JP2000516827A - Biocompatible medical products and methods - Google Patents

Abstract

  (57) [Summary] A medical product having a metal or glass surface with a surface having an improved biocompatible adhesive coating. The coating first applies a silane compound having a pendant vinyl functionality to the surface such that the silane adheres to the surface, and then in a separate step, the pendant vinyl functionality of the vinyl silane is grafted by covalent bonding to a polymer. Manufactured by forming a graft polymer on the surface with the applied vinyl silane to be incorporated into the polymer. The biopolymer can then covalently bond with the base layer.

Description

DETAILED DESCRIPTION OF THE INVENTION                       Biocompatible medical products and methodsBackground of the Invention   The present invention generally relates to humans with improved tissue and blood biocompatibility. Medical device for implanting into a human or animal body. More specifically The metal or glass portion of the medical device of the present invention has a bioactive molecule (b A surface chemically modified with ioactive molecules) is provided.   The body and its intended connection with the body to assist with surgery or dialysis On blood vessels, synthetic and intraocular lenses, electrodes, catheters etc. or on the body Medical devices that serve as external devices are known. However, in medical devices The use of such biocompatible materials can lead to adverse effects such as rapid clot formation. Can stimulate body response. Various plasma proteins deposit platelets and phylla on plastic surfaces. Take action to initiate brin deposition. These effects are associated with vascular stenosis and impaired blood flow. And leads to an inflammatory response that causes the medical device to lose function.   "Biomaterials" are substantially insoluble in body fluids and Or materials designed and constructed for placement on or contact with bodily fluids Can be defined as Ideally, a biocompatible material will cause unwanted reactions ( For example, blood clotting, tissue death, tumor formation, allergic reactions, foreign body reactions (rejection) Or inflammatory response); does not elicit the physical properties necessary to function for the desired purpose ( E.g., strength, elasticity, permeability and flexibility); easily purified, manufactured and sterilized Gain; its physical properties and function while implanted or in contact with the body Performance will be substantially maintained.   As used herein, a solid surface of a biocompatible material is produced with a purely beneficial effect on the organism. If it can exist or function in contact with body tissue and / or biological fluids, Characterized as "biocompatible". Reduce host organism interference Therefore, long-term biocompatibility is desired. Improved biocompatibility of biocompatible materials One attempt at compatibility is to allow the body to accept the device as a normal part of the body. As described above, various "biopolymers" which can promote the attachment and growth of a normal cell or protein layer (biomolecules) ". Growth factors and fine particles attached to the device surface Biomacromolecules such as cell adhesion proteins could be used for this purpose. Furthermore, anticoagulation Biopolymers such as clumps, antiplatelets, and anti-inflammatory improve surface biocompatibility. It has also been used for:   Various approaches have been suggested for attaching such biopolymers . One such approach is Dekker et al.'S "Adhesion of endothelial  cells and adsorption of serum proteins on gas plasma-treated polytetraf luoroethylene ", Biomaterials, Vol. 12, March 1991. In this approach, the PTFE support is denatured by high-frequency plasma and its surface Improved wettability. Human serum albumin, human fibronectin, human immunoglobulin Brine and human high density lipoproteins are adsorbed to the plasma-treated support and then Give rise to endothelial cells. Another approach is described in U.S. Patent No. 5,055,316 to Hoffman et al. No. of albumin, immunoglobulin, fibrinogen Is a serum protein such as fibronectin, or a protein such as protein-A or glycoprotein. Proteins from different sources are first plasma-deposited to provide a deposition surface Using a plasma gas discharge in the presence of a polymerizable hydrogen fluoride gas, By binding to a surface by exposure to a quality solution. like that The covalent bond of biopolymers is based on Ito et al.'S Materials for Enhancing Cell Adhesion by  Immobilization of Cell-Adhesive Peptide ", Journal of Biomedical Materia ls Research, 25: 1325-1337 (1991), which discloses fibronectin. Or RGD protein is bound to the hydrogel using water-soluble carbodiimide. You. In this method, a biopolymer extending from the surface is bonded, Due to the fact that it is firmly fixed in the gel layer, for example, Reduces the usefulness of biopolymers with respect to interactions with cells that are trying to adhere I have.   Spacer molecules have been used to address this problem. Came. The spacer molecule can attach to the solid surface and be sufficient to extend from said surface. Molecule or compound capable of immobilizing one or more biopolymers Things. Spacers are used to efficiently activate biological macromolecules for efficient contact with body fluids. Secure the site outside the support. Spacers are more commonly organic molecules Derived from organic molecules having at least two functional groups located at opposite ends of the . Such groups can serve as attachment media that can attach spacers to solid surfaces and biopolymers. (vehicles). For example, U.S. Pat.No. 5,132,108 to Narayanan et al. Exposes the copolymer surface to a high-frequency electric field in the presence of a steam plasma medium. Therefore, high-frequency plasma treatment was performed. Polyethyleneimine (PEI) and 1- (3-dimethyl (Propyl) -3-carbodiimide (EDC) aqueous solution of coupling agent It was applied to a polyurethane surface modified by discharge. Then, the aqueous solution of heparin and EDC The solution is applied to the PEI-treated surface and the port with the anti-coagulant firmly fixed to the surface. A rimmer surface was provided. However, coated with multifunctional spacer molecules Consideration of the heterogeneity of the resulting polyurethane surface is not guaranteed.   For example, Golander et al., US Pat. No. 4,565,740 or Larn et al., US Pat. No. 403, additional applications may be provided. Smell the first of these patents Polymeric cationic surfactants (e.g., polyalkylenimines) and A complex of aldehyde (eg, glutaraldehyde) is adsorbed on the support material. This In the second of these patents, a polyamine is adsorbed on a support surface and croton Crosslink with aldehyde. Then, a multi-layer coating comprising an intermediate layer of anionic material The coating is applied to obtain an effective coating. However, these crosslinked Coating depends on adsorption on the surface and ionic binding to the surface, Would not provide a good bond to the coating.   The present inventors have disclosed U.S. Pat.Nos. 5,229,172, 5,308,641 and 5,350,800. The use of multilayer coatings to improve the biocompatibility of biocompatible materials Has contributed. For example, in U.S. Pat. Grafting on polymer surfaces that can be used to attach pacers and biopolymers Surface properties of polymeric materials by providing a base layer of fluorinated acrylamide A method for denaturation was found. Also, in U.S. Pat.No. 5,308,641, the present inventors A bifunctional crosslinker covalently bonded to an aminated support and with an aldehyde group Discovered improved spacer materials including cross-linked polyalkyleneimines Was. Also, in U.S. Pat.No. 5,350,800, we have a carboxyl group. Biopolymer is attached to the aminated solid surface with carbodiimide, and then A method for selectively restoring the bio-functionality of the boxyl group was found.   On a metal or glass surface, a metal or glass support and a grafted base layer Such multilayer coatings are lacking because there is no organic structure to provide a covalent bond between them. Bonding of the base layer of the ring can be problematic. Others have to adhere to the surface Aminosilanes are applied and then bioavailable by the amine functionality of the aminosilane. Adhesion of the molecule to the aminosilane addresses the problem of adhesion to metals and glass. I've got involved. This means that heparin is applied to the tantalum oxide surface using aminosilane. Adhesion of molecules can be found in US Pat. No. 5,355,433 to Rowland et al. Aminosilanes are disclosed in U.S. Pat.No. 4,118,485 to Eriksson et al. Has also been disclosed for attaching heparin molecules to metal surfaces. However The use of aminosilanes in this type of coating is Not very good at producing biologically effective and stable surfaces Was.   Accordingly, an object of the present invention is to provide improved stability on metal or glass supports. To provide a base for attaching biomolecules and / or spacer molecules That is.   Another object of the present invention is to provide a stable platform for attaching biopolymers. A spacer, whereby the attached biopolymer is embedded in the spacer layer. Is to provide a mixed base / spacer.Summary of the Invention   Accordingly, the present invention relates to a metal or glass surface with a surface having an adhesive coating. Medical products having a surface. The coating causes the silane to sag from the surface Having a vinyl functionality such that it adheres to the surface with The pendant vinyl functionality of the orchid is covalently linked to the graft polymer to Graph on the surface with the silane applied to be incorporated into the raft polymer And silane compounds forming a copolymer.   Preferred silanes usually have the structure:                                 C_TwoH_Three-Si-X_Three Wherein X is a halogen, methoxy or ethoxy group. This species Preferred examples of the compound of the above include trichlorovinylsilane. other Can also be used as described in detail below.   The base layer containing the vinyl functionality of the silane is also a thin but densely formed graft polymer. Including Preferably, the graft polymer is formed from an ethylenically unsaturated monomer. It is formed by a free radical reaction. Therefore, the reaction to form the graft polymer Also activates the pendant vinyl groups of the silane, Include vinyl groups in the copolymer. Using metal oxide such as cerium ion The polymerization reaction can be started. Monomers have a tendency to precipitate with cerium ions When not available, for example, when used with acrylamide, the cerium ion graph Is known to work best. Present in commercial products of acrylic acid Under the condition that the polymerization inhibitor is first removed by distillation, acrylic acid Is also a good candidate monomer for use in cerium ion grafting. Aku Blends of lylic acid, acrylamide and other monomers may also provide the desired properties of the graft. Can be used depending on   Bifunctional molecules attached to the grafted surface can be, for example, anticoagulants (e.g., Phosphorus, heparin sulfate, dermatan sulfate, glycosaminoglycan sequences and analogs, Hirudin, thrombin inhibitors), thrombolytics (e.g., streptokinase, tissue Bioactive agent), procoagulant, platelet adhesion inhibitor, platelet activity inhibitor, cell adhesion Proteins, growth factors / cytokines, wound healing agents, antibacterial agents , Biomacromolecules such as anticancer drugs, hormones, analgesics, and detoxifying agents. these Biopolymers can be obtained by methods known to those skilled in the art. Amine and carboxyl groups in the grafted polymer reacting with the corresponding groups above Can be covalently linked to the grafted surface.   Preferably, the medical product of the present invention comprises a spacer as an attachment means for a biopolymer. -. Such spacers are available in the industry as described in the background of the invention. And is known. Preferred spacers are incorporated herein by reference in their entirety. Polyamine spectroscopy as described in Applicant's U.S. Pat.No. 5,308,641. May be a sourcer.   Examples of devices that can be provided on a biocompatible surface according to the present invention include vascular grafts. Or, parts of prosthetic devices such as hard tissue prosthetics and implanted prosthetic devices, Invasive devices such as catheters or dialysis devices or vascular circulation or An extracorporeal blood handling device such as an oxygen transport device used in cardiovascular surgery is exemplified. Departure In a particular vascular prosthesis mode, the bioactive coating is Implant or use the above base layer to resist bending without peeling or peeling Sometimes it can be attached to metal medical devices that withstand operation. An example of this is A generally radially expandable tube made of metal, commonly known as a stent There are endoprotheses. An exemplary stent in this regard is U.S. Pat.Nos. 4,886,062 and 5,51, Wiktor, the subject matter of which is incorporated by reference. No. 33,732. Such stents are made of very fine gauge gold Metal wire, typically tantalum wire or stainless steel wire. Have been. When implanted, these stents partially occlude along blood vessels, etc. Installed on a balloon such as an angioplasty catheter until it arrives A balloon and a balloon for the purpose of opening the occlusion upon arrival and supporting the vessel at that location The stent expands radially and circumferentially. To do this, use tantalum wire It is necessary to bend sharply. Many coatings have been exposed to this kind of curvature The flexibility and / or flexibility required to prevent deep cracking and / or Or has no adhesive properties. Furthermore, heparin is used as a biopolymer according to the present invention. And a stent implanted in a blood vessel, Thrombus formation on the metal member, which may occur as a result of this process.Detailed description of the invention   The base layer of the multilayer coating is pendant so that the silane adheres to the surface Produced by first providing a silane with vinyl functionality to the surface. use The structure of the silane is:                                 C_TwoH_Three-Si-X_Three Or, in some cases,                                 C_TwoH_Three-R-Si-X_Three Wherein X is a halogen, methoxy or ethoxy group, and R is Which is a kill group). Preferred silane compounds are trichlorobi Nylsilane.   Those skilled in the art should clean the surface before applying silane to the surface. And recognize that the application of silane involves controlling the moisture on the surface. Would. Therefore multi-stage cleaning and drying to provide a clean surface and control moisture Use operations. Exemplary methods of cleaning and drying are found in the Examples herein. Can be   Thin but densely formed graft polymer with a base layer containing silane vinyl functionality including. Preferably, the graft polymer is free from ethylenically unsaturated monomers. -Produced by radical reaction. Therefore, the reaction to form the graft polymer is It also activates the pendant vinyl groups of the orchid and causes the graft polymer to form Is included. The polymerization reaction can be initiated using a metal oxide such as cerium ion. You.   Preferred grafting steps include other solvent polymerization methods such as organic solvent polymerization or bulk polymerization. In contrast, the reaction is carried out on a support in an aqueous solution (20 to 40% by weight of monomers). preferable The composition of the monomer solution is used to attach the biopolymer or spacer layer. Primarily to provide the desired density of carboxyl groups on the resulting grafted surface. Crylic acid and acrylamide. Or use acrylamide exclusively And then subjecting the resulting polymer to hydrolysis treatment to give the desired carboxyl group Density can be obtained.   The grafting reaction of the present invention can be performed at a temperature of about 18C to 25C. The present invention Pressure or partial vacuum, but as long as the reaction proceeds very advantageously at that pressure. Preferably uses atmospheric pressure. Grafting solution with cerium ammonium nitrate The pH of the liquid is typically about 1.4.   The amount of cerium ions used in the practice of the method of the present invention may vary over a fairly wide range. You. For example, about 0.0001 to 0.002 cerium ions per mole of polymerizable monomer Mole can be used. Preferably, cerium ions are added in an amount of 0.1 mol per acrylamide. 0002-0.0005 mol are used. The cerium ion is preferably in the form of a cerium salt Into the reaction mixture. Some cerium salts suitable for use in the present invention include nitric acid. Cerium, cerium sulfate, cerium ammonium nitrate, cerium ammonium sulfate Cerium ammonium pyrophosphate, cerium iodide, cerium salts of organic acids, For example, there are cerium naphthenate and cerium linoleate. These compounds May be used alone or in combination with each other.   Generally, the time required to achieve the desired degree of polymerization can be determined empirically. Thus, for example, acrylamide can be grafted at various time intervals and The degree of grafting can be reduced by coloring the functional groups introduced into the graft by Can decide. Polymer chain length and graft density are determined by acrylamide concentration, cerium It can be varied by varying the ion concentration, temperature and oxygen concentration.   Anticoagulants (e.g., heparin, heparin sulfate, dermatan sulfate, glycosamino Glycan sequences and analogs, hirudin, thrombin inhibitors), thrombolytics (e.g., Streptokinase, tissue bioactive agent), procoagulant (e.g., factor VIII, Lebrand factor, collagen), platelet adhesion inhibitors (eg, albumin, Bumin-adsorbed surface, hydrophilic hydrogel, phospholipid), platelet activity inhibitor (e.g. Spirin, dipyrimadole, forskolin, cells Adhesion proteins (fibronectin, vitronectin), various collagens Species, laminin, elastin, base membrane protein, fibrin, peptide sequence), Growth factors / cytokines (e.g., transforming growth factor, basal fibroblast growth factor) , Platelet-derived growth factor, endothelial cell growth factor, gamma interferon), hydro Gels, collagen, epidermal growth factor, antibacterial agents (e.g., gentamicin, rifan Pins, silver salts), anticancer drugs (e.g., 5-fluorouracil), hormones (insulin , Vasopressin progestin, human growth hormone), analgesics, detoxifiers (e.g. Biofunctional molecules (biopolymers) such as chelating agents) First, the grafting method of the present invention may be applied to provide a surface suitable for And can be ionic or covalently bound to the metal support. Such a molecule Can be covalently bonded to the grafted surface produced by the method of the invention. Such as amine and carboxyl groups introduced into the gel by chemical denaturation The functional groups react with the corresponding groups on the biofunctional molecule by methods known to those skilled in the art.   Preferably, the medical product of the present invention comprises a spacer as an attachment means for a biopolymer. -Including molecules. Such spacer molecules may be used as described above in the context of the present invention. It is known in the art.   Preferred spacer molecules are polyalkyleneimines or other branched polyamines. It is. Thus, the term polyalkyleneimine is defined as 1-unsubstituted imines, 1-substituted Basic imines, activated imines (1-acyl-substituted imines), isomeric oxazolines Water derived from aziridine and azetidine monomers such as oxazines / oxazines It shall contain soluble and hydrophilic polyamines. Polyal used in the present invention Kerenimine is preferably highly branched, so that primary, secondary and And tertiary groups. Therefore, other monomers suitable for homopolymerization or copolymerization with ethyleneimine Ethyleneimine polymerized by conventional cationic chain extension polymerization with Could be used.   In order to provide additional stability of the polyamine spacer, the present invention provides a crosslinker Can be used. Crosslinker reacts with amine groups present in polyamine spacer Any crosslinking agent that is at least difunctional in the group Thus, the crosslinking agent Has aldehyde functionality. For example, glutaraldehyde, crotonaldehyde , Goxal, maonaldehyde, succinaldehyde , Adipaldehyde and dialdehyde starch could be used. Other suitable crosslinking agents Include cyanuric chloride and derivatives, divinyl sulfone, epoxy compounds Imidate esters and other cross-linking agents that are reactive with amines. I can do it.   Therefore, the spacer of the present invention has a polyalkyleneimine suitable for the grafted surface. Prepared by treating the applied polyalkyleneimine with a crosslinking agent I can do it. Preferably, the crosslinking agent used to crosslink the polyalkyleneimine is Apply in a suitable pH and dilute solution to achieve mild crosslinking. For example, about Aldehyde solutions having a concentration in the range of 0.0005 to about 0.05M may be used, Concentrations ranging from 05 to about 0.005M are preferred. Also, for example, an arc of about 7 to about 10 The pH of the aldehyde solution is preferred. The time required to complete the mild crosslinking reaction is Typically only a few minutes for dialdehydes to longer for other crosslinkers It is time. Preferably, a cross-linking reaction using a polyamine is performed on the grafted surface. Begin before applying polyimine.   The polyalkylenimine activates carboxyl groups on the grafted surface, Activator for bonding carboxyl group to the alkylene imine and grafted surface To form a covalent bond to the grafted surface. Covalent binder used Preferably has the structure: R₁N = C = NR_Two(Where R₁Is an alkyl or cycloalkyl group Yes, and R_TwoIs 1-ethyl-3- (3-dimethyl-aminopropyl) carbodiimide hydrochloride Salts or salts such as 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide A water-soluble carbodiimide). Can get. The reaction with carbodiimide is carried out in a cold (0-4 ° C.) solution at a pH of about 5. However, room temperature is acceptable. The grafted surface is pretreated with carbodiimide and then Can be contacted with a polyamine or, preferably, the grafted surface can be contacted with a polyamine. Coat with min and then treat with carbodiimide. Polyamine and carbodi The imide is preferably premixed together at a pH of about 9 prior to application to the graft. No. During the reaction, the carbodiimide converts the carboxy of the graft after reaction with the polyamine. To form a suitable amide bond, and apply a polyamine to the grafted surface. And finally fix it.   The immobilized polyamine is then converted to a platform for immobilization of various bifunctional molecules. Can be used as For example, in the case of heparin, it does not inhibit the biological activity of heparin Reacts with the amine groups of the polyamine to produce NaCNBH_ThreeIn the presence of a suitable reducing agent such as Denatured to include reactive aldehyde moieties that covalently attach palin to polyamines I can make it. Aldehyde groups are converted to heparin by controlled periodate oxidation. Can form on phosphorus. Some of the saccharide molecules in heparin have an unsubstituted glycol structure: (C (2) -OH and C (3) -OH), which combine with periodate to separate C (2) -C (3) bonds. React to form a dialdehyde structure, and then leave the polysaccharide backbone intact. After oxidation (in the absence of light), the activated heparin-containing solution is brought to a suitable concentration in a suitable buffer. Can be diluted. The solution is then applied to the polyamine immobilized on the surface. F The aldehyde function on palin then reacts with the free amine group to form a stable secondary Form a Schiff base that can be reduced to provide a secondary amine. As an exemplary reducing agent Sodium borohydride, sodium cyanoborohydride, dimethylamine Orchids and tetrahydrofuran-borane. When the binding reaction is complete, clean the surface with water And washed with sodium chloride solution to remove loosely bound heparin or unreacted heparin. Phosphorus may be removed.Experimental example 1   A piece of coiled tantalum wire is ultrasonically cleaned with 2% microclean for 30 minutes. Then sonicated with deionized water for 30 minutes. Rinse the coil in isopropanol This last step was repeated after drying and drying at 50 ° C. for 20 minutes.   The cleaned coils were placed in a 2% solution of trichlorovinylsilane in xylene (Merk Darmsta (dt, FRG) for 60 seconds, then in xylene for 60 seconds, in isopropanol For 60 seconds, in water for 60 seconds, and finally in acetone. Then the coil Was air-dried overnight.   The dried coils are then combined with 35% and 5% by weight of freshly distilled acrylic acid. It was set in a glass tube filled with 15 ml of an aqueous solution of acrylamide. Monomer solution 15 0.9 ml of a cerium ammonium nitrate solution (0.1 M) in nitric acid (0.1 M) Was. Degas for 3-5 minutes at about 18 mmHg, then sonicate for 10 minutes, Incubated for 40 minutes. All were performed at room temperature. Then the grafted sump The tubes were rinsed 10 times with deionized water at 50 ° C. and then incubated at 50 ° C. overnight. The collected sample became deeply colored when immersed in a toluidine blue solution.   A solution of 375 ml crotonaldehyde (pH = 9.1) in 0.1 M sodium borate was prepared. After stirring for 10 minutes, polyethyleneimine (PEI, Mw 60,000, Polymin SN manufactured by BASF) was added. Added. After stirring for another 5 minutes, the coil was stirred for 1 hour in a cross-linked PEI solution. For a while. After rinsing with deionized water, remove the coil from 0.1 M sodium borate Contact with a solution of 0.5 wt% PEI (Polymin SN) in pH = 9.1 for 10 minutes. Water-soluble cal Bodiimide (1- (3-diethylaminopropyl) -3-ethylcarbodiimide HCl) 0.05 M was added at a concentration of M. Allow binding to proceed for 1 hour with shaking, then with deionized water Rinse for 10 minutes.   Oxidized heparin, excluding light, 0.165 mg NaIO_Four/ ml-5mg natural hepari (Akzo) / ml 0.05M phosphate buffer (pH = 6.88, 0.025M K_TwoHPO_Four+ NaH_TwoPO_Four ^*2H_Two O). After overnight oxidation, the resulting heparin solution was diluted to 0.4 M acetate pH = 4.6 diluted 1:20. 0.1mg NaCNBH_Three/ ml to diluted heparin The coils were incubated in this solution at 50 ° C. for 2 hours. Rinsed with deionized water Thereafter, 1M NaCl and water were added again to remove loosely bound heparin, and toluene was added. When incubated with idine blue, the coil becomes lilac colored and It showed that parinization was successful. Additional bioactivity tests have been successfully performed, To deactivate thrombin via activation of pre-adsorbed antithrombin III The ability of the heparinized surface was determined. 1% at 50 ° C with 1% sodium dodecyl sulfate The biological activity was also tested after overnight challenge, but the coating on the metal Excellent Showed stability.Comparative Experimental Examples 2 to 8   Comparative tests were performed with various variables. Amination of the metal surface described in Experimental Example 1 The ability to bind heparin via various and reductive amination methods did. The variables tested were silane free, aminosilane, aminopropyl Liethoxysilane (APTES), and vinylsilane, trichlorovinylsilane (TCVS) Use of grafted polymers (acrylamide (AAm) and acrylic acid (Ac)) Use of copolymer as base layer; adsorbed or grafted PEI layer; and PEI layer (black Tolaldehyde (Ca), glutaraldehyde (Gda) and divinyl sulfone (DVS)) Various crosslinks. Regarding Experimental Example 8, as described in Experimental Example 1, Were made with grafted hydrogels. 0.1 M borate pH = 0.1 0.1 wt% PEI in pH 9.0 (M w A 60,000 solution of BASF Polymin SN) is prepared and (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HCl, Aldrich) Added to a concentration of 5M. Immediately after dissolving the carbodiimide, slowly release the grafted coil The solution was contacted for 50 minutes with shaking. After rinsing with water, heparin 1. Coupled to coil as described in 1. The test results of Experimental Examples 2 to 8 are shown in Table 1 below. You.                                  Table 1   The comparative test results in Table 1 show the biological activity (DEA / cm) of the adsorbed PEI layer.^TwoIU) This was lower than the value of the covalent layer present in Examples 7 and 8. further, Coloring after overnight challenge with 1% sodium dodecyl sulfate (0 = no color ~ 5 = dark (Coloring scale) indicates that the heparin layer is a test sample with aminosilane and adsorbed PEI. The heparin layer was not effectively retained on the Indicates that it was retained.   It will be apparent to those skilled in the art that the present invention has been described above with respect to particular embodiments and experimental examples. The description is not intended to be limited to these and various other modifications may be made without departing from the inventive concept. Aspects, experimental examples, uses, modifications, and developments from aspects, experimental examples, and uses are possible. It will be understood that

────────────────────────────────────────────────── ─── Continuation of front page    (72) Verhufen, Miher             Nuel-6221 vedes             Maastricht, Parallel Wake 39 (72) Inventor Hendrix, Marc             Nuel 6432 Elfe, The Netherlands               Hundsbruck, Rambaustraat               118 (72) Inventor Fauahe, Benedicte             Nuel-6211 Jesse               Maastricht, After de Moren             Z 7

Claims (1)

[Claims]   1. An endoprosthesis having a metal surface in contact with bodily fluids, on the surface, (a) a silane containing vinyl functionality, wherein the silane has a vinyl functionality from the surface Adhered to the metal surface in a depending manner; and (b) such that the pendant functionality of the silane is covalently attached to a graft polymer. Graft polymer on silane bonded surface An endoprosthesis having a coating comprising:   2. (a) a polyamine spacer covalently bonded to the graft polymer; and (b) a biopolymer covalently bonded to the spacer The endoprosthesis of claim 1, further comprising:   3. The silane is selected from the group consisting of halogen, methoxy and ethoxy groups 2. The endoprosthesis of claim 1, further comprising a functional group.   4. The in-vivo protein according to claim 3, wherein the silane is trichlorovinylsilane. -Se.   5. The graft polymer is free radical reactive from ethylenically unsaturated monomers. The endoprosthesis of claim 1, formed by a reaction.   6. 6. The method according to claim 5, wherein the monomer is selected from acrylamide and acrylic acid. An endoprosthesis as described.   7. 3. The polyamine spacer of claim 2, wherein the polyamine spacer is a polyalkylenimine. Body prosthesis.   8. The endoprosthesis according to claim 2, wherein the biopolymer is an anticoagulant.   9. The anticoagulant is selected from the group consisting of heparin and heparin derivatives An endoprosthesis according to claim 8.   10. A medical device having a metal or glass surface in contact with bodily fluids, The surface is (a) Structure:                               C_TwoH_Three-R-Si-X_Three Wherein X is halogen, methoxy or ethoxy, and R is an additional short chain An alkyl group), the silane having a vinyl functional group on the surface. Adhered to the surface so as to hang from it; and (b) Graft formed from ethylenically unsaturated monomer by free radical reaction A polymer, wherein the graft polymer is a pendant vinyl functionality of the silane. Is formed on the silane bonding surface so as to be included in the graft polymer, The medical device further comprising a coating comprising:   11. (a) a polyalkyleneimine spacer covalently bonded to the graft polymer -; And (b) a biopolymer covalently bonded to the spacer 11. The medical device according to claim 10, further comprising:   12. The medical use according to claim 10, wherein the silane is trichlorovinylsilane. apparatus.   13. 2. The method of claim 1, wherein said monomer is selected from acrylamide and acrylic acid. The medical device according to 0.   14． The medical device according to claim 11, wherein the biopolymer is an anticoagulant.   15. The anticoagulant is selected from the group consisting of heparin and heparin derivatives The medical device according to claim 14, wherein   16. Radial expansion of the stent from a first diameter to a second expanded diameter A hollow cylindrical shape made of low memory level metal so that it can be controllably deformed The metal is biologically compatible in the constituent radially expandable stent Coated with a coating, (a) a silane adhered to the metal; and (b) allowing the coating to be retained on the wire as the stent expands Graft polymer covalently bonded to the silane Improvements including.   17． A pendant vinyl agent in which the silane is incorporated into the graft polymer 17. The stent of claim 16, having a performance.   18. Biopolymer with the biocompatible coating covalently bonded to the spacer 18. The stent of claim 17, further comprising:   19. (a) a silane having a vinyl functionality so that the silane adheres to the surface Applied to; (b) Graph such that the vinyl functionality of the silane is incorporated into the graft polymer A polymer on the silane-bonded surface Steps on a medical product having a glass or metal surface on a glass or metal surface A method for providing a biocompatible coating.   20. The silane has the structure:                                 C_TwoH_Three-R-Si-X_Three Wherein X is a halogen, methoxy or ethoxy group, and R is an additional short 20. The method of claim 19, which is a chain alkyl group).   21. The silane is trichlorovinylsilane applied to the surface in a dilute solution 21. The method of claim 20, wherein the method comprises:   22. The graft polymer is bonded to the silane in the presence of a free radical initiator. By applying an ethylenically unsaturated monomer to the surface, the 20. The method of claim 19, wherein the method is formed.   23. Claims: Also comprising the step of covalently attaching a biopolymer to the graft polymer. 20. The method according to 19.   24. (a) covalently attaching a spacer molecule to the graft polymer; (b) Covalently bind biopolymer to spacer molecule 24. The method of claim 23, wherein the step comprises covalently binding the biopolymer.   25. (a) a silane having a vinyl functionality so that the silane adheres to the surface Applied to; (b) the silane so that the vinyl functionality of the silane is incorporated into the graft polymer. Forming a graft polymer on the adhesive surface; (c) covalently bonding a polyamine spacer to the graft polymer; (d) treating heparin to form an aldehyde function on heparin; so (e) covalently binding the heparin to the polyamine spacer Steps on medical products having a glass or metal surface on a glass or metal surface A method for providing a bioactive heparin coating.