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WO2004112863A1 - Implant recouvert d'une membrane biodegradable comportant du chitosane - Google Patents

Implant recouvert d'une membrane biodegradable comportant du chitosane Download PDF

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Publication number
WO2004112863A1
WO2004112863A1 PCT/CA2004/000906 CA2004000906W WO2004112863A1 WO 2004112863 A1 WO2004112863 A1 WO 2004112863A1 CA 2004000906 W CA2004000906 W CA 2004000906W WO 2004112863 A1 WO2004112863 A1 WO 2004112863A1
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WIPO (PCT)
Prior art keywords
chitosan
membrane
solution
peo
covered
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PCT/CA2004/000906
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English (en)
Inventor
Maryam Tabrizian
Benjamin Thierry
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Mcgill University
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Publication of WO2004112863A1 publication Critical patent/WO2004112863A1/fr

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    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially resorbable by the body
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials

Definitions

  • the present application relates to the field of medical implants such as stents, which can be coated with a biodegradable membrane containing or not an active ingredient or medicament.
  • Membrane-covered-stents are used or investigated in the treatments coronary diseases such as aneurysm, pseudoaneurysm, large dissection of the vascular wall during angioplasty and thrombus containing lesions (Baldus S, et al., Catheter Cardiovasc Interv; 53: 1-4, 2001).
  • covered-stents may be useful to stabilize the friable plaque in saphenous vein graft diseases. This may in turn reduce the risk of distal embolization following angioplasty of such vessels. Their uses have also been questioned in the treatment of peripheral diseases (Stockx L. Eur J Radiol; 28:182-188, 1998).
  • Chitosan is a biocompatible, non-immunogenic and biodegradable polymer with bioadhesive, wound healing, and antimicrobial properties.
  • Chitosan blend with various polymers have been widely investigated to improve the mechanical properties of chitosan.
  • chitosan-polyethylene oxide (PEO)/polyethylene glycol (PEG) interpenetrated networks display excellent mechanical properties with improved ductility in comparison to chitosan alone (Kolhe P, and Kannan RM. Biomacromolecules; 4:173-180, 2003; and Budtova T, et al., J Appl Polym Sci; 84: 1114-1122, 2002).
  • Chitosan is also widely used in drug delivery application and promotes absorption of drugs, peptides and proteins through biological tissues (Singla AK, and Chawla M. J Pharm Pharmacol; 53:1047-1067, 2001 ). In revascularization procedures, neointimal hyperplasia within the stent struts remained however a consistent cause of failure.
  • Systemic pharmaceutical strategies have been up to date mainly unsuccessful. Local drug/gene delivery conjugated with stent implantation yields the hope to eliminate clinical restenosis (Fattori R, and Piva T. Lancet; 361 :247-249, 2003). In particular, antiproliferative drug-eluting stents have been shown to significantly reduce restenosis. The long term safety and efficiency as well as the cost/efficiency of these therapeutic strategies remain however questioned.
  • One aim of the present invention is to provide a chitosan-based membrane covered device, such as a stent, with properties that could be tailored to specific applications of such endoprosthesis.
  • Another aim of the present invention is to provide a new method for preparing the device of the present invention.
  • a biodegradable membrane covered endovascular device said device being coated with a solution comprising chitosan and chitosan plasticizer or cross- linker dried on the device, forming a flexible polymeric membrane on the device upon rehydration.
  • the solution is freeze-dried on the device, forming a porous flexible polymeric membrane on the device, upon rehydration.
  • the chitosan plasticizer or cross-linker can be for example (without limitation) polyethylene oxide (PEO), cellulose, keratin, collagen, anionic polysaccharide, glutaraldehyde or poly( ⁇ -hydroxy acid).
  • the membrane so produced has a further commercial potential as it can be used for treating various diseases when an active ingredient is coupled to the membrane.
  • the active ingredient can simply be added at the time of forming the membrane, to the solution of chitosan/chitosan plasticizer or cross-linker prior to coating the device.
  • Active ingredients that can be useful and that are thus envisioned in the present invention are for example, without limitation, growth factors, anti-proliferative drugs, anti-inflammatory drugs, nitric oxide donor compounds, radionuclides, nucleic acids, peptides, and proteins*.
  • the device is a stent, a stent graft or a coil, having preferably a metallic scaffold made of stainless steel, NiTi alloy, titanium alloys, Conichrome, Phynox, MP35N, cobalt- based alloys, tantalum titanium-zirconium-niobium alloys, titanium-aluminum- vanadium alloy, platinum, tungsten, tantalum, or a combination thereof.
  • the solution is a 70:30 weight to weight chitosan:polyethylene oxide solution.
  • chitosan used herein is meant to include chitosan, chitosan blends or composites complex with a biocompatible synthetic or natural polymer.
  • step b) contacting a device to be covered with the solution of step a); and c) allowing the solution to dry onto said device.
  • the solution in step c) above is freeze-dried onto the device, forming a porous biodegradable membrane- covered device.
  • the method may also comprise after step c) the steps of:
  • step c) rinsing the device of step c) with an alkaline solution
  • step d) rinsing the device of step d) with a physiological buffer
  • step f) allowing the device of step e) to dry.
  • the solution of step a) above is prepared by dissolving in solution chitosan in an acidic medium and the chitosan plasticizer or cross-linker in another acidic medium and mixing the solutions of chitosan and chitosan plasticizer or cross-linker together to form the solution used in step a).
  • a method for treating aneurysm comprising the steps of implanting a device as defined above in a blood vessel of a patient suffering from an aneurysm, such that the device is implanted over the opening of the aneurismal sac in the blood vessel, the chitosan/polyethylene oxide coated device allowing cells to adhere to the device, thereby closing the aneurismal sac.
  • the device of the present invention should not be limited to stent and restenosis, but should also include devices that need to be implanted and that need to release a medicament or an active ingredient at the site of implantation.
  • the device of the present invention can also be used for treating a vasculature-related disease such as stenosis or restenosis, or for treating a disease located at the surface of a vessel, such as a blood vessel or the esophagus.
  • the device of the present invention can also be used for treating tumors or cancer, such as esophagus tumors or cancer, for treating vein graft-induced diseases.
  • bioactive drug active drug
  • active drug active drug
  • immediatecament any compound able to stimulate or inhibit cellular events.
  • examples of such drugs are, without limitation, an anti- proliferative or anti-inflamatory drug, nitric oxide donor compounds, and proteins, DNA, and radionuclides able to stimulate/inhibit cellular events.
  • an anti-pr ⁇ liferative or anti-inflamatory drug is loaded into the membrane.
  • anti-proliferative drugs can include paclitaxel, sirolimus, tacrolimus, everolimus, dexamethasone, angiopeptin, somatostatin analogue, angiotensin converting enzyme inhibitors (Captopril, Cilazapril and Lisinopril), calcium channel blockers (Nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil, heparin, histamine antagonists, lovastatin, methotrexate, monoclonal antibodies (to PDGF receptors, etc.), nitroprusside, phosphodiesterase inhibitors, prostacyclin analogues, prostaglandin inhibitor, seramin (PDGF antagonist), serotonin blockers, steroids, thioprotease inhibitors, and triazolopyrimidine.
  • FGF fibroblast growth factor
  • Fig. 1 is a schematic representation of the CH-PEO membrane covered stent with or without external porous layer, in accordance with one embodiment of the invention
  • FIG. 2 illustrates an in vitro assay showing inhibition of platelet adhesion of CH-PEG membrane incubated in the presence of sodium nitroprusside.
  • Figs. 3A and 3B illustrate a macroscopic observation of the CH-PEO membrane covered stent showing the ability of the membrane to sustain a mechanical deformation following a compression (Fig. 3A) and the return to the original conformation (Fig. 3B) of a metallic stent;
  • FIGs. 4A to 4C illustrate scanning electron microscopic images of the membrane covered stent in which Fig. 4A represent an external view* of the stent showing the adhesion of the membrane to the metallic struts, Fig. 4B is a view of the inside of the membrane showing the stent-struts underlaying and Fig. 4C is a 450X enlarged view the box in Fig. 4A;
  • Fig. 5A illustrates the swelling behavior in PBS at pH 7.4 of the CH- PEO membrane (A), and of the CH-PEO porous membrane ( ⁇ ) in accordance with one embodiment of the present invention
  • Fig. 5B illustrates in an inlet of Fig. 5A the swelling behavior in PBS at pH 7.4 of the CH-PEO membrane ( ⁇ ) in comparison with the chitosan (CH) membrane of the prior art (•);
  • Fig. 6 illustrates 51 Cr-platelet adhesion (n>5) in an ex vivo porcine model on CH-PEO membrane of the present invention, damaged (Media) and intact arteries (Endo), * p ⁇ 0.05 vs. Media;
  • FIG. 7 illustrates 111 ln-leukocyte adhesion (n>5) in an ex vivo porcine model on CH-PEO membrane of the present invention, damaged (Media) and intact arteries (Endo), * p ⁇ 0.05 vs. Media;
  • FIG. 8 illustrates 111 ln-Platelet adhesion (n>4) after a 90 min incubation in platelet rich plasma (PRP) on chitosan (CH) and CH-PEO or heparin complexed-CH-PEO (CH-PEO-Hep) membranes, where damaged arteries (Media) were used as control, * p ⁇ 0.05 vs. Media, + p ⁇ 0.05vs. CH- PEO; and
  • Fig. 9 illustrates the Arginine release behavior in PBS of the CH-PEO membrane of the present invention, either following direct loading ( ⁇ ) or following precomplexation with anionic low molecular weight hyaluronic acid (LMW HA) (o).
  • ⁇ direct loading
  • LMW HA anionic low molecular weight hyaluronic acid
  • chitosan-PEO based biodegradable membrane covered devices such as stents.
  • the membrane covered devices described here are intended to be used in a wide range of application such as the treatment of aneurysm, the treatment of vascular graft diseases, malignant obstructive disease and tissue engineering applications.
  • the properties of the membrane were investigated in order to gain insight on its ability to be used in endovascular applications. Looking for vascular tissue engineering applications, an external porous membrane that could be used as a biodegradable scaffold was added.
  • the haemocompatibility of the devices was characterized both in an ex vivo porcine model and in vitro and optimized through complexation with heparin. Finally, the ability of the membrane to act as a drug reservoir was investigated using the peptide precursor of nitric oxide L-Arginine and the NO donor sodium nitroprusside (SNP).
  • CH-PEO film was synthesized as a film or used for the membrane covered stent.
  • Chitosan was dissolved in 0.1 M aqueous acetic acid (2% w/w) overnight and filtered to get ride of any insoluble material.
  • PEO dissolved in glacial acetic acid was then added to a ratio of CH/PEO: 70/30 by weight.
  • the mixture was then stirred for 4 h and then degassed.
  • a jelly-like solution was then obtained that was either poured in glass mold for characterization or used to prepare the membrane covered stent as described hereinafter.
  • the gel was allowed to dry at room temperature (to obtain the membrane of the present invention upon rehydration) or was freeze dried (to obtain the porous membrane of the present invention upon rehydration).
  • the dry material was then washed with aqueous 1 N NaOH to remove residual acid and finally thoroughly wash with ultrapure water.
  • Self-expandable stents made from NiTi alloy were mounted on a glass rod as schematized in Fig 1.
  • the glass rod could be rotated on its longitudinal axis at controlled speed (rpm).
  • a known amount (depending on the experiments, from 0.1g to few grams) of CH-PEO gel was then cast on the stent maintained in rotation. Controlling the rotation speed and as a function of the viscosity of the gel, a uniform layer of CH-PEO covered the stent in a controlled fashion. While maintained in rotation, the gel-covered stent was allowed to dry at room temperature. The dried membrane covering the stent was then neutralized as described above before removing the stent from the glass rod. The membrane-coated stent was then allowed to dry and was stored for characterization or further modifications.
  • Heparin is being used herein as a model for anionic polymers.
  • Heparin solution was prepared (1 mg/mL in water) and used to complex with CH-PEO film.
  • the CH-PEO film was immersed in the heparin solution for two hours at room temperature (RT) to allow the electrostatic interaction between heparin and CH to occur and then thoroughly rinsed with water.
  • RT room temperature
  • CH-PEO-Hep heparin complexed-CH-PEO-membrane
  • Membrane covered-stents were observed using SEM.
  • the devices were allowed to equilibrate in water and then freeze-dried.
  • the membranes were processed (i.e. cut) prior to metallization with an ultrathin sputter coated gold layer.
  • the samples were imaged using scanning electronic microscopy (SEM) at an accelerating voltage of 5 kV.
  • the porosity of the membrane has been characterized by complex permitivity measurements using a vector network analyzer (Model PNA 8358, Agilent Technologies) and a dielectric probe (85070C, Agilent Technologies).
  • the water permeation and burst strength of the membrane covered stent was determined in PBS as previously described (Berglund JD, et al., Biomaterials; 24:1241-1254, 2003).
  • the devices were hydrated for 30 min and completely crushed 5 times to simulate extensive manipulations. They were then cannulated with surgical sutures on semi-rigid silastic tubes at both sides.
  • Water permeability is defined here as the amount of saline solution leaked per unit area and time under a physiologic pressure of 120 mm Hg.
  • the burst pressure was characterized by pressurizing the device with an increasing hydrostatic liquid pressure (20 mmHg incremental steps) until membrane failure.
  • Radiolabeled platelets and leukocytes were re-injected into the animals one hour before the beginning of the experiments.
  • CH-PEO mixture was cast on glass slide, dried, rinsed with NaOH and water and finally allowed to dry and stored.
  • Intact endothelium and injured arterial segments were used as respectively thromboresistant and thrombogenic control (Gold B, et al., Biomaterials; 23: 2997-3005, 2002).
  • To simulate damaged arteries intima denuded artery were prepared as followed. Normal porcine aortas were first dissected and then cut into rings, longitudinally opened and cut into segments. The aortic media was then exposed by lifting and peeling off the intima and the adventia together with a thin portion of the subjacent media. The segments were then cut to appropriate size using a cutting device.
  • Such aortic media segments were shown in previous experiments to be very thrombogenic and closely simulate angioplasty damaged arteries.
  • the samples were hydrated in saline at least 30 min prior to the experiments and then placed in the perfusion chamber.
  • the perfusion procedure was initiated by a 1 min saline wash.
  • the blood was then allowed to circulate into the extracorporeal circuit for 15 min at a wall shear rate of 424 sec "1 .
  • the circuit was then flushed with saline for 30 sec and the samples recovered and fixed in 1.5% glutaraldehyde in gamma-counter vials.
  • the amount of radioactivity was then measured and calculated for background, decay and overlapping of the radionuclides.
  • the total amount of platelets and leukocytes adsorbed on the surface was calculated knowing the activity of blood samples used as reference and using hematology achieved prior to each experiment.
  • the samples were placed into the bottom of a 96 well polystyrene plate (Corning Inc.). 250 ⁇ of freshly prepared 111 ln-platelet solution was then added to each well taking special care that both sides of the samples were in contact with platelet solution. The platelet adhesion was allowed to proceed for 90 min with gentle shaking. After incubation, the samples were recovered and washed 4 times with saline. The samples were then fixed in 1.5 % glutaraldehyde solution and the amount of platelet was determined using a gamma counter.
  • L-Arginine (Arg) the precursor of nitric oxide (NO) has been used in the present invention as a model drugs. Arginine has been shown to reduce clinical restenosis when locally delivered through a NO mediated actions (Suzuki T, et al., Am J Cardiol; 89:363-367, 2002).
  • the cationic drug has been either loaded directly in the membrane or precomplexed with anionic low molecular weight hyaluronic acid (LMW HA)(as a plasticizer polysaccharide). The complexation of the cationic drug with the plasticizer polysaccharide was expected to delay its release and to minimize drug lost during the washing procedures of the membrane.
  • LMW HA anionic low molecular weight hyaluronic acid
  • CH-PEO mixture was prepared as described above.
  • a stock solution of unlabeled Arg/[ 3 H] Arg was prepared in water (10 "3 M with 2 ⁇ L [ 3 H] Arg/mL).
  • L-Arginine was added to 2 g of the CH-PEO mixture to a final concentration of wt. 0.2 %.
  • LMW HA solubilized in water (1 mg/mL) was mixed with 100 ⁇ L of the Arg solution (COOH/Arg molar ratio: 5:1 ) and allowed to complex for 1 h. 260 ⁇ L of this . mixture was then added to 2 g of the CH-PEO solution.
  • the GH-PEO/Arg mixture with or without LMW HA was left under agitation for 2 h and then poured in polystyrene wells.
  • the membranes were allowed to dry and then neutralized for 2 min with 750 ⁇ L NaOH 1 M and rinsed twice with 1 mL water (2 min each).
  • the rinsing solutions were kept for quantification of Arg released during the washing steps.
  • the method described here to obtain the chitosan membrane-covered stent is reliable and reproducible. Once allowed to dry overnight and then neutralized with NaOH and rinsed with water, the device could be easily recovered from the holder without any damaged. Macroscopic observations showed that a thin membrane uniformly covered the whole stents as shown in Figs. 3A and 3B. Experiments have shown that the thickness of the membrane could be easily controlled by changing the viscosity of the chitosan mixture and to a lesser extent by controlling the speed of rotation of the glass holder. The thickness of a one-layer CH-PEO membrane was in the range of 100 ⁇ m.
  • a stent was dilated and then quickly freeze-dried using liquid nitrogen.
  • the lyophilized sample was then gold coated for SEM observations. Using low magnification, it was noted that the membrane conserved its integrity and remained firmly attached to the metallic structure (Figs. 4A to 4C). The luminal surface of the membrane was relatively smooth despite "waves".
  • the water permeation at 120 mm Hg was determined to be less than 1 mL/cm 2 min "1 . No significant linkage of the membrane was observed when the device was pressurized at 120 mm Hg for 30 min.
  • the burst pressure resistance of the 4 tested membrane-covered stents was determined to be higher than 500 mm Hg but the apparatus used in this work did not allow us to pressurize the membrane high enough to its failure.
  • An external membrane could be added to the device as described herein with a mean porosity of about 95%.
  • the thromboresistance of the CH-PEO membrane was investigated in an ex vivo porcine assays using radiolabeled platelets and leukocytes. Under the physiological flow conditions used in the study, the CH-PEO presented low amounts of platelet adhesion in comparison to damaged arteries (P ⁇ 0.05). Similar results were obtained with leukocytes (P ⁇ 0.005). Both platelet and leukocyte adhesion onto CH-PEG was in the same range as that on arteries with an intact endothelial layer (Figs. 6 and 7). [0055] The effect of PEO and heparin complexation on the haemocompatibility was investigated in the in vitro assays.
  • the present invention describes the development of chitosan-based biodegradable membrane covered endovascular devices such as stents.
  • the main finding was that metallic stent could be covered by a chitosan-based membrane displaying suitable properties for endoluminal implantation.
  • such membrane should (1 ) be able to sustain the deformation during the endoluminal expansion of the stent; (2) not elicit extensive biological response; (3) be thromboresistant; (4) allowed cellular ingrowths both at the luminal and external surfaces and (5) be able to resists physiological blood pressure.
  • stents/membrane-covered stents are widely used in the treatment of obstructive/degenerative pathologies such as coronary and peripheral artery diseases, aneurysm, ruptures and fistulas. They are also investigated in non- vascular malignant diseases in urology or gastroenterology for instance.
  • obstructive/degenerative pathologies such as coronary and peripheral artery diseases, aneurysm, ruptures and fistulas. They are also investigated in non- vascular malignant diseases in urology or gastroenterology for instance.
  • the most straightforward applications of membrane-covered stents are currently the endoluminal exclusion of aneurysm and the revascularization of vein graft.
  • the excellent mechanical properties of the chitosan-PEO blend allowed the hydrated device to be completely crushed on a catheter without noticeable damages to the membrane upon redeployment.
  • the membrane covered stent could be loaded onto a delivery catheter and expanded through the self-expanding properties of the supporting metallic stents.
  • Assays have investigated the use of reticulated membranes, using glyoxal or glutaraldehyde, or chitosan alone but these membranes failed to sustain the elastic deformation required during expansion.
  • the blend of chitosan with high molecular weight PEO have been shown to drastically improve the elasticity and strength of chitosan (Kolhe P, and Kannan RM.
  • chitosan is well-known biocompatible biodegradable materials.
  • chitosan is currently widely investigated as wound dressing material, drug delivery vehicle and tissue engineering scaffold (Rao SB, and Sharma CP., J Biomed Mater Res; 34:21-28, 1997; and Madihally SV, and Matthew HW., Biomaterials; 20: 1133-1142, 1999) .
  • Chitosan supports cell attachment and growth and has been successfully investigated in vascular tissue engineering applications (Chupa JM, et al., Biomaterials; 21 :2315-2322, 2000).
  • chitosan supports the attachment and growth of endothelial cells which may in turn enhanced the mid-term biocompatibility of the device.
  • Acute blood compatibility of chitosan have however been reported to be an issue with reported ability of the polymer to activate both complement and blood coagulation systems.
  • a recent exhaustive investigation of the blood compatibility of chitosan has however showed that despite large adsorption of plasma proteins, the polymer was a weak activators of the alternative pathway of the complement and intrinsic pathway of coagulation (Benesch J,' and Tengvall P., Biomaterials; 23:2561-2568, 2002).
  • CH-PEO membranes were tested in an ex Vo extracorporeal porcine model using radiolabeled platelets and leukocytes. Amount of adsorbed platelets and leukocytes were low and in the same range than those measured on intact aortic segments used a negative control. Both values were significantly lower than the damaged artery model used as positive control. Endothelial denuded arteries have been previously used to simulate angioplasty-damaged blood vessels. To get further insight of the haemocompatibility of the CH-PEO membrane, an in vitro assay was used to compare the platelet adhesion on CH-PEO membrane with chitosan alone and heparin complexed CH-PEO membrane.
  • chitosan tends to reduce the adhesion of platelets. This may be related to the hydrophilicity of PEO that may decrease non-specific adhesion.
  • a further improvement was observed upon surface complexation with heparin.
  • Complexation of chitosan with anionic polysaccharide such as heparin has been widely used to improve its thromboresistance.
  • electrostatic complexation with glucosaminoglycans (GAGs) such as hyaluronic acid or heparin has been reported to modulate its biological activity (Chupa JM, et al., Biomaterials; 21 :2315-2322, 2000).
  • GAGs glucosaminoglycans
  • Complex of chitosan and heparin have also recently been reported to enhance wound healing (Kweon DK, et al., Biomaterials; 24:1595-1601 , 2003).
  • chitosan has been investigated in therapies directed against cancer or hyperproliferative vascular disease using drugs such as doxorubicin or paclitaxel (Mitra S, et al., J Control Release; 74:317-323, 2001 ; and Nsereko S, and Amiji M., Biomaterials; 23:2723-2731 , 2002;).
  • drugs such as doxorubicin or paclitaxel
  • the loading and delivery of the NO-precursor L-Arginine was investigated in the present application.
  • Arginine is a low molecular weight cationic drug that has been proved to be effective in the reduction of neointimal hyperplasia (Suzuki T, et al., Am J Cardiol; 89:363-367, 2002; and Kalinowski M, et al., Radiology; 219:716-723, 2001).
  • the release behavior presented in Fig. 9 shows an initial burst release with small amount of the drug being released after 1 h. Importantly, a significant amount (86.4 %) of the drug was lost during the neutralization and washing procedures. The possibility to control the release behavior by precomplexation of the cationic drug with the plasticizer low molecular weight hyaluronic acid (LMW HA) was thus investigated.
  • LMW HA plasticizer low molecular weight hyaluronic acid
  • the membrane-covered device was initially designed for the treatment of occlusive diseases and vein graft stenoses, its potential use in the setting of endovascular aneurysm closure is also considered as a promising application in the present invention.
  • the possibility to exclude the aneurysm by the chitosan-based membrane as well as the potential for local delivery of biologically active components such as growth factors are appealing.
  • the CH- PEO membrane acts as a temporary barrier while being used as a template for arterial reconstruction.
  • Organization of the blood thrombi into connective tissue may be expected to solve the issue of endoleak that plague endovascular aneurysm exclusion. Such organization is enhanced by the presence of the chitosan based membrane and further accelerated by incorporation of appropriate growth factors.
  • Hybrid graft using dacron sleeves combined with collagen-based construct have been proposed to assure enough burst resistance for in vivo implantation (Berglund JD, et al., Biomaterials; 24:1241-1254, 2003; and Xue L, and Greisler HP., J Vase Surg; 37:472-480, 2003;).
  • the presence of synthetic sleeves may however be damageable for the long term success of the graft.
  • graft made completely from biodegradable polymers required lengthy in vitro tissue formation to display appropriate mechanical properties for implantation.
  • a hybrid device conjugating the mechanical scaffold of the metallic device and the biodegradable chitosan-based porous matrix open new opportunities in this field.
  • Metallic stents do not elicit intensive biological reactions such as those commonly observed with polymeric synthetic materials.
  • the metallic component of the hybrid construct can provide the necessary mechanical strength, at least at the acute phase of the tissue organization, while minimizing the amount of non-biodegradable material within the artery in comparison to synthetic polymeric sleeves.
  • cell ingrowths naturally occurring in chitosan matrix could be easily enhanced by incorporation of growth factors in the chitosan-based membrane (Lee JY, et al., J Control Release; 78 : 187-197, 2002).

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  • Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Vascular Medicine (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention se rapporte à des implants médicaux du type endoprothèses vasculaires, qui peuvent être recouverts d'une membrane biodégradable contenant ou non un ingrédient ou médicament actif, ainsi qu'à leur procédé de préparation et à leur utilisation. La présente invention se rapporte à un dispositif endovasculaire recouvert d'une membrane biodégradable. Ce dispositif est enduit d'une solution comportant du chitosane ainsi qu'un plastifiant ou un agent de réticulation du chitosane, et lorsque la solution sèche sur le dispositif, elle forme lors de sa réhydratation une membrane polymère souple sur ledit dispositif, ou lorsqu'elle est lyophilisée sur le dispositif, elle forme lors de sa réhydratation une membrane polymère souple poreuse.
PCT/CA2004/000906 2003-06-20 2004-06-18 Implant recouvert d'une membrane biodegradable comportant du chitosane WO2004112863A1 (fr)

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WO2006031398A3 (fr) * 2004-09-10 2006-07-27 Advanced Cardiovascular System Compositions renfermant des plastifiants a lixiviation rapide et permettant d'ameliorer les performances de dispositifs medicaux
WO2007142738A3 (fr) * 2006-05-31 2008-03-20 Abbott Cardiovascular Systems Couches de revêtement pour dispositifs médicaux et procédés de fabrication de celles-ci
WO2007149539A3 (fr) * 2006-06-21 2008-04-03 Abbott Cardiovascular Systems Procédé de congélation-décongélation visant à modifier un revêtement de stent
WO2008141495A1 (fr) * 2007-05-23 2008-11-27 Lepu Medical Technology (Beijing) Co., Ltd. Procédé de fixation d'anticorps sur la surface d'un instrument médical
WO2007015761A3 (fr) * 2005-07-21 2009-04-16 Fmc Biopolymer As Dispositifs medicaux revetus d'un revetement biocompatible a dissolution rapide
CN101703813B (zh) * 2009-11-25 2012-11-28 南开大学 利用内源性no供体构建抗凝血性血管支架材料的方法
US8834912B2 (en) 2005-12-30 2014-09-16 Boston Scientific Scimed, Inc. Medical devices having multiple charged layers
US9038260B2 (en) 2006-05-26 2015-05-26 Abbott Cardiovascular Systems Inc. Stent with radiopaque markers
US9198785B2 (en) 2010-01-30 2015-12-01 Abbott Cardiovascular Systems Inc. Crush recoverable polymer scaffolds
US9381280B2 (en) 2014-06-13 2016-07-05 Abbott Cardiovascular Systems Inc. Plasticizers for a biodegradable scaffolding and methods of forming same
US9532888B2 (en) 2006-01-04 2017-01-03 Abbott Cardiovascular Systems Inc. Stents with radiopaque markers
US9827119B2 (en) 2010-01-30 2017-11-28 Abbott Cardiovascular Systems Inc. Polymer scaffolds having a low crossing profile
EP3238752A4 (fr) * 2014-12-25 2017-12-20 Dongguan Dianfu Product Design Co., Ltd. Endoprothèse cardiovasculaire extensible ayant une membrane de revêtement de collagène
US9999754B2 (en) 2014-12-09 2018-06-19 Gyrus Acmi, Inc. Delivery method for biodegradable stents
US9999527B2 (en) 2015-02-11 2018-06-19 Abbott Cardiovascular Systems Inc. Scaffolds having radiopaque markers
US10307274B2 (en) 2011-07-29 2019-06-04 Abbott Cardiovascular Systems Inc. Methods for uniform crimping and deployment of a polymer scaffold
US10610387B2 (en) 2015-06-12 2020-04-07 Abbott Cardiovascular Systems Inc. Scaffolds having a radiopaque marker and methods for attaching a marker to a scaffold
CN111035813A (zh) * 2018-10-15 2020-04-21 复旦大学附属中山医院 一种液体创可贴式冠脉带膜支架及其制作方法
RU2730531C1 (ru) * 2019-12-19 2020-08-24 Федеральное государственное бюджетное учреждение науки Институт металлургии и материаловедения им. А.А. Байкова Российской академии наук (ИМЕТ РАН) Способ получения композиционного материала "Ti-Nb-Ta-Zr - полигликолидлактид с введенным лекарственным препаратом"
CN112713339A (zh) * 2020-12-07 2021-04-27 乐凯胶片股份有限公司 铝塑软包装膜、制备方法以及软包电池
WO2021243796A1 (fr) * 2020-06-04 2021-12-09 青岛大学 Nouveau matériau d'endoprothèse vasculaire à nanofibres présentant des fonctions de double charge de médicament et de libération lente échelonnée et son procédé de préparation
CN114716582A (zh) * 2022-04-07 2022-07-08 洛阳师范学院 一种角蛋白肽修饰的壳聚糖衍生物及其制备方法、应用和药物组合物
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5885609A (en) * 1997-05-23 1999-03-23 Northeastern University Biocompatible articles and method for making same
US5904927A (en) * 1997-03-14 1999-05-18 Northeastern University Drug delivery using pH-sensitive semi-interpenetrating network hydrogels
WO2000071136A1 (fr) * 1999-05-20 2000-11-30 Chitogenics, Inc. Revetements n,o-carboxymethylchitosane adhesifs inhibant la fixation de cellules et de proteines a des substrats
WO2003020771A1 (fr) * 2001-08-31 2003-03-13 Mucobiomer Biotechnologische Forschungs- Und Entwicklungs Gesmbh Conjugues de chitosane-thio-amidine et utilisation cosmetique et pharmaceutique de ces conjugues
US20030065377A1 (en) * 2001-09-28 2003-04-03 Davila Luis A. Coated medical devices
WO2003037219A2 (fr) * 2001-10-30 2003-05-08 Alvito Biotechnologie Gmbh Utilisation de produits a base de chitosan
WO2004012676A2 (fr) * 2002-08-02 2004-02-12 Gp Medical Materiau biologique charge de medicament traite chimiquement par la genipine

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5904927A (en) * 1997-03-14 1999-05-18 Northeastern University Drug delivery using pH-sensitive semi-interpenetrating network hydrogels
US5885609A (en) * 1997-05-23 1999-03-23 Northeastern University Biocompatible articles and method for making same
WO2000071136A1 (fr) * 1999-05-20 2000-11-30 Chitogenics, Inc. Revetements n,o-carboxymethylchitosane adhesifs inhibant la fixation de cellules et de proteines a des substrats
WO2003020771A1 (fr) * 2001-08-31 2003-03-13 Mucobiomer Biotechnologische Forschungs- Und Entwicklungs Gesmbh Conjugues de chitosane-thio-amidine et utilisation cosmetique et pharmaceutique de ces conjugues
US20030065377A1 (en) * 2001-09-28 2003-04-03 Davila Luis A. Coated medical devices
WO2003037219A2 (fr) * 2001-10-30 2003-05-08 Alvito Biotechnologie Gmbh Utilisation de produits a base de chitosan
WO2004012676A2 (fr) * 2002-08-02 2004-02-12 Gp Medical Materiau biologique charge de medicament traite chimiquement par la genipine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BRIEGER DAVID ET AL: "Local drug delivery systems and prevention of restenosis", CARDIOVASCULAR RESEARCH, XX, XX, vol. 35, no. 3, 1997, pages 405 - 413, XP002202664, ISSN: 0008-6363 *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7229471B2 (en) 2004-09-10 2007-06-12 Advanced Cardiovascular Systems, Inc. Compositions containing fast-leaching plasticizers for improved performance of medical devices
WO2006031398A3 (fr) * 2004-09-10 2006-07-27 Advanced Cardiovascular System Compositions renfermant des plastifiants a lixiviation rapide et permettant d'ameliorer les performances de dispositifs medicaux
WO2007015761A3 (fr) * 2005-07-21 2009-04-16 Fmc Biopolymer As Dispositifs medicaux revetus d'un revetement biocompatible a dissolution rapide
US8257727B2 (en) 2005-07-21 2012-09-04 Fmc Biopolymer As Medical devices coated with a fast dissolving biocompatible coating
US8834912B2 (en) 2005-12-30 2014-09-16 Boston Scientific Scimed, Inc. Medical devices having multiple charged layers
US9532888B2 (en) 2006-01-04 2017-01-03 Abbott Cardiovascular Systems Inc. Stents with radiopaque markers
US10070975B2 (en) 2006-01-04 2018-09-11 Abbott Cardiovascular Systems Inc. Stents with radiopaque markers
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US9694116B2 (en) 2006-05-26 2017-07-04 Abbott Cardiovascular Systems Inc. Stents with radiopaque markers
US9038260B2 (en) 2006-05-26 2015-05-26 Abbott Cardiovascular Systems Inc. Stent with radiopaque markers
US9180227B2 (en) 2006-05-31 2015-11-10 Advanced Cardiovascular Systems, Inc. Coating layers for medical devices and method of making the same
US8828418B2 (en) 2006-05-31 2014-09-09 Advanced Cardiovascular Systems, Inc. Methods of forming coating layers for medical devices utilizing flash vaporization
WO2007142738A3 (fr) * 2006-05-31 2008-03-20 Abbott Cardiovascular Systems Couches de revêtement pour dispositifs médicaux et procédés de fabrication de celles-ci
US8715707B2 (en) 2006-06-21 2014-05-06 Advanced Cardiovascular Systems, Inc. Freeze-thaw method for modifying stent coating
US8246973B2 (en) 2006-06-21 2012-08-21 Advanced Cardiovascular Systems, Inc. Freeze-thaw method for modifying stent coating
WO2007149539A3 (fr) * 2006-06-21 2008-04-03 Abbott Cardiovascular Systems Procédé de congélation-décongélation visant à modifier un revêtement de stent
US8361536B2 (en) 2007-05-23 2013-01-29 Lepu Medical Technology (Beijing) Co., Ltd. Method for fixing antibody on the surface of medical instrument
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WO2008141495A1 (fr) * 2007-05-23 2008-11-27 Lepu Medical Technology (Beijing) Co., Ltd. Procédé de fixation d'anticorps sur la surface d'un instrument médical
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US10123894B2 (en) 2010-01-30 2018-11-13 Abbott Cardiovascular Systems Inc. Method of crimping stent on catheter delivery assembly
US9198785B2 (en) 2010-01-30 2015-12-01 Abbott Cardiovascular Systems Inc. Crush recoverable polymer scaffolds
US9763818B2 (en) 2010-01-30 2017-09-19 Abbott Cardiovascular Systems Inc. Method of crimping stent on catheter delivery assembly
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US11324614B2 (en) 2010-01-30 2022-05-10 Abbott Cardiovascular Systems Inc. Balloon expanded polymer stent
US9867728B2 (en) 2010-01-30 2018-01-16 Abbott Cardiovascular Systems Inc. Method of making a stent
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US9610387B2 (en) 2014-06-13 2017-04-04 Abbott Cardiovascular Systems Inc. Plasticizers for a biodegradable scaffolding and methods of forming same
US9999754B2 (en) 2014-12-09 2018-06-19 Gyrus Acmi, Inc. Delivery method for biodegradable stents
EP3238752A4 (fr) * 2014-12-25 2017-12-20 Dongguan Dianfu Product Design Co., Ltd. Endoprothèse cardiovasculaire extensible ayant une membrane de revêtement de collagène
US9999527B2 (en) 2015-02-11 2018-06-19 Abbott Cardiovascular Systems Inc. Scaffolds having radiopaque markers
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WO2021243796A1 (fr) * 2020-06-04 2021-12-09 青岛大学 Nouveau matériau d'endoprothèse vasculaire à nanofibres présentant des fonctions de double charge de médicament et de libération lente échelonnée et son procédé de préparation
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