KR100511030B1 - Blood compatible metallic materials and preparation thereof - Google Patents

Abstract

The present invention relates to a circulatory medical metal material with improved antithrombogenicity by binding heparin or sulfonated polyethylene oxide (PEO) to a metal material surface.

Currently, medical metals are used in the circulatory system as stents, artificial heart valves, and catheter components, but have a fatal disadvantage in that thrombus is generated when used in contact with blood. In particular, the stent has not been solved such as restenosis when implanted into the blood vessel. In the present invention, it was found that the antithrombogenicity of the material is greatly improved by chemically bonding a silane compound to an oxidized surface of a metal such as stainless steel and binding heparin or sulfonated polyethylene oxide using a functional group of the silane.

The surface modified metals obtained can reduce thrombus formation when used as artificial heart valves, catheter parts, and especially stent materials.

Description

 Blood compatible medical metal materials and preparation method thereof

FIELD OF THE INVENTION The present invention relates to metal materials which significantly improve antithrombogenicity by modifying the surface of medical metal materials, especially metal materials used in the circulatory system. More specifically, a functional silane compound is chemically bonded to a metal surface such as stainless steel, and a functional group of silane is also used as a polyethylene oxide [PEO, poly (ethylene oxide), also known as polyethylene glycol. (PEG, also referred to as poly (ethylene glycol)), and a surface-modified metal material and a method for surface modification, wherein the heparin is chemically bonded using PEO functional group or the functional group of PEO is converted to sulfonic acid group. Metals surface-modified in this way have greatly improved antithrombogenic properties and are useful as artificial heart valves, stents, and catheter materials.

Artificial heart valves are implanted and used instead of congenital or acquired heart valves, for example, a tissue valve made of biological tissue or a mechanical valve made of a metallic material such as titanium. Among these, the biotissue valve has good biocompatibility but has a disadvantage of poor durability in the body due to calcification, and the mechanical valve has excellent durability, but it is accompanied by the generation of thrombus, so it is necessary to take anticoagulant for life. There is a disadvantage. To this end, many studies have been conducted to improve the antithrombogenic properties of mechanical valves. However, thrombus generation is a normal physiological function of the human body, which is difficult to prevent completely.

Percutaneous transluminal coronary angioplasty has been performed to inflate blood vessels by inserting an intraarterial baloon cathetor into the coronary artery to treat stenosis. Although the procedure is relatively good and the methods and instruments continue to develop, problems such as acute occlusion and restenosis are still not resolved.

Stent is a spring-shaped metal implant that is inserted into the vessel wall to support the vessel after the procedure to prevent restenosis, and its use has recently been expanded. Stent materials are stainless steel, tantalum and titanium-nickel alloys, and various forms such as a balloon type and a tube type have been developed and used. However, 20-30% of patients fail after the stent implantation. The main cause is restenosis caused by acute thrombus formation and proliferation of smooth muscle cells in the lining of blood vessels due to stent wounds. It turned out to be.

Many studies have been conducted on hydrophilic, hydrophobic, hydrophilic / hydrophobic micro-domain structures, and anionic surfaces to improve the antithrombotic properties of the material. Among them, the surface on which PEO is bound has been reported to improve antithrombogenicity due to decreased adhesion of blood components such as proteins and platelets (see J.D.Andrade et al., Biomaterials 11, 455, 1990). The surface of the metal has a large critical surface tension and generally has a positive charge, so that it has a high interaction with negatively charged blood and is easy to generate a blood clot (MFAGoosen et al. Biomaterials 17, 685-694, 1996).

Heparin is an antithrombotic agent currently used in clinical practice, and it is widely known that heparin has an antithrombotic effect. In addition, heparin has been reported to inhibit the proliferation of smooth muscle cells in addition to antithrombogenicity (Guyton et al., "Inhibition of rat arterial smooth muscle cell proliferation by heparin", Cir. Res. 46, 625-634, 1980; Cavender et al., "The effects of heparin bonded tantalum stents on thrombosis and neointimal proliferation", Circulation 82, III-541, 1990). Therefore, the binding of heparin to medical metals, especially stents, is expected to effectively prevent restenosis because it prevents the formation of blood clots during the stent procedure and inhibits the proliferation of smooth muscle cells in the blood vessel wall. Heparin is a polydisperse polysaccharide synthesized in the body and contains a large amount of sulfonic acid groups, a small amount of carboxyl groups, hydroxyl groups and amino groups, and has a negative charge as a whole.

Medical products that improve antithrombogenicity by physically coating or chemically binding heparin to a substrate, such as a catheter and a blood circuit, have already been developed and used (for example, JMToomasian et al. "Evaluation of Duraflo II heparin coating in prolonged extra-corporeal membrane oxygenation ", ASAIO Trans. 34, 410-414, 1988; J.Sanchez et al.," Control of contact activation on end-point immobilized heparin ", J. Biomed. Material Res. 29, 655-661, 1995, etc.). As described in these related papers and patents, the methods of coating or binding heparin vary widely. For example, a method of coating a cationic compound and a polymer on a substrate and coating negatively charged heparin by ionic bonding thereon, and a polymer in which heparin is dispersed or dissolved (see US Patent No. 5,980,972, N.Ding et al.) And methods of coating a hydrogel on a substrate (see US Pat. No. 5,954,706, RA Sahatjian et al.). However, the coated heparin is not permanently effective because it is slowly released into the body fluids during use. On the other hand, in the case of chemical bonding of heparin, the activity of bound heparin is often decreased depending on the type of substrate, the binding method, and the reaction conditions. This is because when the general enzymes and bioactive materials are immobilized on the surface of the material, their conformation changes and their bioactivity decreases compared to the free state. This problem can be solved by introducing a spacer between the substrate and a bioactive material such as heparin. As such a sequestering unit, a water-soluble polymer having a molecular weight of 500 to 10,000, in particular, PEO is used.

In order to improve the antithrombotic properties of metal materials used for stents and the like, a number of studies have been conducted to coat a surface with a hydrophilic polymer or a polymer containing a drug. Although PEO, polyvinyl alcohol, etc. have been applied as hydrophilic polymers (see JYYan U.S. Patent 5,843,172 and JPLoeffler U.S. Patent 5,897,911), since they are simply coated on a metal surface, they are not excellent in adhesive force and satisfy the antithrombogenic effect. It wasn't. See also heparin-bound polymers (see S. Sheth et al. J. Am. Coll. Cardiol 23, 187A, 1994) or dexamethasone (AMLincoff et al. J. Am. Coll. Cardiol 23, 18A, 1994). The method of slowly releasing the drug by coating a polymer containing a drug such as) has been proposed but did not show a great effect.

Two methods are largely used to chemically modify the surface of a metal. One is to coat a thin film of gold or silver on a metal surface and adsorb a sulfur compound, and the other is to bond a silane compound. M. Grunze et al. Reported that the adsorption of proteins on the surface of PEO self-assembled monolayers deposited using gold thin films / sulfur compounds has been reduced and similar studies are underway (J. Phys. Chem. B, 102). , 426-436, 1998). However, PEO alone is not capable of obtaining the level of antithrombogenicity of practical application, and there are no reports on commercialization yet.

We reported earlier that sulfonated PEO showed antithrombotic properties (14% of heparin) similar to heparin (Kim Young-ha et al., Biomaterials 16, 467, 1995). It has been invented that the antithrombotic effect of the sulfonic acid group is added to the sex to significantly increase the antithrombogenicity (Kim Young-ha et al., Korean Patent 62,921). In addition, after depositing a thin film of gold or silver on the metal and adsorbing the sulfur compound having a functional group, the modified metal exhibited superior antithrombogenicity by combining sulfonated PEO or heparin using the functional group of the sulfur compound. (Kim Young-ha et al., Korean patent applications 00-1,095 and 00-16,775). However, the sulfur compound adsorbed on the deposited gold or silver thin film gradually detached over time and showed no tendency to have stability.

Accordingly, the present inventors have conducted extensive research to overcome the above-mentioned problems of the prior art, and as a result, the functional silane compound is chemically bonded to the surface of the metal, and further, heparin or sulfonated PEO is also chemically bonded. And antithrombogenicity can be significantly improved.

Accordingly, an object of the present invention is to chemically bond a functional silane compound to the surface of a metal, and to bond a PEO derivative which is also functional with a functional group of silane, and then chemically bind heparin using a functional group of PEO. Or to convert the functional group of PEO into sulfonic acid group to provide a medical metal material and a method for producing the same, which have greatly improved antithrombogenicity and biocompatibility.

It is yet another object of the present invention to provide a circulatory medical device, in particular stents, cardiac valves and catheter components, using metal materials that reduce the formation of blood clots upon contact with blood due to the antithrombogenicity of heparin or sulfonated PEO. .

In one aspect of the invention,

Base metal,

A functional silane compound bonded to the surface of the base metal, and

Provided is a blood compatible medical metal material comprising a PEO / heparin conjugate or sulfonated PEO derivative chemically bonded through a functional group of the silane compound.

In another aspect of the invention,

Bonding the functional silane compound to the surface of the base metal,

Binding the PEO derivative through the functional group of the silane compound, and

Chemically binding heparin through the functional group of the PEO, or converting the functional group of the PEO group to a sulfonic acid group, a method for producing a blood compatible medical metal material is provided.

In the medical metal material of the present invention, the metal which can be used as the base metal includes iron, stainless steel, titanium, nickel, chromium, nickel-chromium alloy, nickel-titanium alloy, tantalum and alloys thereof, but in principle no limits.

 Silane is strongly adsorbed to all metals, and particularly metals forming an oxide protective film on the surface of stainless steel and the like form stable bonds through chemical bonding with silanes. In some cases, the metal sample may be treated for 60 minutes at 50 ° C. in a 25 vol / vol% nitric acid solution in accordance with the method of ASTM F86 in order to completely produce an oxide protective film on the metal surface.

Silane compounds are widely used as coupling agents in the preparation of polymer / inorganic composites. That is, the silane compound has 1 to 3 alkoxy groups or chlorine groups at one end thereof, and they are hydrolyzed to be converted into silanol groups to strongly bond to the glass fiber and metal surface, and an alkyl group at the other end thereof. Or have a functional alkyl group and combine with the polymer to increase the interfacial bond of the polymer / inorganic (see Ind. Eng. Chem., Prod. Res. Dev., 11 (2), 170, 1972). In practice, silane compounds having various functional groups such as alkyl, alkyl chloride, vinyl, amino, epoxy, mercaptan, hydroxy, and isocyanate are commercially available.

Further studies have been reported in the literature, in which PEO derivatives are further bound using functional groups of silanes bound to the metal surface. K. Park et al. Bind vinylsilane and PEO-polypropylene oxide copolymers (K. Park et al., J. Biomed. Mater. Res. (Appl. Biomater.) 38, 289-302, 1997). Or a reactant of isocyanatopropyltriethoxysilane and PEO to a metal (K. Park et al., Biomaterials 21, 605-616, 2000), and ETKang et al., For example, gamma-mercaptopropyltrimethoxysilane. Graft polymerization of PEO-methacrylate after binding (ETKang et al., Biomaterials 22, 1541-1548, 2001) reported a decrease in blood protein adsorption, but the antithrombogenicity was not sufficient. In contrast, the inventors have obtained superior antithrombogenicity by using sulfonated PEO or heparin.

More specifically, in the present invention, a functional silane compound is chemically bonded to a metal, particularly a stainless steel to form an oxide protective film on the surface thereof, and a heparin / PEO complex or sulfonated PEO is bonded using a functional group of the silane.

Silane compounds that can be used in this study are silane (a is 0), methylsilane (a is 1) and dimethylsilane (a is 2) compounds which can be represented by the following formula (1). The silane compound containing a functional group and the sulfonated PEO derivative to be bonded thereto are in principle infinitely selected, but it is preferable to select one which is easy to obtain raw materials, simple to manufacture and economically advantageous.

YR-Si (CH ₃ ) _a -X _3-a

In the above formula,

X is an ethoxy group, a methoxy group, butoxy group, an aceoxyl group, a chloro group, etc.,

a is an integer of 0, 1 or 2,

R is an alkyl group having 2 to 4 carbon atoms,

Y is an amino group, an epoxy group, an isocyanate group, a hydroxyl group, a mercapto group, a vinyl group, etc.

Examples of the functional silane compound that can be used include N-β- (aminoethyl) -gamma-aminopropyltriethoxysilane and gamma-aminopropyltriethoxysilane containing an amino group; Beta- (3,4-epoxycyclohexyl) ethyltrimethoxysilane and gamma-glycidooxypropyltrimethoxysilane containing an epoxy group; Isocyanatopropyltriethoxysilane containing an isocyanate group; N-bis (beta-hydroxyethyl) -gamma-aminopropyltriethoxysilane containing a hydroxyl group; Gamma-mercaptopropyltrimethoxysilane having a mercapto group; Vinyl trichloride silane containing vinyl groups, vinyltriethoxysilane, vinyltrimethoxysilane, vinyltriacetoxysilane, methacryloxypropyltrimethoxysilane, vinylbenzylaminotrimethoxysilane, and the like. Also included are silane (a1) and dimethylsilane (a2) compounds. The silane compound may be chemically bonded by coating or refluxing the metal with an aqueous solution of several percent concentration or a solution in an organic solvent and drying at 90-120 ° C.

The PEO derivative bonded to the functional group Y of the silane compound is a structure having a functional group Z capable of bonding with Y at both ends as shown in the following formula (2).

Z-A-PEO-B-Z

In the above formula,

PEO is a repeating unit of ethylene oxide represented by-(CH ₂ -CH ₂ -O) n- (n is an integer of 10 to 200),

A and B is an alkylene group having 1 to 3 carbon atoms which may be the same or different from each other,

Z is a carboxyl group and its derivatives are acid chlorides, acid anhydrides, acid amide groups, isocyanate groups, hydroxyl groups, amino groups, aldehyde groups, epoxy groups, mercapto groups, vinyl groups, vinyl sulfone groups, maleimide groups, succinimidyl ester groups, From the group consisting of an N-hydroxysuccinimide group and a benzotriazole carbonate group, it is selected as shown in Table 1 according to the kind of the functional group Y of the silane to be bonded.

The molecular weight of the PEO unit is usually 440 to 8,800, more preferably 500 to 6,000. If the molecular weight of the PEO is less than 500, the physiological effect of the PEO is very small, and if it is greater than 6,000, the effect no longer increases. Such PEO compounds are readily available from some companies (e.g., Shearwater, USA or NOF, Japan), and chemical methods using various PEO derivatives are known in the literature (eg, PEG Chemistry and Biological Applications, ACS, 1997). Reactions for chemically bonding the silane compound and the PEO derivative are well known esterification reactions, amidation reactions, substitution reactions or addition reactions, and therefore known catalysts may be used.

Range of functional group selection of silanes and PEO derivatives Functional group of silane (Y) Functional group (Z) of PEO derivative -Amino group -Carboxyl groups and derivatives thereof, acid chlorides, acid anhydrides, acid amide groups-isocyanate groups-aldehyde groups-epoxy groups-vinyl sulfone groups-succinimidyl ester groups, N-hydroxysuccinimide groups, benzotriazole carbonate groups Epoxy -Hydroxyl group-amino group-carboxyl group Isocyanate group -Hydroxyl group-amino group -Hydroxyl group Carboxyl groups and derivatives thereof, acid chlorides, acid anhydrides, acid amide groups, isocyanate groups, aldehyde groups, epoxy groups, succinimidyl ester groups, N-hydroxysuccinimide groups, and benzotriazole carbonate groups Mercapto group Vinyl sulfone group-maleimide group Vinyl group Mercapto group-amino group-vinyl group

The end group of the bound PEO derivative is further reacted with propanesultone [-(CH ₂ ) ₃ -O-SO _2- ] or taurine [NH _2- (CH ₂ ) ₂ -SO ₃ H] under conventional conditions to form a sulfonic acid group. Can be substituted. As an example, the following Reaction Formulas 1-3 can be mentioned, A well-known catalyst can be used for such esterification reaction, amidation reaction, substitution reaction, or addition reaction.

In addition, as described above, heparin contains a small amount of carboxyl, hydroxyl, and amino groups in addition to a large amount of sulfonic acid groups, and thus can be chemically bonded to the functional groups of the bonded PEO derivative under ordinary conditions. However, heparin is dissolved only in water and formamide, so that it is reacted in such a solvent, and an acid, an alkali, a water-soluble carbodiimide compound or the like, which is usually a condensation reaction or an addition reaction catalyst, can be used. As an example, the following reaction schemes 4-6 can be mentioned.

The amount of heparin introduced is optically quantified by the toluidine blue method. Since heparin bound by the method of the present invention is a permanent chemical bond, its efficacy is long-term, and since PEO, a water-soluble polymer, is used as a sequestration unit, its physiological function is superior to that of free heparin.

The chemical composition of the modified metal surface is analyzed by electron spectroscopy for chemical analysis (ESCA). The ratios of O / C, N / C, S / C and Na / C were calculated using the AlKα x-ray of ESCA 2803-S (SSI, USA) based on the binding energy of the CH group C1s absorption band at 285.0 eV. . Hydrophilicity was evaluated by measuring the contact angle of the metal surface (model CA-DT 11931, Kyowa Interface Sci., Japan). In addition, antithrombogenicity was evaluated by measuring the degree of adhesion of platelets to the modified metal surface, and the process was as follows. Place the metal specimen in a disposable syringe and add 2 ml phosphate buffer solution, replace the buffer with 2 ml of human platelet rich plasma (platelet 52 x 10 mm / μl) and replace the syringe at 37 ° C. Place in a controlled shake incubator and hold for a period of time. The syringes were recovered and the non-adhesive platelets in plasma were measured by a coulter or cytometer to back-calculate the adherent platelets (see Hee Jung et al., Polymer (Korea), 21, 1045-1052, 1997).

The present invention will be described in more detail with reference to the following Examples, but the present invention is not limited to these Examples.

<Example 1>

Stainless steel 316 specimens (Korea Special Steel Co., Ltd., size 1x1 cm and 1x3 cm) were oxidized at 25 ° C./vol. Washed and dried. The treated metal specimens were placed in a solution of 10% gamma-aminopropyltriethoxysilane (Aldrich, USA) in toluene, refluxed under nitrogen atmosphere for 3 hours, washed with toluene, acetone and water, and dried in a vacuum oven at 110 ° C. Heat treatment was carried out for 4 hours. The treated metal specimens were placed in a solution of 100 mM diepoxyPEO (molecular weight 1,000 of PEO, Nagase Chemicals, Japan) in tetrahydrofuran, a small amount of triethylamine was added and reacted at 50 ° C. for 1 day, followed by washing with water. And dried at room temperature in a vacuum oven. Subsequently, the metal specimen was added to 15 ml of an aqueous solution of heparin (Sigma, Inc., IA grade, 1 million units, USP 170 units / mg activity) at a concentration of 1 weight / vol% and reacted for 24 hours. ESCA analysis showed that the element ratio of the surface was 60.6% carbon, 36.0% oxygen, 3.4% silicon for silane-bonded surfaces, 53.7% carbon, 43.2% oxygen, 3.1% silicon for diepoxyPEO-bonded surfaces. After the heparin bond, it was confirmed that the reaction proceeded as intended as 50.6% carbon, 45.8% oxygen, 3.2% silicon, and 0.4% sulfur. As a result of measuring the contact angle of the treated stainless steel, it was found that the contact angle was completely wetted to be more hydrophilic than 60.5 degrees of the untreated specimen. The amount of bound heparin was 4.2 μg / cm ² as determined by toluidine assay. As a result of platelet adhesion test, the platelet adhesion rate was about 70% lower than that of untreated stainless steel surface at 60 minutes after the start of the experiment, indicating superior antithrombogenicity.

<Example 2>

A stainless steel 316 specimen whose surface was oxidized as in Example 1 was placed in an aqueous solution of 1 wt / vol% gamma-aminopropyltriethoxysilane (Aldrich, USA), reacted for 1 minute, and then vacuum oven at 100 ° C. Heat treatment for 4 h at. The silane bonded specimens were treated in the same manner as in Example 1 to bind diepoxyPEO. To convert the ends of the introduced epoxyPEO into sulfonic acid groups, the specimens were placed in a solution of 100 mM taurine (Dong-A Pharmaceutical) in dimethylformamide, a small amount of triethylamine was added and reacted at 50 ° C. for 1 day, It was dried at room temperature in a vacuum oven. ESCA analysis showed that the element ratio of the surface was 60.6% carbon, 36.0% oxygen, 3.4% silicon for silane-bonded surfaces, 53.7% carbon, 43.2% oxygen, 3.1% silicon for diepoxyPEO-bonded surfaces. After the taurine bond, it was confirmed that the reaction proceeded as intended as 50.1% carbon, 45.4% oxygen, 3.0% silicon, and 0.5% sulfur. As a result of measuring the contact angle of the treated stainless steel, it was found that the contact angle was completely wetted and larger than 60.5 degrees of the untreated specimen. As a result of the platelet adhesion test, the platelet adhesion rate was about 75% lower than that of the plated stainless steel surface at 60 minutes after the start of the experiment, indicating superior antithrombogenicity.

<Example 3>

Nickel-titanium alloy specimens whose surface was oxidized in the same manner as in Example 1 were placed in a solution of 10% isocyanatopropyltriethoxysilane (United Chemical Technology, Inc.) in anhydrous toluene and refluxed under nitrogen atmosphere for 3 hours. After the reaction, the mixture was washed with toluene, acetone and water and heat-treated for 4 hours in a vacuum oven at 110 ° C. The specimen was added to 15 ml of a solution (5% by weight / vol%) of diaminoPEO (NOF Japan, molecular weight 3,000 of PEO) in chloroform, reacted for 24 hours, and washed with water. DiaminoPEO-bound specimens were added to 20 ml of a solution of propanesultone (5% by weight) in chloroform and reacted for 24 hours and washed with water. As in Example 1, the element ratio of the surface was analyzed by ESCA, and the surface of the silane-bonded surface was 60.4% carbon, 36.2% oxygen, and 3.4% silicon, and the surface of diaminoPEO-bound carbon 53.9%, oxygen It was 43.0% and 3.1% of silicon, and it was confirmed that after propanesultone bonding, reaction progressed as the purpose as 50.2% of carbon, 45.5% of oxygen, 2.9% of silicon, and 0.4% of sulfur. As a result of measuring the contact angle of the treated nickel-titanium specimen, it was found that the contact angle was 17.5 degrees, which was greater than 68.3 degrees of the untreated specimen. As a result of the platelet adhesion test, the platelet adhesion rate was reduced by 75% compared to the platelet adhered to the untreated nickel-titanium surface at 60 minutes after the start of the experiment, indicating excellent antithrombogenicity.

<Example 4>

The surface was oxidized in the same manner as in Example 1 using tantalum specimens (Aldrich, USA). Specimens were refluxed in a gamma-glycidooxypropyltrimethoxysilane (Aldrich, USA) at a concentration of 10% by weight in 15 ml of toluene for 4 hours, and 5% by weight of diaminoPEO (NOF, Japan). It was added to 15 ml of an aqueous solution of 2,000 molecular weight of PEO and reacted for 24 hours. Subsequently, it was added to 15 ml of an aqueous solution of heparin at a concentration of 1 wt / vol% added with a small amount of triethylamine and reacted for 24 hours. As in Example 1, the element ratio of the surface was analyzed by ESCA, and the surface of the silane-bonded surface was 60.6% carbon, 36.2% oxygen, and 3.2% silicon, and the surface of diaminoPEO-bound carbon 55.9%, oxygen It was 42.0% and 2.1% of silicon, and it was confirmed that after heparin bonding, reaction progressed as the purpose as 52.7% of carbon, 45.0% of oxygen, 2.0% of silicon, and 0.3% of sulfur. The contact angle of the treated tantalum was also fully wetted and hydrophilized greater than 48.5 degrees of the untreated specimen. The amount of bound heparin was 3.2 μg / cm ² as determined by toluidine assay. As a result of the platelet adhesion test, the platelet adhesion rate was reduced by 65% compared to the platelet adhered to the untreated tantalum surface at 60 minutes after the start of the experiment, indicating excellent antithrombogenicity.

Example 5

The surface was oxidized in the same manner as in Example 1 using stainless steel 316 specimens. In a solution of 100 mM gamma-aminopropyltriethoxysilane (Aldrich, USA) in ethanol, refluxed for 3 hours in a nitrogen atmosphere, washed with acetone and water, and heat-treated in a vacuum oven at 110 ° C. for 4 hours. The specimen was reacted for 1 day in an aqueous solution of 5 wt / vol% of dialdehyde-do-PEO (the molecular weight of PEO, Shearwater Polymers, USA) for 1 day, and then dried at room temperature. The treated specimens were placed in a solution of 100 mM taurine in dimethylformamide, a small amount of triethylamine was added, reacted at 50 ° C. for 1 day, and dried at room temperature in a vacuum oven. As a result of analyzing the element ratio of the surface by ESCA as in Example 1, the surface of silane-bonded surface was 60.6% of carbon, 36.0% of oxygen, and 3.4% of silicon. It was 43.9% of oxygen and 3.2% of silicon, and it was confirmed that the reaction proceeded as desired as carbon 51.7%, oxygen 46.0%, silicon 2.0%, and sulfur 0.3% after taurine bonding. As a result of measuring the contact angle of the treated stainless steel specimen, it was found that the contact angle was 15.6 degrees, which was greater than 60.5 degrees of the untreated specimen. As a result of platelet adhesion test, the platelet adhesion rate was reduced by 62% compared to platelets attached to the surface of untreated stainless steel at 60 minutes after the start of the experiment, which showed excellent antithrombogenicity.

<Example 6>

In Example 1, instead of gamma-aminopropyltriethoxysilane, gamma-aminopropylmethyldiethoxysilane (Aldrich, USA) was used to bind diepoxyPEO and heparin to the stainless steel surface in the same manner. ESCA analysis showed that the element ratio of the surface was 63.6% carbon, 33.4% oxygen, 3.0% silicon for the silane-bonded surface, and 56.6% carbon, 40.6% oxygen, and 2.8% silicon for the diepoxyPEO-bonded surface. After the heparin bond, it was confirmed that the reaction proceeded as intended as 53.2% carbon, 44.1% oxygen, 2.5% silicon, and 0.2% sulfur. As a result of measuring the contact angle of the treated stainless steel, it was found that the contact angle was 12.5 degrees and was more hydrophilized than the untreated specimen 60.5 degrees. The amount of bound heparin was 2.2 μg / cm ² as determined by toluidine assay. As a result of the platelet adhesion test, the platelet adhesion rate was about 50% lower than that of the plated stainless steel surface at 60 minutes after the start of the experiment, indicating superior antithrombogenicity.

<Example 7>

In Example 2, instead of gamma-aminopropyltriethoxysilane, gamma-aminopropyldimethylethoxysilane was used to bind diepoxyPEO to the surface of stainless steel and react taurine in the same manner. ESCA analysis showed that the element ratio of the surface was 66.6% carbon, 31.5% oxygen, 2.9% silicon for the silane-bonded surface, and 59.2% carbon, 38.1% oxygen, and 2.7% silicon for the diepoxyPEO-bonded surface. After the taurine bond, it was confirmed that the reaction proceeded as intended as 56.4% carbon, 41.1% oxygen, 2.3% silicon, and 0.2% sulfur. As a result of measuring the contact angle of the treated stainless steel, it was found that the contact angle was 15.3 degrees and was more hydrophilized than the untreated specimen 60.5 degrees. As a result of the platelet adhesion test, the platelet adhesion rate was reduced by about 45% from the platelet adhered to the untreated stainless steel surface at 60 minutes after the start of the experiment, indicating excellent antithrombogenicity.

According to the present invention, the metal material to which the functional silane compound is chemically bonded to the surface of the metal material, and in addition to the sulfonated PEO derivative or heparin, has significantly improved antithrombogenic properties, and thus, stents, heart valves, and catheter When used as the same metal material for implantation in the body, the formation of thrombi is advantageous because it is reduced.

Claims (12)

delete Substrate metal, A functional silane compound bonded to the surface of the base metal, and Blood compatible medical metal material comprising a sulfonated PEO derivative chemically bonded through a functional group of the silane compound. The metal material according to claim 2, wherein the functional silane compound is a compound of formula (1). <Formula 1> YR-Si (CH ₃ ) _a -X _3-a In the above formula, X is an ethoxy group, a methoxy group, butoxy group, an aceoxyl group, a chloro group, etc., a is an integer of 0, 1 or 2, R is an alkyl group having 2 to 4 carbon atoms, Y is an amino group, an epoxy group, an isocyanate group, a hydroxyl group, a mercapto group, a vinyl group, etc. The functional silane compound according to claim 3, wherein the functional silane compound is gamma-aminopropyltriethoxysilane, N-β- (aminoethyl) -gamma-aminopropyltriethoxysilane, beta- (3,4-epoxycyclohexyl) ethyl Trimethoxysilane, gamma-glycidooxypropyltrimethoxysilane, isocyanatopropyltriethoxysilane, N-bis (beta-hydroxyethyl) -gamma-aminopropyltriethoxysilane, gamma-mercapto Propyltrimethoxysilane, vinyl trichloride silane, vinyltriethoxysilane, vinyltrimethoxysilane, vinyltriacetoxysilane, methacryloxypropyltrimethoxysilane, vinylbenzylaminotrimethoxysilane, and these A metal material selected from the group consisting of methylsilane or dimethylsilane compounds of the compound. The metal material of claim 2, wherein the PEO derivative is a compound of formula (II): <Formula 2> Z-A-PEO-B-Z In the above formula, PEO is an ethylene oxide repeat unit represented by-(CH ₂ -CH ₂ -O) n- (n is an integer from 10 to 200), A and B is an alkylene group having 1 to 3 carbon atoms, which may be the same or different from each other, Z is a carboxyl group and its derivatives are acid chlorides, acid anhydrides, acid amide groups, isocyanate groups, hydroxyl groups, amino groups, aldehyde groups, epoxy groups, mercapto groups, vinyl groups, vinyl sulfone groups, maleimide groups, succinimidyl ester groups, N-hydroxysuccinimide group, benzotriazole carbonate group. The metal material of claim 5, wherein the molecular weight of the PEO derivative is from 500 to 6,000. delete The metal material of claim 2, wherein the base metal is selected from the group consisting of stainless steel, titanium and alloys thereof, nickel and alloys thereof, chromium and alloys thereof, tantalum and alloys thereof. delete Bonding the functional silane compound to the surface of the base metal, and Chemically bonding the PEO derivative through the functional group of the silane compound, and And converting the functional group of the PEO into a sulfonic acid group. The method of claim 10, wherein an esterification catalyst, an amidation catalyst, a substitution reaction or an addition reaction catalyst is used to chemically bond the bound silane compound and the PEO derivative. A stent, cardiac valve, or catheter made of a metal material according to claim 2 to which a sulfonated PEO derivative is chemically bonded.