WO1992013495A1 - Adhesif a base de fibrinogene - Google Patents
Adhesif a base de fibrinogene Download PDFInfo
- Publication number
- WO1992013495A1 WO1992013495A1 PCT/US1992/000931 US9200931W WO9213495A1 WO 1992013495 A1 WO1992013495 A1 WO 1992013495A1 US 9200931 W US9200931 W US 9200931W WO 9213495 A1 WO9213495 A1 WO 9213495A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- fibrinogen
- plasma
- buffered
- bovine
- composition
- Prior art date
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- 239000004334 sorbic acid Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- 150000003721 vitamin K derivatives Chemical group 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/745—Blood coagulation or fibrinolysis factors
- C07K14/75—Fibrinogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods
- A61B17/00491—Surgical glue applicators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
- A61K38/4833—Thrombin (3.4.21.5)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0028—Polypeptides; Proteins; Degradation products thereof
- A61L26/0042—Fibrin; Fibrinogen
Definitions
- the invention described herein relates to an adhesive composition which is useful for the surgical repair of tissue as well as for its hemostatic effects.
- the invention described herein encompasses a test kit for detecting potentially untoward allergic reactions which may be experienced by patients who receive the fibrinogen based adhesive.
- the invention described herein addresses fibrinogen-containing adhesives which utilize plasma as a fibrinogen source, the preferred plasma being bovine plasma. Hence, the transmission of blood- borne human diseases which are of concern whenever pooled human plasma is used may be avoided.
- one objective of the present invention is to facilitate the use of fibrinogen-based adhesives without requiring the use of autologous or single donor fibrinogen to reduce the transmission of most blood-borne diseases.
- Another objective of the invention described herein relates to the use of higher PEG'S.
- a further aspect of the present invention relates to an improved fibrinogen based adhesive suitable for effecting wound closures.
- Yet another aspect of the invention described herein relates to a fibrinogen based adhesive to facilitate wound healing.
- the present invention relates to a fibrinogen-based adhesive which contains fibrinogen precipitated from plasma with polyethylene glycol.
- the plasma is treated with PEG to form a precipitate.
- the precipitate is re-treated with polyethylene glycol to further purify the precipitate.
- the purified precipitate is then treated with glycine to form a glycine-purified precipitate.
- the glycine-purified precipitate is reconstituted and lyophilized to form a dry composition containing about 90 to about 98 percent fibrinogen, about 0.5 to about 2 to 3 percent fibrin, less than about one percent fibronectin and less than about one percent factor XIII (FXIII) .
- the present invention utilizes a fibrinogen-based adhesive prepared in the manner described below, and having the properties noted.
- fibrinogen is used in the conventional sense to refer to human or animal plasma protein of relatively high molecular weight that is converted to fibrin. As those of ordinary skill in this art will understand, this may occur through the action of thrombin, calcium and other coagulation factors. Also referred to as factor I or Parenogen, fibrinogen is a glycoprotein belonging to the keratin-myosin group. Fibrinogen is synthesized and secreted by hepatic parenchymal cells, and is present in normal human plasma at levels of about 0.3 to 0.4 g/100 ml.
- fibrinogen molecule is believed to contain three peptide chains, alpha (A) , beta (B) and gamma (C) , which are crosslinked by disulfide bridges.
- the molecular weight is approximately 400,000 for the dimeric form. #
- fibrin is used herein to refer
- Fibrin typically refers to polymerized fibrin monomers, and may be present 10 in at least two forms; "fibrin-i”, which is insoluble fibrin, formed through the reaction of a fibrinogen-like plasma protein, (“FSF”), which in the presence of calcium, converts from a weakly bonded gel into a covalently bonded, insoluble clot. 15 "Fibrin-s" refers to fibrin which is soluble in urea.
- FSF fibrinogen-like plasma protein
- Thrombin refers to a serine based protease which is derived from prothro bin, which reacts to form thrombin through 20 the action of thromboplastin in the presence of calcium ions.
- Bovine thrombin contains two polypeptide chains designated chain A and chain B. Chain A contains 49 amino acid residues. It is bound via disulfide linkages to chain B, which contains 25 about 265 amino acid residues as well as carbohydrate.
- Prothrombin refers to the precursor compound of thrombin. Also known as factor II, prothrombin is a coagulation pro-enzyme having a molecular weight of 30 69,000 to 74,000. Prothrombin's fibrinogen- " activating effect is vitamin-K dependent. It is converted to thrombin by the combined action of factor X a , factor V and phospholipid in the presence of divalent calcium ions. It is believed to account 35 for less than 0.2% of the total plasma protein, and is most stable within the range of pH 4 to 9.5. Prothrombin is precipitable at pH 4.2 to 4.5. The dry material (dried from the frozen state) may show reduced activity after a few months.
- Factor XII also known as Hageman factor
- Factor XII is believed to react with calcium, plasma thromboplastin antecedent (also known as factor XI or "PTA") , plasma thromboplastin component (also known as Christmas factor, factor IX and "PCT”) , antihemophilic globulin (also known as factor VIII and "AHG”) , thromboplastin (also known as factor III) , labile factor (also known as factor V) and Stuart-Prower Factor (also known as factor X) to produce intrinsic or blood thromboplastin. This cascade typically occurs in about three to five minutes.
- Extrinsic or tissue thromboplastin is formed rapidly (in less than about 12 seconds) in various tissues, e.g., the lung and brain, in the presence of factor V, factor VII (also known as Stabile Factor, proconvertin, serum prothrombin conversion accelerator and "SPCA") , and factor X.
- factor V also known as Stabile Factor, proconvertin, serum prothrombin conversion accelerator and "SPCA”
- SPCA Stabile Factor
- thromboplastin catalyzes the conversion of prothrombin to thrombin in the presence of factors V, VII and X and calcium.
- stage three thrombin rapidly converts fibrinogen into fibrin, which forms a fiber network.
- the network traps red blood cells, thus forming a blood clot.
- blood typically also contains natural clot inhibitors, such as antithrombin, heparin and antithromboplastin, each of which can interfere with the clotting mechanism cascade. It is believed that the natural balance between the factors described above facilitates clotting at the appropriate time and site. This prevents unnecessary premature clotting, while meeting the needs of the organism when clotting is required, such as to prevent undesirable blood loss from a wound.
- natural clot inhibitors such as antithrombin, heparin and antithromboplastin
- the invention described herein includes a process for producing a fibrinogen-based adhesive having high levels of purity and tensile strength after it has cured and a high level of reproducability in the extraction/purification process.
- a mammalian source of plasma &- ⁇ 5- , cow or pig
- a plasmapheresis unit to obtain the plasma.
- other methods of obtaining plasma may be used.
- a nonhuman mammalian source for plasma most blood-borne diseases which affect humans, e.g., hepatitis, etc., can be avoided.
- the selection of a particularly well-suited species for the production of plasma coupled with carefully controlled and monitored diet and living conditions, as well as routine screening for pathogenic contamination, further reduces the likelihood of transmission of blood borne diseases to humans.
- the preferred source of plasma is the cow, since there is only a small degree of disparity between human fibrinogen and bovine fibrinogen.
- the plasma is drawn into an anticoagulant solution, e.g, acid-citrate-dextrose solution ("ACD") or another suitable anticoagulant containing solution.
- ACD acid-citrate-dextrose solution
- the plasma is treated with polyethylene glycol for a time period and at a concentration and temperature which are effective for precipitating the fibrinogen which is contained in the plasma, without substantially denaturing the fibrinogen or precipitating a high concentration of non-fibrinogen plasma proteins, and without converting the fibrinogen to fibrin prematurely to any substantial degree which would render it inactive for use as an adhesive or hemostatic agent.
- Polyethylene glycol is used as the precipitating agent in the invention described herein for bovine fibrinogen, since it does not precipitate all of the non-fibrinogen plasma protein components, it is biocompatable and has a relatively consistent molecular weight when purchased from reliable commercial suppliers in the appropriate purity grade.
- the preferred PEG for use herein is PEG-8000. It exhibits biocompatability and enables one to achieve higher levels of purity (and fibrinogen yield) than other PEG preparations. PEG- 8000 is commercially available in different purity grades, and the highest purity level, such as that produced by Sigma Chemical Corp., is the most preferred.
- the plasma is treated with PEG using an effective amount thereof to precipitate the fibrinogen from the plasma.
- An effective concentration of PEG is about 50g/liter of plasma.
- This treatment is continued until a fibrinogen- containing precipitate is formed.
- This initial precipitation step typically takes about 10 to 30 minutes for precipitation to be complete.
- the PEG precipitation step may be repeated two or three times at a temperature which does not adversely affect the precipitation reaction, and which does not substantiall * y denature the fibrinogen. This precipitation step is most preferably conducted at about 5°c to about 23°C.
- the PEG is typically added to the plasma in a buffered solution.
- One preferred buffer utilizes a combination of monosodium phosphate, sodium chloride, sodium citrate and epsilon amino ⁇ aproic acid.
- Other buffer systems which are useful in this regard are TRIS, phosphate, borate 5 and bicarbonate systems.
- the PEG/buffer solution is added to the plasma gradually over about 15 minutes with constant stirring, until the fibrinogen precipitates.
- the precipitate is collected by 10 centrifugation at, e.g., about 4000 rpm, at a reduced temperature, e.g., about 5°C over about twenty minutes.
- the supernatant containing non- fibrinogen plasma proteins may then be decanted off and discarded.
- the precipitate is then purified with 15 repeated PEG/buffer treatments until the desired purity level is attained.
- this precipitation reaction is conducted two times, with the shortest time possible between precipitation and redissolution of the precipitate in a buffer 20 solution.
- the precipitate is redissolved in buffer, and the dissolved precipitate is treated with glycine in a concentration of about 1.5 to 2.5M.
- the preferred 25 glycine concentration is about 2.1M.
- the glycine treatment is continued until the precipitate is produced.
- the glycine precipitation step produces a less flocculated precipitate than that seen with PEG-8000 precipitation, and is of higher purity.
- This precipitate is also resuspended in buffer • solution as soon as possible after the precipitate is centrifuged and the supernatant is decanted off. ⁇
- the solution is lyophilized to form the fibrinogen containing powder.
- Lyophilization may be conducted at a cryogenically effective temperature, e.g., at least as low as about -50°C to about -70°C, although liquid nitrogen temperatures, e.g., about -196°C, may be used. Pressure is reduced below ambient, and the shelves contained within the lyophilizer and preparation to be lyophilized are heated to about the eutectic point for fibrinogen, and the other components contained therein. This enhances the freeze drying effect of the lyophilization process and is useful for eliminating water from the preparation without substantially reducing the fibrinogen yield which is obtained.
- a cryogenically effective temperature e.g., at least as low as about -50°C to about -70°C, although liquid nitrogen temperatures, e.g., about -196°C, may be used.
- Pressure is reduced below ambient, and the shelves contained within the lyophilizer and preparation to be lyophilized are heated to about the eutectic point for fibrinogen, and the other components contained therein. This enhances the
- the reduced temperature and pressure, along with the temperature differential between the atmosphere and the shelf, can be maintained in this fashion for an appropriate time period, e.g., from about 4 hours to as long as about 1 week to fully lyophilize the product.
- an appropriate time period e.g., from about 4 hours to as long as about 1 week to fully lyophilize the product.
- Near the end of the lyophilization process when a change in the preparation becomes visually apparent, ambient air is permitted to enter the lyophilizer. This also enhances the yield achieved and reduces any unwanted protein denaturation or premature conversion of fibrinogen to fibrin.
- the fractionation procedure described above produces a composition containing at least about 90 to about 98 percent fibrinogen with a low level of conversion to fibrin, and very low levels of precipitated non-fibrinogen plasma proteins.
- Other components include, e.g., about 0.5 to about 2 to 3 percent fibrin, less than about 1 percent fibronectin and less than about 1 percent factor XIII.
- the most preferred buffer system for use herein is as follows:
- This buffer system is compatable with polyethylene glycol and glycine, and is useful for the PEG 8000 and glycine precipitation and intermediate reconstitution steps as well as for the final reconstitution prior to lyophilization.
- the osmolarity of the buffer system noted above is about 0.267 and the pH is about 7.3.
- the low concentration of citrate is felt to enhance the purification of fibrinogen while minimizing the unnecessary premature conversion of fibrinogen to fibrin.
- Most other buffer systems with about a 0.009M citrate level or other inhibiting substances or buffers of varying concentrations facilitate similar results.
- the time intervals between collection and re-dissolution of the precipitate, as well as the time interval between the final glycine- precipitation step and lyophilization should be kept as short as possible to minimize any undesirable * denaturation of fibrinogen or premature conversion to fibrin.
- the redissolution steps should typically be initiated within about 10-15 minutes.
- the powder is packaged under sterile conditions in pharmaceutically acceptable containers, such as packets, vials or bottles, depending upon the intended use. These packages may be sized to accommodate small or large quantities of adhesive, depending upon the expected needs of the physician, and should be light resistant and stored at refrigerator temperatures, e.g., about 5°C prior to use.
- inert or active additives compatible with the fibrinogen and the buffer system described above may be included in the formulation, such as diluents, preservatives, dispersants and the like.
- Preservatives when used, are typically added to the fibrinogen powder after lyophilization to minimize untoward reactions with the fibrinogen, but may be added prior to lyophilization if appropriate.
- Representative examples of preservatives include thimerosal, antibiotics, BHA, BHT, sorbic acid, sodium metabisulfite and the like. These compounds may be added in amounts which are preservative effective without substantially denaturing or inactivating the fibrinogen, and without adversely affecting the buffer system. Typical concentrations range from about 0.0001 to about 0.01 percent, based upon the weight of the lyophilized powder prior to reconstitution.
- the powdered fibrinogen may be dissolved with diluent and gently shaken.
- the preferred diluent is sterile distilled water, but other diluents can be used as well.
- a sufficient amount of diluent is added to provide a solution containing about 1 to 40 mg ⁇ . of fibrinogen per ml.
- the fibrinogen is dissolved slowly with gentle shaking since vigorous agitation can cause denaturation of the fibrinogen or the premature conversion of fibrinogen to fibrin, thus rendering it less effective.
- the preparation when dissolved in water, appears as a white insoluble material; as it becomes hydrated, the solution becomes translucent and then finally clear over several minutes.
- the fibrinogen solution is activated by combining it with thrombin.
- thrombin Numerous commercial thrombin preparations are available which may be used to activate the fibrinogen composition, converting the fibrinogen to fibrin. Typical thrombin preparations contain about 1 unit to 1000 units per milliliter.
- Different ratios of fibrinogen to thrombin may be used for different applications, and the tensile strength of the adhesive after setting may vary slightly with the concentration and quantity of thrombin added to the fibrinogen solution.
- the appropriate thrombin solution is combined with the appropriate fibrinogen solution, and the liquid combination is applied to the operative site for wound closing or is applied to a vessel for its hemostatic effect.
- set times range from about 20 sec. to as long as about one hour. The set time can be shortened or lengthened to some extent by changing the concentration and amount of thrombin which is added to the fibrinogen.
- fibrinogen and thrombin solutions may be applied to the tissue site separately.
- the lyophilized fibrinogen powder can also be used in powder form as a local hemostatic agent. If the lyophilized preparation is to be used in this fashion, it may be sprinkled directly onto a wound site or surgical incision where it reacts with endogenous thrombin to effect hemostasis. This is typically useful when the vessel or wound to be closed is small, and blood loss is not rapid.
- the fibrinogen and thrombin may be applied to the wound or surgical incision by incorporation into a gauze pad, sponge, collagen or gel-type matrix or into a similar device and treating the area to cause hemostasis or adhesion as necessary.
- the fibrinogen based adhesive described herein affords a number of significant advantages over conventional surgical techniques (e.g., suturing) used alone as a surgical closure means and in combination with other techniques.
- the adhesive described herein provides a matrix for platelet adhesion and cell migration. When the preparation is applied topically to an actively bleeding site, the fibrin matrix effectively traps platelets, and through a series of enzymatic reactions, contributes to the biochemical cascade which culminates in clot formation.
- the fibrin matrix provides a compatible medium for the growth of contiguous cellular tissue.
- cells from surrounding "like" tissue can infiltrate the matrix, thus providing healing and damaged cell replacement.
- the fibrin matrix thus supplements the repair integrity of identical tissue, resulting in the formation of a stronger bond with less scar tissue incorporated.
- the architecture of the effected tissue is therefore substantially restored to that of neighboring tissue by the cells migrating from the surrounding tissue sites.
- Patients may be tested for skin test reactivity before the fibrinogen based adhesive is used to ensure that the individual will not demonstrate an untoward allergic reaction.
- Plasma is collected in sterile one liter plastic bags containing 3.8% sodium citrate.
- PEG 30% solution is prepared by dissolving 300 grams of polyethylene-8000 in water for irrigation (WFI) and bringing to one liter volume.
- Glycine is prepared by weighing 157.5 grams in a 1000 ml beaker. One volume is required for each liter volume of plasma processed. The following materials are weighed and dissolved in WFI:
- Plasma (3.4 liters) is poured into a six liter beaker and a magnetic stir bar added.
- the magnetic stirrer is started and maintained at a moderate speed so as to not cause foam to develop in the flask.
- the first precipitation is started by gradually adding 600 ml of the 30% PEG solution.
- the PEG is added by six 100 ml volumes. Each 100 ml volume is added over a four minute period.
- the plasma and precipitate are poured into four sterile one liter polypropylene centrifuge bottles and capped. The samples are centrifuged at 4000 RPM at a temperature of about 2°C to 8°C for 20 minutes.
- the supernatant is decanted and the precipitate asceptically scraped from the bottles and added to a sterile six liter flask.
- the bottles are washed with buffer to recover as much of the precipitate as possible.
- the resulting slurry is brought to a 3.4 liter volume with buffer A.
- a magnetic stir bar is added and the stirrer is maintained at constant speed until the precipitate is dissolved.
- a second precipitation is accomplished by adding 600 ml of 30% PEG at a rate of 100 ml over four minutes.
- the buffer and precipitate are poured into sterile one liter polyproplylene centrifuge bottles and capped. The samples are centrifuged at 4000 RPM at a temperature of about 2°C to 8°C for 20 minutes.
- the supernatant is decanted and the precipitate asceptically scraped from the bottles and added to a sterile six liter flask.
- the bottles are washed with buffer A to recover as much of the precipitate as possible.
- the resulting slurry is brought to a 3.4 liter volume with Buffer A.
- a magnetic stir bar is added and the stirrer maintained at constant speed until the precipitate is dissolved.
- the final precipitation is accomplished by gradually adding 157.5 grams of sterile glycine per liter, in a dry state, to the redissolved precipitate over a 20 minute period with constant stirring.
- the resulting precipitate and solution are again aseptically transferred to one liter centrifuge bottles and centrifuged at 4000 RPM at a constant temperature of about 2°C to 8°C for about 20 minutes.
- the supernatant is decanted.
- the precipitate is transfered asceptically to a one liter screw cap Erlenmeyer flask. As much of the precipitate is removed as possible by washing with Buffer A.
- the transferred precipitate is dissolved with Buffer A and brought to a volume of 10% of the original volume of plasma, i.e. 10% of 3.4 liters of plasma is 340 ml.
- the final volume of product is filtered through a .22 micron filter.
- the filtered volume is aliquoted asceptically in a Laminar hood; 5 milliliters per vial. Each vial is stoppered and prepared for lypholization.
- the plasma subfractions as described above can be further treated by established fractionation techniques to remove proteins that normally co- purifiy with fibrinogen and FXIII in the PEG/Glycine fractions (e.g. prothrombin, gamma globulins, albumin, fibronectin, plasmin, plasminogen, etc.).
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Abstract
Composition à base de fibrinogène dérivée à partir de plasma bovin par l'utilisation de polyéthylène glycol ('PEG') et de techniques de précipitation métant en oeuvre la glycine. La composition contient du fibrinogène hautement purifié que l'on peut activer et transformer en fibrine par l'addition de trombine ou par l'action de trombine endogène dans le cas de fermeture de petites lésions afin de procéder à une hémostase. De plus, la composition de fibrinogène est suffisamment résistante pour être utilisée comme adhésif chirurgical. L'invention concerne également un matériel de test permettant de détecter une allergie au fibrinogène dérivé de bovins.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US65233291A | 1991-02-07 | 1991-02-07 | |
US652,332 | 1991-02-07 | ||
US76685491A | 1991-09-27 | 1991-09-27 | |
US766,854 | 1991-09-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1992013495A1 true WO1992013495A1 (fr) | 1992-08-20 |
Family
ID=27096273
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1992/000931 WO1992013495A1 (fr) | 1991-02-07 | 1992-02-06 | Adhesif a base de fibrinogene |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU1461592A (fr) |
WO (1) | WO1992013495A1 (fr) |
Cited By (29)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1994020524A1 (fr) * | 1993-03-01 | 1994-09-15 | Fibratek, Inc. | Compositions therapeutiques de fibrinogene |
WO1995023167A1 (fr) * | 1993-02-23 | 1995-08-31 | Haemacure Biotech Inc. | Procede d'obtention d'un adhesif biologique comprenant du fibrinogene, le facteur xiii et de la fibronectine |
WO1996031245A1 (fr) * | 1995-04-06 | 1996-10-10 | Hamilton Civic Hospitals Research Development, Inc. | Adhesif de fibrine autologue et procedes pour le preparer et l'utiliser |
WO1997044015A1 (fr) * | 1996-05-17 | 1997-11-27 | Andaris Limited | Microparticules et utilisation de ces dernieres pour soigner des plaies |
EP0839498A1 (fr) * | 1996-11-05 | 1998-05-06 | Bayer Corporation | Procédé et dispositif pour l'application de colle fibrine |
US5977313A (en) * | 1996-10-10 | 1999-11-02 | Quadrant Healthcare Limited | Platelet substitutes and conjugation methods suitable for their preparation |
WO2000047621A1 (fr) * | 1999-02-12 | 2000-08-17 | Baxter Aktiengesellschaft | Procede de fabrication d'une preparation a base de fibrinogene et de fibronectine et compositions proteiques obtenues par ce procede |
US6168788B1 (en) | 1997-09-26 | 2001-01-02 | Leon Wortham | Fibrin glue without fibrinogen and biosealant compositions and methods |
EP0956869A3 (fr) * | 1998-05-15 | 2001-08-22 | Hogy Medical Co., Ltd. | Agent de scellement tissulaire |
WO2002067867A2 (fr) | 2001-02-23 | 2002-09-06 | The University Of Pittsburgh | Preparation rapide de matrices de cellules souches destinees a etre utilisees pour le traitement et la reparation de tissus et d'organes |
JP2002539087A (ja) * | 1999-02-12 | 2002-11-19 | バクスター・アクチエンゲゼルシャフト | フィブリノーゲンおよびフィブロネクチンをベースとする製剤を生成するための方法ならびにこの方法により入手可能なタンパク質組成物 |
JP2003518513A (ja) * | 1999-12-23 | 2003-06-10 | シーエスエル、リミテッド | 血漿プロテアーゼからのフィブリノゲンの分離 |
WO2004067045A3 (fr) * | 2003-01-24 | 2004-11-18 | Rose Hulman Inst Of Technology | Composite adhesif non actionne par la lumiere, systeme et procedes associes |
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US9439997B2 (en) | 2004-10-20 | 2016-09-13 | Ethicon, Inc. | Reinforced absorbable multilayered hemostatis wound dressing |
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WO2020178419A1 (fr) | 2019-03-06 | 2020-09-10 | Gambro Lundia Ab | Dispositif et procédé de distribution d'un agent d'étanchéité à base de fibrine activé par la thrombine |
US11604026B2 (en) | 2019-03-14 | 2023-03-14 | Terumo Bct Biotechnologies, Llc | Lyophilization loading tray assembly and system |
US11634257B2 (en) | 2017-10-09 | 2023-04-25 | Terumo Bct Biotechnologies, Llc | Lyophilization container and method of using same |
CN116115817A (zh) * | 2022-07-01 | 2023-05-16 | 南方医科大学 | 一种纤维蛋白生物医用胶的研制 |
WO2023119265A1 (fr) | 2021-12-21 | 2023-06-29 | Omrix Biopharmaceuticals Ltd. | Formulation renfermant du fibrinogène et ses utilisations |
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1992
- 1992-02-06 AU AU14615/92A patent/AU1461592A/en not_active Abandoned
- 1992-02-06 WO PCT/US1992/000931 patent/WO1992013495A1/fr active Application Filing
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US4177188A (en) * | 1977-01-21 | 1979-12-04 | Nordisk Insulinlaboratorium | Process for recovering purified albumin from blood plasma using PEG and caprylic acid |
US4298598A (en) * | 1979-02-15 | 1981-11-03 | Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte | Tissue adhesive |
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