THROMBORESISTANT SURFACE TREATMENT FOR BIOMATERIALS

Abstract: A biomaterial with a thromboresistant surface and a method for forming same are provided. The thromboresistant surface is comprised of a distinct coating layer of a chitosan-based membrane and a bioactive material. The bioactive material is capable of converting the chitosan membrane coating from a highly thrombogenic to an essentially non-thrombogenic one. The bioactive material can be a polymeric substance, such as polyvinyl alcohol, forming a polymeric blend with the chitosan, or, can be a biological substance, such as serum albumin, embedded in or attached to the chitosan membrane which has been activated with a treatment of glutardialdehyde. The thromboresistant biomaterial is suitable for use in vascular grafts having an inside diameter of less than 6 millimeters.

Description: THROMBORESISTANT SURFACE TREATMENT FOR BIOMATERIALS BACKGROUND OF THE INVENTION Field of the Invention The present invention generally relates to medical devices having a blood contacting surface which has thromboresistant properties, more particularly, the invention relates to the surface treatment of medical devices with a thromboresistant coating on the surface which is intended for contacting blood and other body fluids where said coating is composed of a chitosan-based membrane incorporating thromboresistant components affecting surface properties. Description of Related Art A well-recognized problem in the medical community is the development of a thrombus or blood clot or obstruction that forms when any number of devices are used either within the body or within systems wherein blood or other body fluids are contacted or circulated. Such devices include, for example, catheters, vascular grafts, cardiac pacemaker leads, replacement heart valves, sutures, angioplasty devices, and various blood diagnostic, treatment, and storage systems and may be composed of a variety of biomaterials, for example, metals, polymers, and rubbers. Of special interest are the approximately 350,000 small vessel bypass grafts performed annually in the United States. The saphenous vein is the choice for small vessel replacement but involves many possible limitations and complications; for example, adequate saphenous vein may not be available due to disease or previous usage. Prosthe grafts made of expanded polytetrafluoroethylene (ePTFE) or Dacron have been used qui successfully for large vessel replacement but almost uniformly fail when used in sizes of le than 6 mm internal diameters. Callow, A.D.. Current Status of Vascular Grafts. Surg. Cli No. Amer. 65, 501 (1982). There is an urgent need for the development of a small vascul prosthesis (about 3-4 mm inside diameter) that exhibit thromboresistance for use in dist extremity bypasses, coronary artery bypasses, and a variety of other vascular acce procedures. The host response to biomaterials at the cellular and molecular level complex. For example see, Implantation Biology, The Host Response and Biomedical Devic (Greco, R.S. ed. 1994). The composition of the biomaterial surface appears to play important role in thrombosis. Thrombosis is initiated by the adsorption of plasma protei on the biomaterial surface. This adsorption results from, and is dependent upon, t physical and chemical properties of the biomaterial surface. For example, Dacron has be shown to have a greater effect on platelet activation than ePTFE, while ePTFE is kno to be a stronger stimulator of fibrous hyperplasia. Deposition of plasma proteins on t biomaterial surface mediates platelet adhesion via platelet surface receptors. Surfa morphology and chemical characteristics, for example, smoothness and hydrophilicity, ha been shown to enhance low plasma protein adsorptive properties. As a consequence of t decrease in plasma proteins deposited on the surface, less adhesive matrix proteins will available to mediate platelet binding and activation on the surfaces, thus leading to reduc surface-initiated thrombosis. A variety of approaches have been attempted to increase the thromboresistance of these surfaces. These approaches include the bonding of heparin, albumin, or polyurethanes to the surface, the seeding of endothelial cells onto the surface, and the pretreatment of platelets with adhesion receptor specific monoclonal antibodies. All of these approaches, however, have had limited success. The known practice of graft polymerization of monomers onto the substrate to form thromboresistant polymers on the surface of biomaterials has several drawbacks. Graft polymerization can affect the original chemical structure of the coated biomaterial and has the danger of toxic low molecular residues of the toxic monomers, as discussed in U.S. Patents No. 4,978,481 to Janssen et al. and 4,311,573 to Mayhan et al. The grafting process can be complicated and expensive, e.g., requiring elaborate chemical treatment of the substrate. For example, United States Patent No. 5,053,048 to Pinchuk teaches the pretreatment of a substrate before grafting a polymer; in U. S. Patent No. 4,978,481 the substrate is pre-treated with ozone before grafting the monomer; and in U. S. Patent No. 4,311,573 the substrate is pre-treated with ozonization or high energy ionizing radiation before the graft polymerization. An alternative approach to graft polymerization which is based on absorption of biopolymers has been described. Malett, et al, Chitosan: A New Hemostatic, Annals of Thoracic Surgery, 36, 55 (1983) examined the effect of soaking large diameter Dacron vascular grafts in an acidic chitosan solution, a deacetylated derivative of arthropod chitin, as related to the leakage of these grafts. Examination of these grafts at 24 hours reveale no rebleeding. The data establishes that chitosan has thrombogenic properties whic induced clot formation rendering the vascular grafts impermeable to blood. Simila thrombogenic properties of chitosan were reported by van der Lei, et al., Improved Healin of Microv oscular PTFE Prostheses by Induction of a Clot Layer: An Experimental study in Rats Plastic and Reconstructive Surgery, 84, 960 (1989). In their study ePTFE grafts soaked i a diluted acidic chitosan solution that were implanted into rats were covered with a clo layer, indicative of a highly thrombogenic surface. Both studies demonstrate th thrombogenic properties of chitosan as exhibited by the molecular adsorption of chitosa on the surface of the grafts employed. Neither study reported that the adsorbed chitosa solution formed a distinct coating layer. In contrast to chitosan's thrombogenic properties, polyvinylalcohol (PVA) ha been reported to exhibit non-thrombogenic properties. Miyake et al., New Small-Calibe Antithrombotic Vascular Prosthesis: Experimental Study, Microsurgery, 5, 144 (1984), reporte that tubes made of polyvinylalcohol were non-thrombogenic. These tubes, however, wer not suitable for anastomosis since they were not durable enough to withstand tearing b suture. What is needed is a biomaterial with a non-thrombogenic surface suitable fo use in vascular grafts having an inside diameter of less than 6 millimeters and a inexpensive, efficient means for providing consistent non-thrombogenic properties to th surface of the biomaterial. The present invention provides a biomaterial with a thromboresistant coating, and a method for preparing same. The features and advantages of this invention will be clearly understood through a consideration of the following description. SUMMARY OF THE INVENTION The present invention pertains to the surface treatment of biomaterials for use in medical devices which provides a non-thrombogenic surface as a result of a surface coating with a chitosan-based membrane. The construction of a non-thrombogenic chitosan- based membrane is affected by contacting the biomaterial surfaces with mixtures comprising acidic chitosan solutions, polymer solutions, and non-ionic detergents. Following a stabilization treatment by air drying or cross-linking, the adsorbed film forms a stable membrane that affects both the morphology and the chemical characteristics of the biomaterial surface. Coated biomaterials obtained using this process exhibit a smoother surface and strong structural morphology with improved chemical surface characteristics resulting in a significant decrease in platelet binding to the surface. This effect may be further improved by bioactive agents that may be embedded in the complex or bound to activated sites on the chitosan membrane. BRIEF DESCRIP ION OF THE DRAWINGS Figure 1 is a cross-sectional view of an illustration of a vascular graft with a thromboresistant surface of the present invention. Figure 2 is a cross-sectional view of an illustration of a vascular graft wit another embodiment of the thromboresistant surface of the present invention. DETAILED DESCRIPTION OF THE INVENTION The present invention produces medical devices which are composed o biomaterials having a thromboresistant surface. The thromboresistant properties ar provided by a distinct coating layer applied to the surface which comprises a chitosan-base membrane and biologically and/or chemically active materials. The active materials can b incorporated into the chitosan-based membrane and/or bound onto the surface of activate chitosan in the coating layer. The characteristics of the resulting coating and the method of forming th coating make possible thromboresistant medical devices which could not be manufacture with other coatings and/or methods. For example, vascular grafts with an inside diamete of less than 6 millimeters may now be effectively used and consistently manufactured havin a thromboresistant surface according to the present invention. The process for applying the thromboresistant coating to the biomateria surface comprises the steps of: 1. Preparing a coating solution comprising a sterile aqueous solution of chitosa with any necessary additives such as hydrophilic polymers, surfactants PCMJS95/11646 stabilizers, buffers, catalysts, and cross-linking agents. 2. The surface of the biomaterial is coated with the coating solution, for example, by pumping or by dipping; any excess solution is removed by draining. 3. The adsorbed solution is cured either by air or gas drying or by chemical cross-linking, using a cross-linking agent in an aqueous solution. 4. If desired, biologically active reagents, such as surfactants, antithrombotic agents, antibiotics or antibodies may be entrapped within the chitosan-based membrane during the initial coating formation or bonded and immobilized to its surface at activated sites on the chitosan after the initial coating formation. The biomaterials which can be coated include polytetrafluoroethylenes, polyamides, polyesters, polyurethanes, polythiloxines, polyolifins, Dacron, silicone rubber, polyvinyl chlorides, copolymers, metals, and the like. These biomaterials are commonly used in medical devices and protheses including catheters, vascular grafts, cardiac pacemakers, pacemaker leads, heart diaphragms, heart valves, sutures, needles, angioplasty devices, tubing, dialysis membranes, filters and other artificial implants and machines. Chitosan is a natural polysaccharide which is soluble in acidic aqueous solutions (pH less than 5.5) and becomes insoluble at physiological pH, with a general structure resembling cellulose. Preferred chitosan concentrations range from about 0.5 - 3% (w/v). The construction of a chitosan-based membrane on certain biomaterials (f example, ePTFE) may require the incorporation of suitable additives, for example, a no ionic detergent such as Triton X-100; without which, the chitosan coating solution would repelled from the ePTFE surface. Due to the presence of free amino groups on t chitosan, it may be readily chemically activated for the chemical binding of bioacti molecules. Preferred polymer solutions are comprised of about 1 - 5% (w/v) polyvin alcohol (PVA) having a molecular weight between about 10,000 to about 125,000. PV containing coatings are preferably prepared with aqueous solutions and cured by air dryin A preferred embodiment of the coating is a complex of chitosan and polyvin alcohol (PVA). The PVA is incorporated into the chitosan-based membrane forming polymer blend. The coating solution for such a chitosan-PVA coating is prepared by addi a PVA solution to the chitosan solution with a chitosamPVA ratio in the range of about 9 to about 1:1. The resulting coating layer unexpectedly exhibits essentially only the desirab qualities of the individual components. The chitosan provides a stable structural base f the incorporation of the PVA. The chitosan-PVA coating exhibits both the strong structur qualities of a chitosan membrane and the thromboresistant qualities of a PVA surfac These chitosan-PVA coatings exhibit none of the thrombogenic properties of chitosan a are significantly more strong and more stable than plain PVA coatings. A second preferred embodiment of a chitosan-based coating is comprised a chitosan-based membrane and further comprising one or more bioactive materials, f example antithrombotic agents, antibiotics or antibodies, attached to the chitosan layer at sites which have been activated, for example by glutardialdehyde. The biologically active molecules can also be similarly bound to the thromboresistant chitosan-PVA coatings above. A preferred embodiment of a medical device incorporating the thromboresistant biomaterial is illustrated in figure 1 in the form of a vascular graft 1 used for small vessel bypass grafts comprising a section of vascular tubing 2, preferably made of Dacron or ePTFE, having an inside diameter of less than 6 mm, preferably less than 4 mm. On the inner surface of the tubing 4 is a thromboresistant coating 6 comprised of a chitosan- PVA blend. Another preferred embodiment of a medical device incorporating the thromboresistant biomaterial is illustrated in figure 2 in the form of a vascular graft 10 used for small vessel bypass grafts comprising a section of vascular tubing 12, preferably made of Dacron or ePTFE, having an inside diameter of less than 6 mm, preferably less than 4 mm. On the inner surface of the tubing 14 is a thromboresistant coating 16 comprised of a chitosan membrane 18 with a bonded layer of biologically active molecules 20. The invention is further and more specifically illustrated by the following examples and tests. EXAMPLE 1 Biomaterials with a thromboresistant coating of PVA were prepared as follows: Preparation of PVA solution A 5% (w/v) polymer solution was prepared by stirring 2.5 grams PVA (BD Cat. No. 2979) in 50 mLs of warm distilled water. Similar polymer solutions were prepare at concentrations of 0.5%, 1%, and 2.5% (w/v). Biomaterial Discs Discs, 6 millimeters in diameter, were prepared by cutting ePTF cardiovascular straight graft tubes (regular wall tubes, 8 millimeters in diameter Impr Tempa, AT., USA). Discs were gradually dipped in the 5% (w/v) PVA solution. The disc were removed and excess solution was carefully drained. The coated discs were allowed t dry overnight at room temperature. Additional discs were prepared by independentl dipping discs in PVA solutions of differing concentrations of 0.5, 1, and 2.5% (w/v). EXAMPLE 2 Biomaterials with a thromboresistant coating of a chitosan-PVA coating wer prepared as follows. Preparation of PVA solution A 5% (w/v) polymer solution was prepared by stirring 2.5 grams PVA (BD Cat. No. 2979) in 50 mLs of warm distilled water. Similar polymer solutions were prepare at concentrations of 0.5%, 1%, and 2.5% (w/v). Preparation of Chitosan Solution A 3% (w/v) chitosan solution in 1% (v/v) acetic acid was prepared b suspending three grams of chitosan (70,000 MW Fluka CAT. No. 22741) in 99 mLs of wate with magnetic stirring for 15 minutes. One mL of glacial acetic acid was then added and mixing continued for 16 hours at room temperature. Preparation of coating solution A solution for the preparation of a chitosan-PVA coating containing 1.2% (w/v) chitosan and 0.6% (w/v) PVA was prepared by mixing 4 volumes of 3% chitosan solution with 1.2 volumes of 5% PVA solution. To this solution was added one volume of a 1% (v/v) Triton X-100 (BDH, CAT. No. 30632) and 3.8 volumes of 1% acetic acid. A second solution for the preparation of a chitosan-PVA coating containing 0.6% (w/v) chitosan and 0.3% (w/v) PVA was prepared by mixing 2 volumes of 3% chitosan solution with 0.6 volumes of 5% PVA solution. To this solution was added 1 volume of a 1% (v/v) Triton X-100 (BDH, CAT. No. 30632) and 6.4 volumes of 1% acetic acid. Solutions for the preparation of chitosan coatings containing 0.6% (w/v) chitosan and 1.2% (w/v) chitosan were prepared by mixing 4 or 2 volumes of 3% (w/v) chitosan solution with 5 or 7 volumes of 1.0% acetic acid, respecxtively, with 1 volume 1% (v/v) Triton X-100 (BDH, CAT. No. 30632). Biomaterial Discs Discs, 6 millimeters in diameter, were prepared by cutting ePTFE cardiovascular straight graft tubes (regular wall tubes, 8 millimeters in diameter Impra, Tempa, AT., USA). Discs were gradually dipped, independently, in either of the chitosan-PVA solutions or chitosan solutions prepared above. The discs were removed and the excess solution was carefully drained. The coated discs were allowed to dry overnig at room temperature. EXAMPLE 3 Biomaterials with a thromboresistant coating of a Activated Chitosan/Human Seru Albumin coating were prepared as follows. Preparation of Chitosan Solution A 3% (w/v) chitosan solution in 1% (v/v) acetic acid was prepared suspending three grams of chitosan (70,000 MW Fluka CAT. No. 22741) in 99 mLs of wat with magnetic stirring for 15 minutes. One mL of glacial acetic acidic was then added an mixing continued for 16 hours at room temperature. Preparation of chitosan and glutardialdehyde solutions A diluted chitosan solution (0.6% (w/v)) was prepared by mixing one volu of 3% (w/v) chitosan solution with 4 volumes of 1.0% acetic acid. A 1% (v/v) solution glutardialdehyde to be used for the activation of a chitosan coating was prepared by mixi one volume of 25% (v/v) glutardialdehyde solution (Merck, CAT. No. 4239) with 2 volumes of standard phosphate buffered saline (PBS) buffer. Activated Chitosan/Biomaterial Discs Discs, 6 millimeters in diameter, were prepared by cutting ePTF cardiovascular straight graft tubes (regular wall tubes, 8 millimeters in diameter Impr Tempa, AT., USA). Discs were gradually dipped in the 0.6% (w/v) chitosan solutio prepared above. A number of the discs were activated (next step) while still wet. The remainder of the discs were dried. A number of the dried discs were set aside and another group were washed with PBS and then set aside. The chitosan coating, both wet and dry, was then activated by treatment with 1% (v/v) glutardialdehyde in PBS for 15 minutes at room temperature, followed by PBS wash to remove excess of non-bound aldehyde. The activated coating was then treated with 0.5% (w/v) human serum albumin solution in HANKS medium for one hour at room temperature. Excess non-bound albumin was removed by washing with HANKS medium. Alternatively, as a control, the activated coating was treated with 0.1 M TRIS (Tris[hydroxymethyl]aminomethane) buffer solution to block the aldehyde groups. EXAMPLE 4 Human blood platelets were isolated and labelled with sl Cr as follows: Platelet binding Assay Venous blood was collected from healthy human volunteers using protocols approved by the Robert Wood Johnson Medical School Ethics Committee. Human platelets were isolated by gel filtration from freshly drawn blood anti-coagulated with acid-citrate dextrose (56 mM sodium citrate, 65 mM citric acid, 104 mM glucose) supplemented with prostaglandin E j (1 M Sigma). Platelet-rich plasma was prepared by centrifugation of the blood at 180 x g for 20 minutes at room temperature. Platelets were pelleted from the platelet-rich plasma by centrifugation at 1000 x g for 16 minutes at room temperature. Th pellet was gently resuspended in platelet-poor plasma. Prostaglandin E 1 (1 μM) and apyras (1 unit/mL Sigma) were added to each isolation step to minimize activation of the platelet Platelets were isolated from the plasma by filtration through a Sepharose 2B colum equilibrated with Walsh buffer ( 137 mM NaCl, 2.7 mM KC1, 1 mM MgCl 2 , 3.3 m NaH 2 P0 4 , 5.6 mM glucose, 20 mM HEPES, 0.1% bovine serum albumin (sigma), pH 7.4) The plasma free platelet count was adjusted to 2-3 x 10 8 platelets/mL using Walsh solutio Platelet quantitation was done using a hemocytometer (Fisher Scientific). To label platelets with 5l Cr, 500 μCi of 51 Cr (5 mCi/mL normal saline, IC Biomedicals) was added to each mL of resuspended platelet solution in plasma. Th resulting solution was incubated at 37°C for 60 minutes. The labeled platelets were filtere and diluted as stated above. TEST 1 Platelet Adhesion Assay The 6 millimeter coated discs of Example 1 were placed at the bottom of well in 96-well microtiter plates (Corning). The surface of the discs were coated with platelet poor plasma ( lOO μL/well) for one hour at room temperature. Non-adherent proteins wer removed by aspiration and the wells were washed three times with phosphate buffered salin (PBS, 200 L/well). 51 Cr-labelled platelets (100 L/well) (prepared in Example 4) wer added to the wells for one hour. Non-adherent platelets were removed by aspiration an the wells were washed three times with phosphate buffered saline (PBS, 200 μL/well). Adhered platelets were lysed with lysis buffer (2% SDS, 66 mM Tris pH 7.4, 100 μL/well). The lysates were collected and 51 Cr-labelled platelet adherence was quantitated using a gamma counter (LKB Wallac, Model 1282). Each condition was examined in triplicate. Platelet binding to untreated ePTFE discs was normalized in all experiments to 100%. Adhesion to the treated ePTFE surfaces is expressed as percentage binding relative to the binding to the untreated ePTFE surface. Results of different coatings are shown on the following table. Table I - PVA Treatment of ePTFE Discs Treatment % Platelet Binding Control - No coating 100 Coated using a 0.5% PVA solution 26 Coated using a 1.0% PVA solution 18 Coated using a 2.5% PVA solution 20 Coated using a 5% PVA solution 15 Treatment of the ePTFE discs with PVA at concentrations greater than about 1 % reduced platelet binding to the surface by 80%. TEST 2 Platelet Adhesion Assay The 6 mm coated discs of Example 2 were placed at the bottom of wells in 96-well microtiter plates (Corning). The surface of the discs were coated with platelet-poor plasma ( 100 μL/well) for one hour at room temperature. Non-adherent proteins we removed by aspiration and the wells were washed three times with phosphate buffered sali (PBS, 200 μL/well). 51 Cr-labelled platelets (100 μL/well) (prepared in Example 4) we added to the wells for one hour. Non-adherent platelets were removed by aspiration a the wells were washed three times with phosphate buffered saline (PBS, 200 μL/well Adhered platelets were lysed with lysis buffer (2% SDS, 66 mM Tris pH 7.4, 100 μL/well The lysates were collected and 51 Cr-labelled platelet adherence was quantitated using gamma counter (LKB Wallac, Model 1282). Each condition was examined in triplicat Platelet binding to untreated ePTFE discs was normalized in all experiments to 100 Adhesion to the treated ePTFE surfaces is expressed as percentage binding relative to t binding to the untreated ePTFE surface. Results of different coatings is shown on t following table. Table II - PVA-Chitosan Treatment of ePTFE Discs Treatment % Platelet Binding Control - No coating 100 Coated using a 0.6% chitosan solution 130 Coated using a 1.2% chitosan solution 105 Coated using a 20 0.6% chitosan/0.3% PVA solution Coated using a 15 1.2% chitosan/0.6% PVA solution Treatment of the ePTFE surface with the chitosan/PVA mixture reduced platelet bindi by 80%. Treatment using only chitosan increased platelet binding to the ePTFE surfac TEST 3 Platelet Adhesion Assay The 6 mm coated discs of Example 3 were placed at the bottom of wells in 96-well microtiter plates (Corning). The surface of the discs were coated with platelet-poor plasma (100 μL/well) for one hour at room temperature. Non-adherent proteins were removed by aspiration and the wells were washed three times with phosphate buffered saline (PBS, 200 μL/well). Sl Cr-labelled platelets ( 100 μL/well) (prepared in Example 4) were added to the wells for one hour. Non-adherent platelets were removed by aspiration and the wells were washed three times with phosphate buffered saline (PBS, 200 μL/well). Adhered platelets were lysed with lysis buffer (2% SDS, 66 mM Tris pH 7.4, 100 μL/well). The lysates were collected and 5l Cr-labelled platelet adherence was quantitated using a gamma counter (LKB Wallac, Model 1282). Each condition was examined in triplicate. Platelet binding to untreated ePTFE discs was normalized in all experiments to 100%. Adhesion to the treated ePTFE surfaces is expressed as percentage binding relative to the binding to the untreated ePTFE surface. Results of different coatings is shown on the following table. Table III - Chitosan Treatment and Post Treatment of ePTFE Discs Treatment % Platelet Binding Control - No coating 100 Coated using a 0.6% chitosan solution / 130 Drying Coated using a 0.6% chitosan solution / 135 Drying, PBS wash Coated using a 0.6% chitosan solution / 45 Drying GDA, PBS wash, HSA treatment Coated using a 0.6% chitosan solution / 120 No Drying, GDA, TRIS wash Coated using a 0.6% chitosan solution / 40 No drying, GDA, PBS wash, HSA treatment GDA - glutardialdehyde TRIS - Tris[hydroxymethyl]aminomethane buffer PBS - phosphate buffered saline HSA - human serum albumin Platelet adhesion to the HSA-chitosan surface was reduced by 50%. Activated TRIS-treat chitosan membrane increased platelet binding to the surface. While the foregoing description, examples, and tests have disclos embodiments of the invention in considerable detail for purposes of illustration, it will understood by those skilled in the art that these details may be varied without departi from the spirit and scope of the invention.

Claims: WHAT IS CLAIMED IS: Claim 1. A biomaterial having a thromboresistant surface, wherein said surface is comprised of a coating layer of chitosan and one or more bioactive materials. Claim 2. The biomaterial of claim 1 wherein one said bioactive material is polyvinyl alcohol. Claim 3. A medical device comprised of the biomaterial of claim 1. Claim 4. The medical device of claim 3 wherein said device is a prosthetic vascular graft. Claim 5. The graft of claim 4 wherein the graft is substantially tubular in cross-section. Claim 6. The graft of claim 5 wherein having an interior diameter of less than about 4mm. Claim 7. A surface treatment for biomaterials comprising the application of a coating comprising chitosan and one or more bioactive materials to said biomaterial. Claim 8. The surface treatment of claim 7 wherein said bioactive material is selected from the group consisting of surfactants, antithrombotic agents, antibiotics and antibodies. Claim 9. The surface treatment of claim 7 wherein said biomaterial is selected from t group consisting of polytetrafluoroethylenes, polyamides, polyesters, polyurethan polythiloxines, polyolifins, Dacron, silicone rubber, polyvinyl chlorides, copolymers, a metals. Claim 10. The surface treatment of claim 7 wherein said coating is cured. Claim 11. The surface treatment of claim 10 wherein said coating is cured by crosslinki Claim 12. The surface treatment of claim 11 wherein said biomaterial is Dacron expanded polytetrafluoroethylene. Claim 13. The surface treatment of claim 12 wherein said bioactive material polyvinylalcohol. Claim 14. The surface treatment of claim 13 wherein the ratio of chitosan polyvinylalcohol is in the range of about 4:1 to about 1:1. Claim 15. The surface treatment of claim 7 wherein the application process comprises t steps of: A) preparing a coating solution comprising a sterile aqueous solution of chitos B) coating the surface of the biomaterial with the coating solution; and, C) curing the adsorbed solution Claim 16. The surface treatment of claim 15 wherein the coating solution further comprises additives such as hydrophilic polymers, stabilizers, buffers, catalysts, and cross-linking agents. Claim 17. The surface treatment of claim 16 wherein the surface of the biomaterial is coated with the coating solution by pumping or by dipping; Claim 18. The surface treatment of claim 17 wherein the adsorbed solution is cured either by drying or by chemical cross-linking, using a cross-linking agent in an aqueous solution Claim 19. The surface treatment of claim 18 wherein the bioactive materials may be entrapped within the membrane during the initial coating formation or bonded and immobilized to its surface at activated sites on the chitosan. Claim 20. The surface treatment of claim 19 wherein the activated sites on the chitosan membrane are activated by glutardialdehyde.

Inventors: FREEMAN AMIHAY, GRECO RALPH, HAIMOVICH BEATRICE, FREEMAN, AMIHAY, GRECO, RALPH, HAIMOVICH, BEATRICE
Applicants: FREEMAN AMIHAY, GRECO RALPH, HAIMOVICH BEATRICE, FREEMAN, AMIHAY, GRECO, RALPH, HAIMOVICH, BEATRICE
Application year: 1995
Main classification: A01N1
IPC codes: A61F2, A61L27, A61L33