movat ' s stain dye with the tissue growth around the assessment carotid artery to section.Quantize by the thickness of area of computer aided morphometric analysis all granulation tissuies of film and blood vessel in tunicle inner membrance, the tunicle.The histopathology result is presented at 1 month and 3 months local responses identical to Pulvis Talci with morphometric analysis.Big tissue reaction has caught Pulvis Talci on circumvascular practical site.The feature of this tissue is a macrophage a large amount of in fine and close extracellular matrix, is accompanied by minority neutrophil cell, lymphocyte and blood vessel.The blood vessel of handling shows excellently and is not subject to processing influence.Generally speaking, this result shows that Pulvis Talci induced slight long-term fibre modification reaction, and it is subclinical in natural and does not damage any adjacent tissue.See Figure 11.

Embodiment 21

The preparation of silk powder

Several silk fabrics (Ethicon, 4-0,638) are cut into the length of about 0.4cm.These sections are placed the 100ml round-bottomed flask that comprises 50ml 2M NaOH.Utilize magnetic stirring apparatus sample to be stirred 24 hours in room temperature.Utilize among the dense HCl and sample.Utilize subsequently based on cellulosic Dialysis tubing (WMCO approx 3000; Spectrum) composition that will neutralize is dialysed with respect to deionized water.With sample dialysis 48 hours, be accompanied by 5 times and change water.The sample of will dialysing is subsequently poured in the 100ml round-bottomed flask.Sample is carried out freezing and lyophilizing to produce fluffy powdered substance.

Embodiment 22

With Powdered silk/PLGA coating coating medical implant

Medical implant (for example, aneurysm coil) invests on the stainless steel (assisting down of bulldog clamp), and described stainless steel invests on the Fisher suspension type agitator of perpendicular positioning.Agitator is set at 30rpm rotates.2% PLGA (9K, 50:50, the Birmingham Polymers) solution that utilizes the airbrush sprayer unit will comprise Powdered silk is sprayed onto on the implant in the rotation.The concentration of Powdered silk in the PLGA solution is changed to 50% from 0.1%.After spray operation, allow air-dry 30 minutes of described device, still be rotated simultaneously.Subsequently described device is removed and under vacuum further dry 24 hours from the aspirator head.

Embodiment 23

Be coated with stringing with pulverous silk/polyurethane coating

Polyurethane tube is shifted onto on the plastics aspirator head of 1ml.The open end of described aspirator head is invested on the stainless steel, and described stainless steel invests on the Fisher suspension type agitator of horizontal location.Agitator is set at 30rpm rotates.2% CHRONOFLEX AL 85A (CT Biomaterials) solution that utilizes the TLC sprayer unit will comprise Powdered silk (utilizing the cryomill preparation) is sprayed onto on the pipe in the rotation.The concentration of Powdered silk in the polyurethane solutions is changed to 50% from 0.1%.After spray operation, allow described manage-style do 30 minutes, still be rotated simultaneously.Subsequently described pipe is removed and under vacuum further dry 24 hours from the aspirator head.

Embodiment 24

With the applied pipe of degradable coating top coating

To invest again on the suspension type agitator and from the applied pipe of embodiment 24 and be rotated in 30rpm.With the TLC sprayer unit 10% 20:80 MePEG (750)-PLA block copolymer solution (acetone) is sprayed onto on the pipe in the rotation.After spray operation, allow described manage-style do 30 minutes, still be rotated simultaneously.Can repeat to spray coating process up to the coating layer thickness or the homogeneity that need to obtain.Subsequently described pipe is removed and under vacuum further dry 24 hours from the aspirator head.

Embodiment 25

With the applied pipe of degradable coating top coating that contains heparin

To invest again on the suspension type agitator and from the applied pipe of embodiment 24 and be rotated in 30rpm.10% 20:80 MePEG (the 750)-PLA block copolymer solution (acetone) that will comprise the heparin benzalkonium chloride complex (PolySciences) of various amounts with the TLC sprayer unit is sprayed onto on the pipe in the rotation.After spray operation, allow described manage-style do 30 minutes, still be rotated simultaneously.Can repeat to spray coating process up to the coating layer thickness or the homogeneity that need to obtain.Subsequently described pipe is removed and under vacuum further dry 24 hours from the aspirator head.

Embodiment 26

Apply applied pipe with heparin coating

To invest again on the suspension type agitator and from the applied pipe of embodiment 24 and be rotated in 30rpm.The solution that will comprise the heparin benzalkonium chloride complex (PolySciences) among the IPA of various amounts with the TLC sprayer unit is sprayed onto on the pipe in the rotation.After spray operation, allow described manage-style do 30 minutes, still be rotated simultaneously.Can repeat to spray coating process up to the coating layer thickness or the homogeneity that need to obtain.Subsequently described pipe is removed and under vacuum further dry 24 hours from the aspirator head.

Embodiment 27

Be coated with stringing with pulverous silk/Ciclosporin A/polyurethane coating

Polyurethane tube is shifted onto on the plastics aspirator head of 1ml.The open end of described aspirator head is invested on the stainless steel, and described stainless steel invests on the Fisher suspension type agitator of horizontal location.Agitator is set at 30rpm rotates.The 2% CHRONOFLEX AL 85A solution (THF) that utilizes the TLC sprayer unit will comprise Powdered silk and Ciclosporin A is sprayed onto on the pipe in the rotation.The concentration of Powdered silk in the polyurethane solutions is changed to 50% (with respect to the w/w of described polymer) and the concentration of Ciclosporin A is changed to 10% (with respect to the w/w of described polymer) from 0.1% from 0.1%.After spray operation, allow described manage-style do 30 minutes, still be rotated simultaneously.Subsequently described pipe is removed and under vacuum further dry 24 hours from the aspirator head.

Embodiment 28

Film with the silk fiber dipping

20% CHRONOFLEX AL 85A solution (THF) is cast on the release liner of silicone coating.Allow solvent seasoning.(Ethicon, Inc.) sheet places on the surface of polyurethane film with the Silk-Black Braided (LIGAPAK) of 3-0.Drop with THF adds on the surface of polyurethane film subsequently.Utilize the glass scintillation bottle as roller, the silk chain is embedded into the surface of polyurethane film.

Embodiment 29

Original position forms the gel that contains silk

Prepare methylated collagen protein by following method: utilize pepsin dissolving cattle dermal collagen albumen and as U.S. Patent number 4,233, carry out purification like that described in 360.Go into the 0.2M sodium radio-phosphate,P-32 solution by neutralization, pH 7.2, and the dissolved collagen albumen of this purification is precipitated.Separate described precipitation by centrifugal final concentration to 70mg/ml.With dry two days of described material, pulverize subsequently.Adding contains the absolute methanol (40ml) of HCl (to 0.1N) and stirred four days.Collagen from acidic methanol, vacuum drying and by radiation sterilization.End-product is soluble in water in pH3-4.

In order to send as gel, methylated collagen albumen with 10mg, four-sense sulfydryl-PEG of 100mg (tetramethylolmethane gathers (ethylene glycol) ether four-sulfydryl), 10,000MW and 100mg four-sense succinimido PEG (tetramethylolmethane gathers (ethylene glycol) ether four-succinimido glutarate), 10,000MW is in the water-soluble final volume to 1ml of pH 3-4 (first kind of component).(the 300mM sodium dihydrogen phosphate mixes with the 300mM sodium carbonate phosphate/carbonate buffer solution that second kind of component is 1ml.If desired, regulate pH with NaOH or HCl and reach pH 9.6.Final molar concentration is about 117mM phosphate and 183mM carbonate).The silk powder (1mg-100mg) (utilizing the cryomill preparation) of various amounts is added in phosphate/carbonate buffer solution.(FibriJet Micromedics) places syringe with various components and mixes and be sprayed on the required test site to utilize manual double syringe delivery system or air to assist the double syringe delivery system.

Embodiment 30

With polymer/biological reagent coating silk fabric-direct impregnation

It is long that silk fabric (Ethicon, 4-0,638) is cut into about 10cm.Described silk fabric is immersed poly-(lactide-co-glycolide) (PLGA) in the chloroformic solution of (9K, 50:50, Birmingham Polymers) and Ciclosporin A.The concentration of PLGA is changed to 20% (w/v) and the concentration of Ciclosporin A the solution is changed to saturated solution from 0.1% from 0.1%.Described silk fabric was immersed in the PLGA/ Ciclosporin A solution 5 minutes.Removing the described silk fabric sector-style of going forward side by side subsequently does.The silk fabric that will be loaded with Ciclosporin A then under vacuum is further dry.Be embedded in the described polyurethane film thereby be positioned on the polyurethane film by the fabric that will be coated with subsequently and in hot pressing, push the about fabric that will be coated with in 10 seconds of described film/fabric subsequently, described silk fabric is attached on the polyurethane film.

Embodiment 31

Original position forms the gel that comprises silk

In order to send as gel, with four-sense succinimido PEG (tetramethylolmethane gathers (ethylene glycol) ether four-succinimido glutarate) 10 of 200mg, 000MW is in the water-soluble final volume to 1ml of pH 2.5 (regulating with HCl) (first kind of component).Second kind of component be 1ml comprise the amino PEG (tetramethylolmethane gathers (ethylene glycol) ether four-amino) of 200mg four-sense, 10, (the 300mM sodium dihydrogen phosphate mixes with the 300mM sodium carbonate phosphate/carbonate buffer solution of 000MW.If desired, regulate pH with NaOH or HCl and reach pH 9.6.Final molar concentration is about 117mM phosphate and 183mM carbonate).The silk powder (1mg-200mg) of various amounts is added in the acidic buffer.(FibriJet Micromedics) places syringe with various components and is sprayed on the required test site to utilize manual double syringe delivery system or air to assist the double syringe delivery system.

Embodiment 32

The coating that comprises Ciclosporin A

Preparation contains 5% CHRONOFLEX AL 85A solution (chloroform) of 0.1%-10% Ciclosporin A.One section polyurethane tube is immersed and from described coating solution, take out subsequently.The sample that will be coated with in fume hood carries out air-dry.By repeating the sample that described immersion-coating process prepares different coating thickness.The sample that will be coated with under vacuum carried out drying 24 hours subsequently.

Embodiment 33

The collagen protein synthesis algoscopy

Described a kind of external test method and determined whether a kind of material promotes the deposition of extracellular matrix (ECM).Normal human dermis fibroblast is carried out trypsinization, in 12 orifice plates, be re-seeded into subsequently and contain in the phosphatic culture medium of ascorbic acid-2-with 150,000 cells/well.With described cell in 37 ℃ and 5% CO ₂Cultivate 2-3 week, changed culture medium, thereby make them form the 3-D substrate of cell and collagen protein every three days.After 14-21 days cultivation, replace described culture medium and allow cell tranquillization 24 hours with the culture medium of serum-free.

With medicine with 10 ^-2M is diluted among the DMSO, dilutes 10 times subsequently to provide 10 ^-2M-10 ^-8The mother liquid concentration scope of M.In the new system serum-free medium, join in the hole subsequently with 1000 times of drug dilutions and with the cumulative volume in 3ml/ hole.Subsequently in 37 ℃ with plate incubation 72 hours.After 72 hours culture medium is removed and puts into microcentrifugal tube from the hole, freezing in-20 ℃ until being used for mensuration.

Utilize Procollagen Type 1 C-Peptide (PIP) EIA test kit (Takara) to measure synthetic collagen protein amount, the collagen protein amount of wherein being produced is represented by carry out stoichiometry by the amount of the propetide of collagen protein shearing when it is secreted.To resist the PIP monoclonal antibody to be fixed on the elisa plate, add sample, will be conjugated to second kind of PIP monoclonal antibody on the horseradish peroxidase subsequently and join in the hole and carry out incubation.Behind the incubation, washing hole adds substrate solution, measures absorbance and compare with the standard curve of PIP (ng/ml) in the plate reader in 450nm.

Embodiment 34

Chicken chorio-allantois (＂ CAM ＂) algoscopy

This embodiment has described a kind of external test method and has determined whether a kind of material promotes blood vessel to take place.The tame Embryo Gallus domesticus that to be fertilized before no shell (shell-less) is cultivated was hatched 3 days.In this process, by removing the shell that is positioned at air gap periphery and with the component emptying of ovum.Separate the shell inner membrance subsequently and with the perforation of the end opposite of shell so that allow the content of ovum skid off gently from flush end (blunted end).The emptying of ovum content is gone in the aseptic glass alms bowl of round bottom and with the culture dish lid to cover.Subsequently in 90% relative humidity and 3%CO ₂These are inserted in the incubator and incubation 3 days.(perhaps, the ovum content can be retained in the shell, opening is coated with Parafilm).

Can be with reagent (for example, paclitaxel) (Sigma) with 0.25,0.5, the cellulosic concentration of 0.5% aqueous dimethylformamide of the per 10 μ l equal portions of 1,5,10,30 μ g is mixed.Concentration can change according to described reagent.Dissolubility according to described reagent can suitably be mixed reagent with other compatible material.This solution of ten microlitre equal portions is carried out drying 1 hour on Parafilm, form the disk of diameter 2mm.The dry disk that will contain reagent on the 6th day in incubation places on the growing edge of each CAM carefully subsequently.The date of placing disk can change according to the blood vessel generation quantity of stimulus that described reagent exceeds contrast.Contrast is to place on the CAMs by the methylcellulose disk that will not have reagent in the phase same time to obtain.Exposing after 2 days (incubation the 8th day) checks vascular system by means of stereoscopic microscope.With Liposyn II, a kind of White-opalescent solution is injected among the CAM to improve the visibility of described vascular cell.Undyed live body embryo's vascular system is carried out imaging with the Zeiss stereoscopic microscope, and (Dage-MTI Inc., Michigan City IN) joins for described Zeiss stereoscopic microscope and video camera.Show these video signals and utilize image analysis system (Vidas, Kontron with the 160x enlargement ratio subsequently; Etching Germany) catches.(Model 3000 at chart recorder subsequently; Matrix Instruments, Orangeburg makes the image egative film on NY).

Film with the no shell embryo of 2% glutaraldehyde submergence, 8 ages in days in the 0.1M sodium cacodylate buffer liquid; The other fixative of injection under CAM.In position after 10 minutes, take out CAM and inserted in the fresh fixative 2 hours in room temperature.Washing tissue subsequently spends the night in containing the dimethyl arsenic acid buffer liquid of 6% sucrose.After the target area is in 1% Osmic acid., fix 1.5 hours in 4 ℃.To be organized in subsequently in the ethanol of gradient series and dewater, and exchange solvent with expoxy propane, and be embedded in the Spurr resin.Cut out slice with diamond knife, place on the copper grid, dyeing, and in the Joel1200EX ultramicroscope, check.Similarly, cut out the section of 0.5mm and be used for light microscopy with C.I. 49410. dyeing.

Growing the 11st day is used to corrode foundry engieering with Embryo Gallus domesticus.(Redding CA) is injected in the CAM vascular system for Ted Pella, Inc. with the Mercox resin to utilize No. 30 hypodermic needles.Founding materials is made up of the Mercox CL-2B polymer of 2.5 grams and the catalyst (55% benzoyl peroxide) of 0.05 gram, and it has 5 minutes polymerization time.After the injection, allow described plastics keep original position to spend the night in baking oven in 65 ℃ subsequently in one hour in room temperature.Subsequently CAM is placed 50% sodium hydrate aqueous solution to digest whole organic components.With described plastic castings thorough washing in distilled water, air-dry, with the coating of gold/palladium, and with Philips 501B sem observation.

The 6th day of incubation, with embryo's centrally-located in the network of the radial expansion of blood vessel; CAM grows near the described embryo.Vascular in these growths is near the surface and can see easily that this makes this system become the ideal model that the research blood vessel takes place.The undyed CAM capillary bed of live body can carry out non-invasive imaging with stereoscopic microscope.

Transverse section by CAM shows the outside ectoderm of being made up of two cellular layers, the mesoderm that contains blood capillary of broad and inner single endoderm cell's layer, and described blood capillary is positioned at ectoderm, under the adventitial cell.Under the ultramicroscope level, show the typical structure details of CAM blood capillary.Typically, the position of these vasculars and ectodermic inner cell layer tight association.

With 0.25,0.5,1,5,10, or the concentration of 30 μ g is exposed to a kind of reagent after 48 hours, under condition of living body each CAM checked the effect that takes place for blood vessel with assessment with the stereoscopic microscope that has been equipped with video/computer interface.Amplification in 160x uses this imaging device, and this allows direct observation hemocyte in blood capillary; Can evaluate blood flow thus easily with the record object zone.The variation of blood vessel generating capacity is defined as the area (diameter measurement 2-6mm) of the CAM of capillary network with increase and vascular blood flow.In whole experiment, on 4 gradients, (table 1) evaluated in the zone.This raising degree of representing blood vessel to take place of measuring is measured maximum the raising in the vascular gradient and is expressed as 3.The score value of reagent is compared with the score value of contrast.

Table 1

The vascular gradient

^*-expression positive vessels reacts

Embodiment 35

Silk suture with the coating of magnetic force active particle

The end of one section silk 5-0 suture is immersed in the THF solution of CHRONOFLEX AL 85A polyurethane solutions (about 10% w/v).Take out described silk, and the end that will be coated with immersion comprises in the bottle of magnetic force active particles.It is terminal to take out the silk that was coated with, and by described end is rolled between two finger tips described granule further is embedded in the polyurethane coating.By air-dry removal solvent.

Embodiment 36

Silk suture with the active pearl coating of magnetic force

The end of one section silk 5-0 suture is immersed in the THF solution of CHRONOFLEX AL 85A polyurethane solutions (about 10% w/v), described solution comprises the magnetic beads of about 5% w/w (pearl is for polymer).Take out described silk, and the end that will be coated with immersion comprises in the bottle of magnetic force active particles.It is terminal to take out the silk that was coated with, and by described end is rolled between two finger tips described granule further is embedded in the polyurethane coating.By air-dry removal solvent.

Embodiment 37

The assessment all PU films of blood vessel that come unstuck or the coating of raw silk chain in the body

To weigh the Wistar rat anesthesia of 300g-400g with halothane.Skin on the shaving neck region is also sterilized described skin.Above trachea, make a vertical incision and expose left neck artery.To or contrast uncoated PU film coated with the polyurethane film of degumed silk chain (degummed silk strands), raw silk chain is rolled in around the common carotid artery tip part.Closure of wound also restores animal.

After 28 days, put to death rat and carry out pressure injection in 100mmHg with 10% buffering formaldehyde with carbon dioxide.Collect two carotid artery and carry out histology's processing.To downcut successive transverse section every 2mm at the left neck artery of handling with on untreated right carotid respective horizontal.Use H﹠amp; E and Movat ' s stain dye with the tissue growth around the assessment carotid artery to section.Quantize by the thickness of area of computer aided morphometric analysis all granulation tissuies of blood vessel.Two types silk all significantly improves circumvascular granulation tissue growth on same degree.Silk chain in two groups all is broken into granule (the about 30 μ m of diameter), is dispersed in around the blood vessel and by giant cell, macrophage, proteoglycan substrate and blood vessel and surrounds.These features are typical foreign body reactions.Variable more in the degumed silk group by the zone ratio that foreign body reaction covered in the raw silk group.See Figure 12,13 and 14.

Embodiment 38

Utilize CRYOMILL preparation silk powder

The fiber of degumed silk is cut into the long fragment of about 1-2cm.Use cryomill (SpexCertiprep Freezer/Mill-Model 6850) that described material is clayed into power subsequently.The powder that a part was ground sieved the metallic sieve of a series of different sizes to obtain the silk powder of different magnitude range subsequently.

Embodiment 39

Be loaded with the electrospinning silk of the material of silk

By 2g PLGA being dissolved into PLGA (50:50, Mw ≈ 54, the 000) solution of 10mL DCM preparation 20%.The silk powder (25-53 μ m) thereby be added to of various amounts is made the silk percentage ratio of polymer in every kind of solution be from 2% to 50%.Subsequently every kind of solution is packed in the 10ml syringe of being furnished with No. 18 syringe needles.Subsequently syringe is packed into and use the 20kV positive high voltage (by Glassman High Voltage, Inc.) in the syringe pump and to syringe needle.The target drum that grinds is the rotary drum with about 12cm diameter.Syringe pump is set at 25 μ L per minutes aspirates and described drum is rotated with about 250rpm.Distance from needle point to described bulging outer side surface is about 14cm.Thereby in spinning process with described rotary drum from one move by side to opposite side make described in the spinning material drum in fact covered fully.After finishing spinning process, on the complete length of spinning material, cause an otch with razor blade.Described material is removed and vacuum drying oven further dry 24 hours from drum.

Embodiment 40

Determine MIC (minimal inhibitory concentration) by microtitre broth bouillon dilution method

The MIC of A. various Gram-negatives and positive bacteria measures

Basically as Amsterdam, D.1996, " Susceptibility testing of antimicrobialsin liquid media; " p.52-111.In Loman, V., ed.Antibiotics in laboratorymedicine, 4th ed.Williams and Wilkins, Baltimore, the described MIC that carries out like that of MD. measures.In brief, in MIC (minimal inhibitory concentration) measures, multiple chemical compound is tested resisting pseudomonas aeruginosa (P.aeruginosa), klebsiella pneumoniae (K.pneumoniae), escherichia coli (E.coli), the antibacterial activity of the separator of staphylococcus epidermidis (S.epidermidus) and staphylococcus aureus (S.aureus), it is to utilize 96 hole polystyrene microtitration plates (Falcon 1177) and Mueller Hinton broth bouillon to carry out in 24 hours in 37 ℃ of incubations under aerobic conditions that described MIC measures.(MHB is used in test to great majority, except the C721 (gathering streptococcus (S.pyogenes)) of use Todd Hewitt broth bouillon, and the hemophilus influenza (Haemophilus influenzae) of using Haemophilus test medium (HTM)).Carry out triple tests.The result provides in following table 2.

Table 2 therapeutic agent resists the minimal inhibitory concentration of various Gram-negatives and positive bacteria

Bacterial isolates	Pseudomonas aeruginosa	Klebsiella pneumoniae	Escherichia coli	Staphylococcus aureus	Staphylococcus epidermidis	The gathering streptococcus
								PAE/K799	ATCC13883	UB1005	ATCC25923
	H187	C238	C498	C622	C621	C721
								Wt	wt	wt	wt	wt	wt
Medicine	Gram-	Gram-	Gram-	Gram+	Gram+	Gram+
							Doxorubicin
	10 -5	10 -6	10 -4	10 -5	10 -6	10 -7
							Mitoxantrone	10 -5	10 -6	10 -5	10 -5	10 -5	10 -6
5-fluorouracil	10 -5	10 -6	10 -6	10 -7	10 -7	10 -4
							The cry of certain animals of first ammonia butterfly	N	10 -6	N	10 -5	N	10 -6
Etoposide	N	10 -5	N	10 -5	10 -6	10 -5
							Camptothecine	N	N	N	N	10 -4	N
Hydroxyurea	10 -4	N	N	N	N									10 -4
							Cisplatin	10 -4	N	N	N	N	N
Tubercidin	N	N	N	N	N	N
							The 2-sulfydryl	N	N	N	N	N	N

Bacterial isolates	Pseudomonas aeruginosa	Klebsiella pneumoniae	Escherichia coli	Staphylococcus aureus	Staphylococcus epidermidis	The gathering streptococcus
								PAE/K799	ATCC13883	UB1005	ATCC25923
	H187	C238	C498	C622	C621	C721
								Wt	wt	wt	wt	wt	wt
Medicine	Gram-	Gram-	Gram-	Gram+	Gram+	Gram+
							Purine
Ismipur	N	N	N	N	N	N
							Cytosine arabinoside	N	N	N	N	N	N

Activity is represented with molar concentration

The Wt=wild type

The N=non-activity

B. the MIC of antibiotic resistance antibacterial

In aforesaid MIC measures to the following compounds of various concentration, mitoxantrone, cisplatin, tubercidin, methotrexate, 5-fluorouracil, etoposide, 2-purinethol, doxorubicin, Ismipur, camptothecine, hydroxyurea and cytosine arabinoside test are to the antibacterial activity of methicillin-resistant toleration staphylococcus aureus clinical isolates and vancomycin tolerance property pediococci (pediococcus) clinical isolates.The chemical compound that shows growth inhibited (MIC value＜1.0 x 10-3) comprises: mitoxantrone (two bacterial strains all are), methotrexate (vancomycin tolerance property pediococci), 5-fluorouracil (two bacterial strains all are), etoposide (two bacterial strains all are) and 2-purinethol (vancomycin tolerance property pediococci).

Embodiment 41

Be coated with hip implant with silk/PLGA

With 5g PLGA (50:50, IV=0.15, Birmingham Polymers, solution Inc.) is dissolved in the 100mL dichloromethane.The Powdered silk of 1g (25-53 μ m, utilize cryomill when sieving as mentioned above and prepare) is mixed in the described solution.With hip implant (SECUR-FIT HA, Stryker Orthopaedics) thus insert the spherical sections of hip implant be fixed in the clamp.Described clamp is fixed on the suspension type agitator (Fisher Scientific) subsequently.Described agitator is set at the speed of about 30rpm.Silk/PLGA solution is placed glass TLC sprayer unit (Sigma-Aldrich Corp).Utilize TLC sprayer unit (connection nitrogen pot) to be coated with about 1/3 implant under the described implant polishing part (polished section) with silk/PLGA.The described sprayer unit of turn intersperses among silk in the PLGA solution equably guaranteeing in spray process.Thereby the speed of control spray applications can not ooze solution from described device.In case finish initial coating, just stop spray process and carry out described device air-dry.Can repeat described spraying coating/dry run if desired up to obtaining required thickness.After last air-dry step, described device is removed and places vacuum drying oven from clamp.With implant under vacuum dry 6 hours.Other example that can be applied to the fibrous tissue formation agent on the hip implant device similarly comprises: fibronectin, Talcum, Silicon stone, starch, poly-(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.Other implant device such as knee joint implant, shoulder implant and refer to that (digit) implant can be to be coated with to above-mentioned similar mode.

Embodiment 42

Be coated with hip implant with silk/Ciclosporin A/PLGA

With 5g PLGA (50:50, IV=0.15, Birmingham Polymers, solution Inc.) is dissolved in the 100mL dichloromethane.The Powdered silk of 1g (25-53 μ m, utilize cryomill when sieving as mentioned above and prepare) is mixed in the described solution.The 0.5mg Ciclosporin A is joined in the described solution.With hip implant (SECUR-FIT HA, Stryker Orthopaedics) thus insert the spherical sections of hip implant be fixed in the clamp.Described clamp is fixed on the suspension type agitator (Fisher Scientific) subsequently.Described agitator is set at the speed of about 30rpm.Silk/PLGA solution is placed glass TLC sprayer unit (Sigma-Aldrich Corp).Utilize TLC sprayer unit (connection nitrogen pot) to be coated with about 1/3 implant under the described implant polishing part with silk/PLGA.The described sprayer unit of turn intersperses among silk in the PLGA solution equably guaranteeing in spray process.Thereby the speed of control spray applications can not ooze solution from described device.In case finish initial coating, just stop spray process and carry out described device air-dry.Can repeat described spraying coating/dry run if desired up to obtaining required thickness.After last air-dry step, described device is removed and places vacuum drying oven from clamp.With implant under vacuum dry 6 hours.Other example that can be applied to the fibrous tissue formation agent on the hip implant device similarly comprises: Talcum, Silicon stone, starch, fibronectin, poly-(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.Other implant device such as knee joint implant, take on implant and refer to that implant can be to be coated with to above-mentioned similar mode.

Embodiment 43

Be coated with hip implant with silk

By the 10g raw silk fiber being joined preparation silk solution in the 100mL hexafluoroisopropanol (HFIP).Allow described solution in stirring at room 48 hours.With hip implant (SECUR-FIT HA, Stryker Orthopaedics) thus insert the spherical sections of hip implant be fixed in the clamp.Described clamp is fixed on the suspension type agitator (Fisher Scientific) subsequently.Described agitator is set at the speed of about 30rpm.Use the Pasteur pipette silk/HFIP solution to be dripped on the part of hydroxyapatite (HA) coating of hip implant.Whenever the volume that is added dropwise to is the volume that makes that described solution can not drip from implant.In case with the moistening of HA coating, just stop that material is used and to allow described implant carry out air-dry with silk/HFIP solution.Repeat described process once more and behind drying steps, described device is removed and place vacuum drying oven from clamp.With implant under vacuum dry 6 hours.Other example that can be applied to the fibrous tissue formation agent on the hip implant device similarly comprises: Talcum, Silicon stone, starch, fibronectin, poly-(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.Other implant device such as knee joint implant, take on implant and refer to that implant can be to be coated with to above-mentioned similar mode.

Embodiment 44

Be coated with implant for into bones with silk/PLGA

With 5g PLGA (50:50, IV=0.15, Birmingham Polymers, solution Inc.) is dissolved in the 100mL dichloromethane.The Powdered silk of 1g (25-53 μ m, utilize cryomill when sieving as mentioned above and prepare) is mixed in the described solution.With (endosteal) in the bone thus insert can be easily near linear parts in the clamp system for implant.Described clamp is fixed on the suspension type agitator (Fisher Scientific) subsequently.Described agitator is set at the speed of about 30rpm.Silk/PLGA solution is placed glass TLC sprayer unit (Sigma-Aldrich Corp).Utilize TLC sprayer unit (connection nitrogen pot) to be coated with the linear parts of described implant with silk/PLGA.The described sprayer unit of turn intersperses among silk in the PLGA solution equably guaranteeing in spray process.Thereby the speed of control spray applications can not ooze solution from described device.In case finish initial coating, just stop spray process and carry out described device air-dry.Can repeat described spraying coating/dry run if desired up to obtaining required thickness.After last air-dry step, described device is removed and places vacuum drying oven from clamp.With implant under vacuum dry 6 hours.Other example that can be applied to the fibrous tissue formation agent on the implant device similarly comprises: Talcum, Silicon stone, starch, fibronectin, poly-(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.

Embodiment 45

Be coated with implant for into bones with silk/PLGA

With 10g PLGA (50:50, IV=0.15, Birmingham Polymers, solution Inc.) is dissolved in the 100mL dichloromethane.The linear parts of implant for into bones is immersed in the described PLGA solution.It is dry and subsequently the silk powder is spread the part of the coating of coating implant that the device that was coated with is carried out part.Thereby subsequently described implant is rolled on the TEFLON thin slice silk granule is embedded in the PLGA coating.Subsequently with air-dry 3 hours of described implant.After air-dry step, described device is placed vacuum drying oven.With implant under vacuum dry 6 hours.Other example that can be applied to the fibrous tissue formation agent on the implant device similarly comprises: Talcum, Silicon stone, starch, fibronectin, poly-(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.

Embodiment 46

Be coated with intramedullary needle with silk/PLGA

With 10g PLGA (50:50, IV=0.25, Birmingham Polymers, solution Inc.) is dissolved in the 100mL dichloromethane.(cat#:167430000, Sanatmetal) the latter half of implant immerses in the described PLGA solution with intramedullary needle.It is dry and subsequently the silk powder is spread the part of the coating of coating implant that the device that was coated with is carried out part.Thereby subsequently described implant is rolled on the TEFLON thin slice silk granule is embedded in the PLGA coating.Subsequently with air-dry 3 hours of described implant.After air-dry step, described device is placed vacuum drying oven.With implant under vacuum dry 6 hours.Other example that can be applied to the fibrous tissue formation agent on the implant device similarly comprises: Talcum, Silicon stone, starch, fibronectin, poly-(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.

Embodiment 47

With silk/polyurethane coated intramedullary needle

The solution of 10g CHRONOFLEX AL 85A (CT Biomaterials) is dissolved among the 100mLTHF.(cat#:167430000, Sanatmetal) the latter half of implant immerses in the described polyurethane solutions with intramedullary needle.It is dry and subsequently the silk powder is spread on the part of coating of coating implant that the device that was coated with is carried out part.Thereby subsequently described implant is rolled on the TEFLON thin slice silk granule is embedded in the polyurethane coating.Subsequently with air-dry 3 hours of described implant.After air-dry step, described device is placed vacuum drying oven.With implant under vacuum dry 6 hours.Other example that can be applied to the fibrous tissue formation agent on the implant device similarly comprises: Talcum, Silicon stone, starch, fibronectin, poly-(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.

Embodiment 48

Be coated with intramedullary needle with silk/PLGA

With 10g PLGA (50:50, IV=0.25, Birmingham Polymers, solution Inc.) is dissolved in the 100mL dichloromethane.Stainless steel metal wire is surrounded circle pass wide hone lamella (cat #:934016005, apical pore Sanatmetal).Described implant is immersed in the described PLGA solution.It is dry and subsequently the silk powder is spread on the part of coating of coating implant that the device that was coated with is carried out part.Subsequently with air-dry 3 hours of described implant.After air-dry step, described device is placed vacuum drying oven.With implant under vacuum dry 6 hours.Other example that can be applied to the fibrous tissue formation agent on the implant device similarly comprises: Talcum, Silicon stone, starch, fibronectin, poly-(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.

Embodiment 49

With Talcum/polyurethane coated gastric restriction device

The solution of 10g CHRONOFLEX AL 85A (CT Biomaterials) is dissolved among the 100mLTHF.The outer surface of BIOENTERICS LAP-BAND system (Inamed Health) loop section is immersed in the described polyurethane solutions.Coating is carried out air-dryly being clamminess up to it, and spread Talcum (hydrous magnesium silicate, powder particle size 10 μ m, Aldrich Corp.) on the viscous coating this moment.The described device of jog is to remove unnecessary material.Subsequently the TEFLON rod is rolled across gently the surface further Talcum is embedded in the coating.Subsequently with air-dry 2 hours of described implant.After air-dry step, described device is placed vacuum drying oven.With implant under vacuum dry 24 hours.Other example that can be applied to the fibrous tissue formation agent on the implant device similarly comprises: Silicon stone, fibronectin, starch, silk, poly-(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.

Embodiment 50

With silk/PLGA coating gastric restriction device

With 10g PLGA (50:50, IV=0.25, Birmingham Polymers, solution Inc.) is dissolved in the 100mL ethyl acetate.The outer surface of BIOENTERICS LAP-BAND system (Inamed Health) loop section is immersed in the described polyurethane solutions.Coating is carried out air-dryly being clamminess up to it, and spread silk powder (25-53 μ m utilizes the preparation of cryomill and screen cloth) on the viscous coating this moment.The described device of jog is to remove unnecessary material.Subsequently the TEFLON rod is rolled across gently the surface further silk is embedded in the coating.Subsequently with air-dry 2 hours of described implant.After air-dry step, described device is placed vacuum drying oven.With implant under vacuum dry 24 hours.Other example that can be applied to the fibrous tissue formation agent on the implant device similarly comprises: Talcum, Silicon stone, fibronectin, starch, poly-(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.

Embodiment 51

With silk/PLGA coating soft palate implant device

With 2g PLGA (50:50, IV=0.15, Birmingham Polymers, solution Inc.) is dissolved in the 100mL ethyl acetate.Utilize clamp to fix PILLAR palate implant (Restore Medical, end Inc).Described clamp is fixed on the suspension type agitator (Fisher Scientific) subsequently.Described agitator is set at the speed of about 30rpm.Place glass TLC sprayer unit (Sigma-Aldrich Corp) also described device to be sprayed PLGA solution and cover described device up to the PLGA thin layer with PLGA solution.Described coating is carried out air-dryly being clamminess up to it.Utilize pair of forceps that described device is removed from clamp and silk powder (25-53 μ m, utilize cryomill and screen cloth preparation) is spread the viscous coating surface.The described device of jog is to remove unnecessary material.Subsequently with air-dry 2 hours of described implant.After air-dry step, described device is placed vacuum drying oven.With implant under vacuum dry 24 hours.Other example that can be applied to the fibrous tissue formation agent on the implant device similarly comprises: Talcum, Silicon stone, starch, poly-(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.

Embodiment 52

With Talcum/polyurethane coated surgical operation mesh

The solution of 10g CHRONOFLEX AL 85A (CT Biomaterials) is dissolved among the 100mLTHF.(hydrous magnesium silicate, powder particle size 10 μ m AldrichCorp.) are added in the described solution with Talcum with 1g subsequently.PROCEED surgical operation mesh (Ethicon) is put down on the release liner that overlays on a silicon coating.Silk/PLGA solution is placed glass TLC sprayer unit (Sigma-Aldrich Corp).Utilize the surface of TLC sprayer unit (connection nitrogen pot) subsequently with polyurethane/described mesh of Talcum solution coat.The described sprayer unit of turn intersperses among Talcum in the polyurethane solutions equably guaranteeing in spray process.Thereby the speed of control spray applications can not ooze solution from described device.In case finish initial coating, just stop spray process and carry out described device air-dry.Can repeat described spraying coating/dry run if desired up to obtaining required thickness.After last air-dry step, described device is removed and places vacuum drying oven from clamp.With implant under vacuum dry 6 hours.Other example that can be applied to the fibrous tissue formation agent on the hip implant device similarly comprises: Talcum, Silicon stone, starch, silk, poly-(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.

Embodiment 53

With silk/PLGA coating surgical operation mesh

With 2g PLGA (50:50, IV=0.15, Birmingham Polymers, solution Inc.) is dissolved in the 100mL ethyl acetate.The Powdered silk of 1g (25-53 μ m, utilize cryomill when sieving as mentioned above and prepare) is mixed in the described solution.(Flat Sheets, Cat #0112680 3 ＂ x 6 ＂ (7.5cm x 15cm) are DAVOL) on the release liner of a silicone coating for Bard Mesh.Silk/PLGA solution is placed glass TLC sprayer unit (Sigma-Aldrich Corp).Utilize the surface of TLC sprayer unit (connection nitrogen pot) subsequently with the described mesh of PLGA/ silk solution coat.The described sprayer unit of turn intersperses among silk in the PLGA solution equably guaranteeing in spray process.In case finish initial coating, just stop spray process and carry out described device air-dry.Can repeat described spraying coating/dry run if desired.After last air-dry step, described mesh placed vacuum drying oven and under vacuum dry 6 hours.Other example that can be applied to the fibrous tissue formation agent on the described mesh similarly comprises: Talcum, fibronectin, Silicon stone, starch, poly-(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.

Embodiment 54

Silk is attached in the surgical operation mesh

With Bard Hernia mesh (Flat Sheets, Cat # 0,112,680 3 ＂ x 6 ＂ (7.5cm x 15cm), DAVOL) flat being overlying on the glass flake.Subsequently by pin is passed mesh to the opposite side of mesh and (PERMA-HAND Silk Suture-Taper Point, Cat:7730G Ethicon) are sewn on the mesh with several silk sutures from a side of mesh.For every suture silk is passed described mesh at least 4 times.Cut off unnecessary suture material.

Embodiment 55

Silk is attached in the embolic coil

(Cook is around platinum silk Inc) and be that a knot is fixed in silk on the platinum coil subsequently in discerptible TORNADO embolic coil with 2 layers of (ply) wire coil.This process is repeated to account for up to the silk amount that exists several times to have about 5% of fiber.

Embodiment 56

With in the silk coating every locking device

By 1g raw silk sign indicating number (virgin silk yard) is joined 5% solution for preparing among the 20mL HFIP among the HFIP.With described solution stirring 48 hours.Subsequently the solution that obtains is dripped among the HELEX on the PTFE part of locking device (W.L.Gore).In case it is the most of PTFE of described device part contacts with HFIP/ silk solution, just that described device is air-dry and carried out vacuum drying subsequently 24 hours.

Embodiment 57

With in the polylysine coating every locking device

Prepare poly-(lysine) [poly--D-lysine hydrobromate, molecular weight 150,000-300,000Sigma-Aldrich] solution of 2% by 0.1g being dissolved in the 2mL deionized water.Described solution is poured in the little metal dish.Subsequently with (AGAMedical Corporation USA) immerses in the solution and by utilizing the Pasteur pipette that solution is sprayed on the described device it is overlying in the solution every occluder (occluder) among the AMPLATZER.Remove and place TEFLON thin slice on and allow it carry out air-dry from coiling out described device subsequently.Subsequently with described device under vacuum dry 24 hours.

Embodiment 58

With silk/PLGA coating fallopian tube implant

With 2g PLGA (50:50, IV=0.15, Birmingham Polymers, solution Inc.) is dissolved in the 100mL ethyl acetate.The Powdered silk of 1g (25-53 μ m, utilize cryomill when sieving as mentioned above and prepare) is mixed in the described solution.Utilize pair of forceps and tinsel to clamp the permanent contraception device of ECLIPSE (Ovion, Redwood City, " stent " part CA).Described tweezers are fixed on the suspension type agitator (Fisher Scientific) subsequently.Described agitator is set at the speed of about 45rpm.Silk/PLGA solution is placed glass TLC sprayer unit (Sigma-Aldrich Corp).Utilize TLC sprayer unit (connection nitrogen pot) to be coated with about 1/3 implant under the described implant polishing part with silk/PLGA.The described sprayer unit of turn intersperses among silk in the PLGA solution equably guaranteeing in spray process.Thereby the speed of control spray applications can not ooze solution from described device.In case finish initial coating, just stop spray process and carry out described device air-dry.Can repeat described spraying coating/dry run if desired up to obtaining required thickness.After last air-dry step, described device is removed and places vacuum drying oven from clamp.With implant under vacuum dry 6 hours.Other example that can be applied to the fibrous tissue formation agent on the device similarly comprises: Talcum, Silicon stone, starch, fibronectin, poly-(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.

Embodiment 59

Be coated with vas clips with silk/PLGA

With 2g PLGA (50:50, IV=0.15, Birmingham Polymers, solution Inc.) is dissolved in the 100mL ethyl acetate.With vas clips (VASCLIP, VMBC, LLC, Roseville MN) immerses the sector-style of going forward side by side in the PLGA solution and does and be clamminess up to it.Subsequently described folder is joined in the Powdered silk in the beaker (25-53 μ m, utilize cryomill when sieving as mentioned above and prepare).At beaker described folder is shaken with Powdered silk.Described folder is removed from the beaker of silk and shakes gently to remove unnecessary silk.The TELFON rod is rolled across the surface of the folder that was coated with so that the silk powder further is embedded in the coating.With air-dry 6 hours of described folder, carried out vacuum drying thereafter 24 hours subsequently.

Other example that can be applied to the fibrous tissue formation agent on the device similarly comprises: Talcum, Silicon stone, starch, fibronectin, poly-(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.

Embodiment 60

Silk is mixed filler

The Powdered silk of 50mg (25-53 μ m, utilize cryomill when sieving as mentioned above and prepare) is joined in the bovine collagen protein solution (35mg/mL) [CONTIGEN, CR Bard] of 2.5mL glutaraldehyde cross-linking.Vibrate described solution to produce final suspension.Other example that can be applied to the fibrous tissue formation agent on the device similarly comprises: Talcum, Silicon stone, fibronectin, starch, poly-(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.

Embodiment 61

Silk is applied to prosthese anal sphincter device

10g CHRONOFLEX AL 85A (CT Biomaterials) solution is dissolved among the 100mLTHF.Big envelope (cuff) part of ACTICON NEOSPHINCTER is placed on the TELFON thin slice.Silk/polyurethane solutions is placed glass TLC sprayer unit (Sigma-Aldrich Corp).Utilize the big envelope part of TLC sprayer unit (connection nitrogen pot) with thin silk/polyurethane coating coating implant.In case finish initial coating, just stop described spray process and described device is carried out air-dry to produce viscous coating.Subsequently Powdered silk (25-53 μ m, utilize cryomill when sieving as mentioned above and prepare) is sprinkling upon on the viscous coating.The surface that subsequently the TELFON rod is rolled across described device is embedded into silk in the coating with help.Subsequently unnecessary silk powder is shaken off from described device.With air-dry 24 hours of described device, under vacuum dry 24 hours thereafter.Other example that can be applied to the fibrous tissue formation agent on the device similarly comprises: Talcum, Silicon stone, fibronectin, starch, poly-(ethyl cyanoacrylate), polylysine, bleomycin, and CTGF.

Embodiment 62

Silk is attached to external fixation device

With the PLGA of 10g (50:50, IV=0.15, Birmingham Polymers, Inc.) solution is dissolved in the 100mL dichloromethane.The Powdered silk of 1g (25-53 μ m, utilize cryomill when sieving as mentioned above and prepare) is mixed in the described solution.(TheHOFFMANN II HYBRID EXTERNAL FIXATION System Stryker) immerses in the PLGA/ silk solution with the skin assembly of wearing of spiral in to the marrow.Be coated with following 1/5 part of these pins.Carry out the pin that was coated with air-dry and carry out vacuum drying subsequently.

Embodiment 63

Silk is attached to surgical operation film implant

By the 1g polymer dissolution is prepared 10% 70:30PLLA:PDLLA polymer (RESOMER LR 708, Boehringer Ingelheim, KG, Germany) solution in 10mL DCM.The Powdered silk of 1g (25-53 μ m, utilize cryomill when sieving as mentioned above and prepare) is added in the described solution.With solution stirring 1 hour.The casting cutter that utilizes 40mil is with in the film of solution-cast on release liner.Described film (50 ℃, 3 hours) in pressure air (forced-air) baking oven is carried out drying and in vacuum drying oven dry 24 hours subsequently.

Embodiment 64

Drip (dripped-on) Ciclosporin A sample of system

Polyurethane (PU) (CHRONOFLEX AL 85A) is dissolved in the oxolane (THF) solution (20mL) to form 20%.By the PU solution-cast is prepared PU film (utilizing the open cutter (opening knife) of 40MIL) on release liner.Described film is dry and carry out drying subsequently in vacuum drying oven in (50 ℃) in the pressure air baking oven.Final film thickness is about 100-120 μ m.Ciclosporin A is dissolved in (500ug/mL) forms the Ciclosporin A alcoholic solution in the ethanol.The Ciclosporin A solution of 50 μ l equal portions is dripped on the PU film of 8 * 8mm2 (precuting).In fume hood ethanol evaporation and in vacuum drying oven further dry described PU sample.

Embodiment 65

The Ciclosporin A sample of sealing

20% polyurethane (the CHRONOFLEX AL 85A) solution of preparation among the THF (2g PU in 10mL THF, 20mL glass scintillation bottle).100 μ g/mL Ciclosporin As/chloroformic solution of 230 μ L is added in the PU solution.Utilize magnetic stirring apparatus with described solution stirring 2 hours.The casting cutter that utilizes 40mil is with in the film of PU/ Ciclosporin A solution-cast on release liner.Film is in the pressure air baking oven in (50 ℃) drying and carry out drying subsequently in vacuum drying oven.Final film thickness is about 100-120 μ m.

Embodiment 66

For releasing research and total content analysis from the ciclosporin of polyurethane film

Utilize following parameters the release from the Ciclosporin A of polyurethane film to be analyzed by HPLC.

Mobile phase	(35:65:5:0.1 water/acetonitrile, tert-butyl methyl ether, phosphoric acid)
		Wavelength	210nm
Post	ACE C18 150 x 4.6mm 5μm
		Flow velocity	1.2mL/min
The dilution of sample agent	1:1 (acetonitrile/water)

Be prepared as follows reference material: the ciclosporin of about 25mg is weighed in the 25mL volumetric flask.Add diluent (1:1 acetonitrile/water) dissolving ciclosporin and add diluent to obtain correct volume.Make following diluent (being shown in the following table) to obtain 0.2,0.5,2,5, the reference material of 10 and 20 μ g/mL.

Mother liquid concentration (μ g/mL)	Diluent volume (mL)	Final volume (mL)	Ultimate density (μ g/mL)
				1000	8	10	800
1000	5	10	500
				1000	3	10	300
1000	2	10	200
				1000	1	10	100
100	1	10	10
				500	1	10	50
50	1	10	0.5
				800	1	10	80
80	1	10	0.8
				200	1	10	20
20	1	10	2

Releasing research:

The following releasing research that carries out.The PU film is cut into the sheet of 1cm x 1cm,, and accurately is weighed in the 15cm test tube if be not this size originally.The release medium of 14mL is added in each test tube that comprises sample, closes the lid, and place on the rotator up to next time point in 37 ℃.Described time point is 5 hours, 1 day, 2 days, 3 days, 4 days, 5 days and subsequently after first week every other day up to detecting less than medicine or up to determining in addition.On each time point, with sample transfer in new test tube and add the release medium of 14mL.Sample is put back to 37 ℃ of baking ovens up to next time point.At different time points release medium solution is injected directly on the HPLC post and analyzes.

Total content is analyzed:

The PU film is cut into the sheet of 1cm x 1cm,, and accurately is weighed in the 15cm test tube if be not this size originally.Join the chloroform of 0.5mL in every test tube and dissolve described sample fully.In case described sample dissolution, the just acetonitrile of adding 6.0mL in each sample.Sample closed the lid and acutely shake with precipitation polyurethane.With sample centrifugal 10 minutes in 2500rpm.The supernatant of 5.0mL is transferred in the clean test tube and under nitrogen carries out drying in 350C.Dried sample is rebuild in the acetonitrile of 1.0mL and is injected among the HPLC.For the results are shown among Fig. 5 of the releasing research of the polyurethane film that has loaded 1.25% and 0.125% ciclosporin.

By preceding described,, still can carry out various improvement and can not deviate from the spirit and scope of the present invention although be appreciated that illustrative purposes this paper has described specific embodiments of the present invention for example.Therefore, except the appended claims qualification, the present invention is not limited.

With mention in this description and/or the application materials list in the full content of listed whole United States Patent (USP)s, U.S. Patent Application Publication thing, U.S. Patent application, foreign patent, foreign patent application and non-patent publications incorporate this paper into as a reference.

Claims (83)

1. method, it comprises that fibrous tissue from the treatment effective dose to its patient's intervertebral disc space of needs that introduce forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification reaction at patient's intervertebral disc space, useful result is provided for thus described patient.

2. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, the treatment of capsula articularis humeri damage is provided for thus described patient.

3. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, provides ligament repair to the patient thus.

4. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, provides the tendon reparation to the patient thus.

5. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, provides the hernia reparation to the patient thus.

6. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, and the sealing of lung is provided to the patient thus.

7. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, provides aneurysmal treatment or prevention to the patient thus.

8. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, provides suberification to the patient thus.

9. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, provides the reaction of the fibre modification between patient and the soft palate implant to the patient thus.

10. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, and the treatment of obesity is provided to the patient thus.

11. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, and the treatment of GERD is provided to the patient thus.

12. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, and the treatment or the prevention of fecal incontinence are provided to the patient thus.

13. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, and the venous treatment or the prevention of varicose are provided to the patient thus.

14. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, and the treatment of urinary incontinence is provided to the patient thus.

15. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, provides contraception to the patient thus.

16. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, provides orthopedics's treatment of diseases to the patient thus.

17. method, it comprises that the fibrous tissue of introducing the treatment effective dose in its patient's body of needs forms agent or contains the compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induce the fibre modification reaction on the intravital concrete site of described patient, and odontopathy's treatment is provided to the patient thus.

18. a medical apparatus that comprises rectificating surgery implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

19. a medical apparatus that comprises orthopedics's prosthese and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

20. a medical apparatus that comprises modular implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

21. a medical apparatus that comprises urine sling and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

22. a medical apparatus that comprises prosthetic joint and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

23. a medical apparatus that comprises modular prosthese and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

24. a medical apparatus that comprises articular prosthesis and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

25. a medical apparatus that comprises part prosthese and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

26. a medical apparatus that comprises hip implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

27. a medical apparatus that comprises knee joint implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

28. a medical apparatus that comprises shoulder implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

29. one kind comprises the medical apparatus that finger or toe implant and fibrous tissue form agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

30. one kind comprises the titanium fixture of the root portion that is used for replacing the natural teeth that loses and the medical apparatus that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

31. a medical apparatus that comprises implant for into bones and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

32. a medical apparatus that comprises subperiosteum implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

33. a medical apparatus that comprises guiding osteanagenesis (GBR) implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

34. one kind comprises the dental implant of the agglutination after the control periodontal and the medical apparatus that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

35. a medical apparatus that comprises internal fixation implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

36. a medical apparatus that comprises external fixation implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

37. a medical apparatus that comprises hold-down screw and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

38. one kind comprises the medical apparatus of interfering screw and fibrous tissue to form agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

39. a medical apparatus that comprises rotor screw and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

40. a medical apparatus that comprises plate implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

41. a medical apparatus that comprises tinsel implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

42. a medical apparatus that comprises collagen protein implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

43. a medical apparatus that comprises fallopian tube implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

44. a medical apparatus that comprises transcatheter inaccessible implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

45. a medical apparatus that comprises prosthese anal sphincter and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

46. a medical apparatus that comprises fallopian tube stent and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

47. a medical apparatus that comprises deferent duct implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

48. a medical apparatus that comprises gastric restriction implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

49. one kind comprises the medical apparatus that intracavity implant and the fibrous tissue based on suture of separating stomach forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

50. a medical apparatus that comprises electricity irritation implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

51. a medical apparatus that comprises soft palate implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

52. a medical apparatus that comprises blood vessel coil implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

53. a medical apparatus that comprises vascular occlusion coil implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

54. a medical apparatus that comprises vascular occlusion implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

55. one kind comprises the vascular occlusion implant of non-coiling and the medical apparatus that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

56. a medical apparatus that comprises hernia mesh implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

57. a medical apparatus that comprises surgical operation film implant and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

58. a medical apparatus that comprises spinal fusion device and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

59. one kind forms the medical apparatus of agent every inaccessible sticking patch and fibrous tissue in comprising, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

60. a medical apparatus that comprises intracavity fastener and fibrous tissue formation agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

61. one kind prepares injectable method for compositions, it comprises fibrous tissue is formed the combination of agent and filler.

62. method for preparing medical apparatus, comprise i) rectificating surgery implant and ii) fibrous tissue form agent or comprise the compositions combination that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

63. method for preparing medical apparatus, comprise i) orthopedics's prosthese and ii) fibrous tissue form agent or comprise the compositions combination that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

64. method for preparing medical apparatus, comprise i) dental implant and ii) fibrous tissue form agent or comprise the compositions combination that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

65. method for preparing medical apparatus, comprise i) the internal fixation implant and ii) fibrous tissue form agent or comprise the combination of compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

66. method for preparing medical apparatus, comprise i) the external stability implant and ii) fibrous tissue form agent or comprise the combination of compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

67. method for preparing medical apparatus, comprise i) the collagen protein implant and ii) fibrous tissue form agent or comprise the combination of compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

68. method for preparing medical apparatus, comprise i) the fallopian tube implant and ii) fibrous tissue form agent or comprise the combination of compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

69. method for preparing medical apparatus, comprise i) prosthese anal sphincter implant with ii) become fiber agent or comprise the combination of compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

70. method for preparing medical apparatus, comprise i) transplantable male contraception device and ii) fibrous tissue form agent or comprise the combination of compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

71. method for preparing medical apparatus, comprise i) the gastric restriction implant and ii) fibrous tissue form agent or comprise the combination of compositions that fibrous tissue forms agent, wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

72. method for preparing medical apparatus, comprise i) separate the inner chamber implant based on suture of stomach, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

73. method for preparing medical apparatus, comprise i) separate the electricity irritation implant of stomach, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

74. method for preparing medical apparatus, comprise i) the soft palate implant, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

75. method for preparing medical apparatus, comprise i) blood vessel coil implant, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

76. method for preparing medical apparatus, comprise i) vascular occlusion coil implant, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

77. method for preparing medical apparatus, comprise i) the vascular occlusion implant, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

78. method for preparing medical apparatus, comprise i) the vascular occlusion implant of non-coiling, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

79. method for preparing medical apparatus, comprise i) hernia mesh implant, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

80. method for preparing medical apparatus, comprise i) surgical operation film implant, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

81. method for preparing medical apparatus, comprise i) the spinal fusion implant, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

82. method for preparing medical apparatus, comprise i) in every inaccessible sticking patch implant, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

83. method for preparing medical apparatus, comprise i) inner chamber fastener implant, ii) fibrous tissue forms agent or comprises the combination of compositions that fibrous tissue forms agent, and wherein said fibrous tissue forms agent and induces the fibre modification between the patient of described device and implanted described device to react.

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