CN1748804A - Anti-blood coagulation surface modifying method of artificial implant - Google Patents

Abstract

The invention relates to an anticoagulant surface modification method of an artificial implant, which belongs to the technical field of anticoagulant materials. Heparin against hard junctions reduces the flexibility of the artificial blood vessel and the anticoagulant performance is not good enough, the concentration of covalently bonded monolayer heparin is too low, and the stability of ionically bonded multilayer heparin molecular film is poor in polar solvents The shortcoming of the present invention is achieved in this way: a. cleaning artificial implant; b. preparing silicone rubber solution; c. coating medical silicone rubber on the inner surface of artificial implant as soft support; d. Coating perfluorosulfonic acid on the surface of the coating; e. Alternately depositing polycations and polyanions on the surface of the perfluorosulfonic acid coating through electrostatic attraction; f. Utilizing ultraviolet light to irradiate the artificially implanted body wall, through Photochemical reactions convert ionic bonds between layers within the membrane to covalent bonds. The invention has the advantages of simple process, mild reaction conditions, easy operation, good reproducibility, environmental friendliness and good application prospect.

Description

Anticoagulation surface modification method of artificial implant

Technical field:

The invention belongs to the technical field of anticoagulant materials, and relates to a method for modifying an artificial implant with a silicon rubber coating as a soft support and covalently bonding a multilayer heparin film so that the surface has anticoagulant performance.

Background technique:

In small-caliber artery reconstruction surgery, the blood compatibility requirements for arterial prostheses are very high. In order to ensure long-term patency after surgery, autologous saphenous vein is usually used as arterial prosthesis. However, when the patient cannot provide an autologous saphenous vein, artificial blood vessels must be used instead. Although expanded polytetrafluoroethylene has been successfully used in the manufacture of larger diameter blood vessels, for blood vessels with diameters less than 6mm, these materials are powerless due to blood clotting or tissue blockage. Although the long-term patency rate has been improved after continuous improvement and modification, it still cannot achieve satisfactory results compared with the autologous saphenous vein. question. The small-diameter arterial prosthesis should not only have sufficient flexibility to facilitate its anastomosis with arteries, but also should have excellent blood compatibility without causing coagulation reactions to maintain long-term patency.

Because only the surface of artificial blood vessels is in contact with blood, current work is mainly focused on modifying and modifying the surface of existing materials to meet the requirements of vascular implantation. Immobilizing heparin molecules on the surface of artificial blood vessels to improve their anticoagulant performance has always been a research hotspot. Earlier researchers used tetravalent ammonium ions to bind heparin, and then complexed the ions to the polymer matrix through long alkyl chains. Ionically bound heparin slowly dissolves from the surface and binds with antithrombin-III (AT-III) near the surface to form the active anticoagulant. This method is suitable for short-term blood catheters, but it is not effective for long-term blood catheters and artificial blood vessels because heparin is quickly exhausted due to dissolution. The second method is to directly attach heparin to the surface of the substrate through covalent bonds. Although the stability of immobilized heparin is much higher through covalent bonding than ionic bonding, the anticoagulant performance of immobilized heparin is generally just the opposite. Because hard-linked heparin not only reduces the elasticity of artificial blood vessels but also cannot cooperate well with antithrombin. Therefore, how to improve the anticoagulant properties of covalently bonded heparin without affecting the bulk properties of the material has always been the main content of the research on heparinization of biomaterials. Studies have shown that if heparin molecules are kept at a certain distance from the polymer surface, the anticoagulant performance will be improved. In addition, in order to make immobilized heparin have higher anticoagulant properties, in addition to reducing the impact of immobilization on the biological activity of heparin, the concentration of immobilized heparin on the surface of the material should also be increased.

Heparin itself has strong negative charge, hydrophilicity and more active functional groups. However, polymers such as polytetrafluoroethylene that make up artificial blood vessels are chemically inert and hydrophobic, and cannot directly react with heparin molecules. Therefore, the main step of the covalent bonding method is to chemically pretreat the surface of the polymer material so that it has the ability to react with heparin, and then bond the heparin molecule. Although there are many pretreatment methods for artificial blood vessels, they are difficult to be widely used due to the problems of expensive instruments and equipment, influence on the structure of the material body, and complicated operation process.

Silicone rubber has excellent elasticity, softness, high heat resistance and aging resistance, and can be sterilized by high pressure steam; it is compatible with human tissue and blood, and is an ideal material for coating artificial blood vessels. Although silicone rubber has a certain anticoagulant effect, it is still difficult to meet the clinical requirements. It is necessary to further immobilize heparin molecules on the surface of the silicone rubber coating to improve its anticoagulant performance. However, silicone rubber, like the materials that make up artificial blood vessels, has strong chemical inertness and hydrophobicity, and cannot directly react with heparin molecules.

Nafion (perfluorosulfonic acid) has high stability and biological inertness, so it has good biocompatibility. Since Nafion has a hydrophobic fluorocarbon backbone molecular structure similar to Teflon (Teflon), there is a strong hydrophobic interaction between Nafion and silicone rubber, which is conducive to the formation of Nafion coating on the surface of silicone rubber. The hydrophilic sulfonic acid groups on the Nafion suspension chain can provide active groups for further immobilizing heparin molecules.

In the past ten years, the electrostatic attraction layer-by-layer self-assembly technology has received extensive attention at home and abroad. The basic method and principle are to alternately adsorb multilayer polymer molecular films of polyanions and polycations on the substrate surface through the electrostatic attraction of polycations and polyanions. This technology can not only conveniently control the composition and structure of the film at the molecular level, but also control the thickness of the film at the nanometer scale. However, the disadvantage of this method is the poor stability of ionically bonded molecular membranes in polar solvents.

Invention content:

The purpose of the present invention is to reduce the flexibility of artificial blood vessels and the anticoagulant performance is not good enough for hard-linked heparin, the concentration of covalently bonded monolayer heparin is too low, and the electrostatic attraction layer-by-layer self-assembly technology has ion-bonded The disadvantage of poor stability of molecular membranes in polar solvents provides an anticoagulant surface modification method for artificial implants. This method uses silicone rubber coatings as soft supports to assemble diazo resin and heparin multilayer membranes, which is sufficient Utilizing the simplicity of layered electrostatic assembly, combined with the photochemical reaction of diazo groups and sulfuric acid groups in the film, the ionic bonds in the film are converted into covalent bonds, so that the heparin multilayer film Stability has been greatly improved. The present invention is realized in the following ways: a. soak the artificial implant in an organic solvent, ultrasonically clean it for 30-120 minutes, and then dry it at 30-90°C for 0.5-2 hours; b. cure the medical silicone rubber at room temperature Adhesive is dissolved in an organic solvent to prepare a silicone rubber solution; c, coating medical silicone rubber on the inner surface of the artificial implant as a soft support; d, coating a full silicone rubber coating on the surface Fluorosulfonic acid; e, positively charged polycations and negatively charged polyanions are alternately deposited on the surface of the perfluorosulfonic acid coating through electrostatic attraction; f, using ultraviolet light to irradiate the artificially implanted body wall, through The photochemical reaction converts the ionic bond between the inner layers of the membrane into a covalent bond, and an anticoagulant surface ultrathin film is obtained.

The method of the present invention has the following advantages:

(1) There is no need for chemical pretreatment of artificial implants, which is economical and can avoid damage to the properties of the material body due to pretreatment.

(2) Coating silicone rubber on the surface of the artificial implant not only increases the flexibility of the artificial implant, but also provides soft support for the heparinization of the artificial implant, so that there is a certain distance between the heparin molecule and the surface of the artificial implant , so as to improve its anticoagulant performance, and overcome the shortcomings of hard-linking heparin to the surface of the material in the traditional heparinization method to reduce the anticoagulant performance.

(3) Not only the composition and structure of the film can be conveniently controlled at the molecular level, but also the thickness of the covalently bonded film can be controlled at the nanometer scale. The concentration of immobilized heparin on the surface can be increased by increasing the number of layers of heparin as needed, which overcomes the shortcomings of low heparin concentration and fast consumption due to dissolution or biodegradation in the traditional single-layer heparin solidification method.

(4) The in situ photochemical reaction converts the ionic bond between the layers into a covalent bond, avoiding the adsorption and aggregation of platelets caused by leaving a positively charged surface after heparin molecules are released from the surface of the artificial implant.

(5) The inner layer and the interlayer of the membrane are covalently bonded, which overcomes the shortcomings of the ionically bonded membrane prepared by traditional electrostatic self-assembly, such as insufficient stability.

(6) The present invention has simple process, mild reaction conditions, easy operation, good reproducibility, and environmental friendliness, and is suitable for anticoagulation of material surfaces of various complex shapes, biomedical devices, porous tissue engineering scaffold materials and macroscopic products thereof Surface modification has good application prospects.

Description of drawings:

Figure 1 shows the absorption spectra of multilayer films (DR/Hep) _n (n=1, 2, 3, 4, 5) assembled on quartz glass slides pre-coated with silicone rubber and Nafion as a function of the number of DR/Hep bilayers Figure 2 is the relationship diagram of the absorption spectrum of the (DR/Hep) ₅ multilayer film assembled on the quartz glass slide coated with silicone rubber and Nafion in advance with the time of ultraviolet light irradiation, Figure 3 is the relationship diagram of heparinization The relationship diagram of the anticoagulant activity of the artificial blood vessel. Figure 4 is the relationship diagram of the effect of multi-layer heparin film on the inactivation of thrombin after photochemical crosslinking on the artificial blood vessel with the change of the number of DR/Hep double layers. Effect of photochemically crosslinked (DR/Hep) ₅ and (DR/Hep) ₁₀ multilayer heparin films on the inactivation of thrombin.

Detailed ways:

Specific Embodiment 1: This embodiment is achieved in the following way: a. Soak the artificial implant in an organic solvent, ultrasonically clean it for 30 to 120 minutes, and then dry it at 30 to 90°C for 0.5 to 2 hours; b. Medical silicone rubber is used as a room temperature curing adhesive, which is dissolved in an organic solvent to prepare a silicone rubber solution; c. Coating medical silicone rubber on the inner surface of the artificial implant as a soft support; d. Coating the silicone rubber coated with perfluorosulfonic acid on the surface; e, positively charged polycations and negatively charged polyanions are alternately deposited on the surface of perfluorosulfonic acid coating through electrostatic attraction; f, artificially irradiated with ultraviolet light Implanted into the inner wall of the body, the ionic bonds between the inner layers of the membrane are converted into covalent bonds through photochemical reactions, and an anticoagulant surface ultra-thin film is obtained.

In this embodiment, the organic solvent used for cleaning the artificial implant is absolute ethanol, acetone or a mixture thereof.

In this embodiment, the organic solvent used to dissolve the silicone rubber is an alkane solvent (n-hexane or other alkane solvent).

In this embodiment, the artificial implant can be artificial blood vessels of various calibers made of various materials including expanded polytetrafluoroethylene, or blood catheters of various calibers made of various materials, Polymer membranes or porous scaffolds, and biomedical devices of various shapes made of materials such as glass, ceramics, silicon, various metals, or various polymers.

In this embodiment, the polyanion can be one or a mixture of heparin, heparan sulfate, sodium alginate, sodium polystyrene sulfonate, glucose sulfate, chondroitin sulfate, sodium polyacrylate, and polymethacrylic acid. The above-mentioned anions can also be selected from various proteins, growth factors and branch-inducing factors with amphoteric charge properties. These proteins, growth factors and differentiation-inducing factors can obtain different charge properties by adjusting the pH value.

In this embodiment, the polycation is diphenylamine-4-diazo resin or substituted diphenylamine diazo resin, such as 3-methoxydiphenylamine-4-diazo resin, N-methyldiphenylamine-4-diazo resin One or more mixtures of resin, 2-nitrodiphenylamine-4-diazo resin, 2-sulfonic acid diphenylamine-4-diazo resin, N-methyldiphenylamine-2-diazo resin, etc. .

Specific implementation mode two: this implementation mode is realized in this way:

1) Cleaning the artificial blood vessel: Soak the expanded polytetrafluoroethylene artificial blood vessel in an organic solvent, sonicate for 30-120 minutes, and then dry it at 30-90° C. for 0.5-2 hours.

2) Dissolving the silicone rubber: dissolving the medical silicone rubber as a room temperature curing adhesive in an organic solvent to prepare a silicone rubber solution with a volume concentration of 0.1-100v/v%.

3) Silicone rubber coating: connect the artificial blood vessel to the syringe, erect it, and then use the syringe to inject the silicone rubber solution into the lumen of the artificial blood vessel from the end until the lumen is filled. Then remove the silicone rubber solution from the end of the artificial blood vessel with a syringe, and dry it in the air at room temperature for 2 to 100 hours.

4) Soak the silicone rubber coating: seal the end of the artificial blood vessel, fill the lumen with absolute ethanol, and let it stand for 0.5-10 hours.

5) Preparation of Nafion solution: remove the solvent from the 5wt% Nafion solution purchased from Aldrich with a rotary evaporator, and then add a new organic solvent to prepare a 1-20wt% Nafion solution. The new organic solvent is n-hexane or other alkane solvents.

6) Coating Nafion: inject the Nafion solution from the end of the artificial blood vessel into its lumen with a syringe until the lumen is filled, remove the Nafion solution and blow dry with nitrogen. Repeat the three-step process of injection, removal, and nitrogen blow-drying for 2 to 100 times.

7) Electrostatic attraction layer-by-layer self-assembly of diphenylamine diazo resin and polyanion ultra-thin films including heparin: use a syringe to inject a positively charged diphenylamine diazo resin solution with a concentration of 0.001 to 100 mg/ml from the end of the artificial blood vessel In the lumen, until the lumen is filled, the adsorption time is 0.5 to 30 minutes. After the inner wall of the artificial blood vessel is adsorbed with a layer of diphenylamine diazo resin, remove the solution and wash it with deionized water. charge; use the same method to fill the artificial blood vessel with 0.001-100mg/ml negatively charged polyanion solution, and the adsorption time is 0.5-30 minutes. After the inner wall of the artificial blood vessel is adsorbed with a layer of polyanion, remove the solution and use The ionized water is washed clean, and the surface is negatively charged at this time. Repeat the above steps to alternately assemble the diphenylamine diazo resin and the polyanion on the inner wall of the artificial blood vessel until the required number of layers is reached (the thickness is generally 1-1000 nm). After the reaction, the solution was taken out, washed with deionized water, and vacuum-dried to constant weight at room temperature.

8) Use ultraviolet light to convert the ionic bond between the self-assembled film layers into a covalent bond: irradiate the inner wall of the artificial blood vessel with ultraviolet light or visible light with a wavelength of 365nm, and a photochemical reaction occurs to make diphenylamine diazo resin and heparin Ionic bonds between polyanions are converted to covalent bonds.

In step 1) of this embodiment, the ultrasonic time is preferably 30 minutes, the drying temperature is preferably 60° C., and the drying time is preferably 0.5 hour.

In step 2) of this embodiment, the concentration of the dissolved silicone rubber is preferably 50 v/v%.

In step 3) of this embodiment, the drying time in the air and at room temperature is preferably 24 hours.

In step 4) of this embodiment, the time for soaking the silicone rubber coating with absolute ethanol is preferably 2 hours.

In step 6) of this embodiment, the organic solvent for preparing the Nafion solution is methanol, absolute ethanol or a mixture thereof. The concentration of the Nafion solution is preferably 5 wt%, and the number of cycles of the three-step process of injecting, removing the Nafion solution, and drying with nitrogen is preferably 20 times.

In step 7) of this embodiment, the concentration of diphenylamine diazo resin and polyanion aqueous solution is preferably 0.1-10 mg/ml, and the adsorption time is preferably 1 minute.

In this embodiment, silicone rubber is coated on the surface of biomedical devices such as artificial blood vessels as a soft support, and then Nafion is coated on the surface of the silicone rubber coating to provide active groups for layer-by-layer electrostatic assembly. Then positively charged diphenylamine diazo resin and negatively charged heparin molecules are deposited onto the surface of Nafion coating alternately by electrostatic attraction. Next, the artificial blood vessel is placed under ultraviolet light, the diazo group of DR is positively charged, and the sulfate group of heparin is negatively charged. Through electrostatic attraction, a photochemical reaction occurs between the diazo group and the sulfate group of heparin. The ion complex is formed to generate sulfate ester, and the ionic bond in the membrane is transformed into a covalent bond, and a covalently bonded multilayer membrane is prepared, which greatly improves the stability of heparin in the membrane. After layer-by-layer self-assembly and photochemical reaction, heparin molecules still maintain their original biological activity and have obvious anticoagulant effect. The surface of the heparin film prepared in this embodiment has active groups, and films of other materials, such as polyelectrolytes, biofunctional molecules, conductive polymers, etc., can also be assembled on the surface. The photochemical reaction equation of heparin (Hep) and diphenylamine diazo resin (DR) is:

Specific implementation mode three: this implementation mode is realized in this way:

a. Soak the expanded polytetrafluoroethylene artificial blood vessel in absolute ethanol, sonicate for 30 minutes, and then dry at 60° C. for 1 hour.

b. Using medical silicone rubber as a room temperature curing adhesive, dissolve it in an organic solvent to prepare a 50v/v% silicone rubber solution;

c. Connect the artificial blood vessel to the syringe, stand it upright, and then use the syringe to inject 50v/v% silicone rubber solution into the lumen of the artificial blood vessel from the end until the lumen of the artificial blood vessel is filled. The silicone rubber solution was removed and dried in air at room temperature for 24 hours. Clamp the end of the artificial blood vessel with clips, fill the lumen with absolute ethanol, and let it stand for 2 hours.

d. Remove the ethanol, and inject 5wt% Nafion solution from the end of the artificial blood vessel into its lumen with a syringe until the lumen of the artificial blood vessel is filled. Remove the Nafion solution and dry it with nitrogen. Repeat the three-step process of injection, removal, and nitrogen blow-drying 20 times.

e. Use a syringe to inject a positively charged diphenylamine diazo resin solution with a concentration of 1 mg/ml into the cavity from the end of the artificial blood vessel until the cavity is filled. The adsorption time is 15 minutes. After layering the diphenylamine diazo resin, the solution was removed and washed with deionized water, at this time the surface was positively charged. Use the same method to fill the artificial blood vessel with a heparin solution with a concentration of 1 mg/ml, and the adsorption time is 1 minute. After a layer of heparin is absorbed on the inner wall of the artificial blood vessel, remove the solution and wash it with deionized water. charge. Repeat the above steps to assemble the diphenylamine diazo resin and heparin alternately on the inner wall of the artificial blood vessel. After the reaction, the solution is removed, washed with deionized water, and vacuum-dried at room temperature to constant weight. Except that the adsorption time of the first layer of diphenylamine diazo resin is 15 minutes, the adsorption time of the rest of the diphenylamine diazo resin layer and all the heparin layers is 1 minute. In order to prove that DR and Hep can form a uniform multi-layer polymer film through electrostatic interaction, the above steps were repeated with a quartz glass plate instead of an artificial blood vessel as the substrate.

It can be seen from Figure 1 that the absorption peak with a maximum absorption wavelength of 377nm is attributed to the π-π ^* transition of the diazo group on DR. As the number of DR/Hep bilayers increases, the absorbance at the maximum wavelength increases linearly, strongly demonstrating that DR and Hep can form a uniform coating through electrostatic attraction. This not only shows the occurrence of layer-by-layer electrostatic self-assembly process, but also shows that DR and Hep form a uniform polymer coating.

f. Use a slender long-wavelength ultraviolet lamp [365nm, 0.95cm in diameter, 5.4cm in length] as a light source to irradiate the DR/Hep multilayer film, and the distance between the sample and the light source is 3cm (relative intensity 2mW/cm ² ).

It can be seen from Figure 2 that the illumination time is 0s, 30s, 50s, 90s, and 150s. As the irradiation time increases, the absorbance at 377nm decreases significantly, and the absorption peak disappears; at the same time, a new one appears at 290nm. The peak, the absorbance increases with the irradiation time. This strongly proves that a photochemical reaction occurs between the diazo group of DR and the sulfate group of Hep to generate sulfate ester, thereby converting the ionic bond in the membrane into a covalent bond.

Cut the heparinized artificial blood vessels into small discs with a diameter of 18mm, culture them in Hepes buffer solution (20mM Hepes+190mM NaCl+0.5mg/ml BSA+0.02%NaN ₃ ) at 37°C, and then add human anticoagulant blood Enzyme (antithrombin, AT-III), incubate for 5 minutes, then add thrombin (thrombin) to start the reaction. The final concentrations of thrombin and antithrombin were 10 nM and 20 nM, respectively. 16 μL of the reaction solution was taken out at regular intervals, and 368 μL of Tris buffer solution (50 mM Tris+175 mM NaCl+0.5 mg/ml BSA) containing 20 mM EDTA was added to stop the reaction. Add 16 μL of chromogenic substrate S-2238 (final concentration is 0.2 mM), and detect thrombin with a UV/vis spectrophotometer at 405 nm.

It can be seen from Figure 3 that the [(PLL/Hep) ₄ and (DR/Hep) ₄ ] multilayer films containing heparin greatly accelerated the inactivation of thrombin compared with the reference sample without heparin (PLL is a poly- L-lysine). Before photocrosslinking, the ion-bonded (DR/Hep) ₄ and (PLL/Hep) ₄ were similar, and the heparin was released into the solution in a short period of time due to the dissolution effect, causing the thrombin concentration to drop sharply. After one week of incubation at 37°C in PBS buffer solution, the effects of (DR/Hep) ₄ and (PLL/Hep) ₄ on thrombin inactivation were similar to those of the reference samples due to heparin lysis loss. On the contrary, due to photocrosslinking, interlayer ionic bonds were transformed into covalent bonds, the effect of (DR/Hep) ₄ on thrombin inactivation did not change significantly after one week of culture, indicating that the stability of the covalently bonded heparin film was greatly improved. improve. Heparin-containing multilayer films [(PLL/Hep) ₄ and (DR/Hep) ₄ ] have good anticoagulant activity, and covalently bonded multilayer films (DR/Hep) ₄ have better stability sex.

From Figure 4, it can be seen that within four bilayers, the effect of heparin on thrombin inactivation increases with the number of DR/Hep bilayers. After more than four bilayers, further increasing the number of DR/Hep bilayers had no significant difference in the effect on thrombin inactivation. This suggests that only the outermost layer of heparin has a direct effect on thrombin inactivation. The effect on thrombin inactivation within four bilayers increases with the number of bilayers because the concentration of heparin in the outermost layer has not reached saturation.

It can be seen from Figure 5 that after 10 days of incubation in buffered solution at 37°C, the heparinized surface remained well active, but there was no significant difference between 5 bilayers and 10 bilayers, further demonstrating that covalent The bonded heparin multilayer film has high stability, and the surface concentration of heparin has reached saturation when the number of bilayers reaches 4.

Figures 4 and 5 show that only the outermost layer of heparin has a direct effect on thrombin inactivation.

Claims (10)

1. The method for modifying the anticoagulant surface of an artificial implant, which is characterized in that it is realized in this way: a. Soak the artificial implant in an organic solvent, ultrasonically clean it for 30-120 minutes, and then dry it at 30-90°C for 0.5-2 hours; b. Using medical silicone rubber as a normal temperature curing adhesive, dissolve it in an organic solvent to prepare a silicone rubber solution; c. Coating medical silicone rubber on the inner surface of the artificial implant as a soft support; d. Coating perfluorosulfonic acid on the surface of the silicone rubber coating; e, positively charged polycations and negatively charged polyanions are alternately deposited on the surface of the perfluorosulfonic acid coating by electrostatic attraction; f. Utilize ultraviolet light to irradiate the artificially implanted body wall, and convert the ionic bond between the inner layers of the film into a covalent bond through photochemical reaction to obtain an anticoagulant surface ultra-thin film. 2. The anticoagulation surface modification method of artificial implant according to claim 1, characterized in that the organic solvent used for cleaning the artificial implant is absolute ethanol, acetone or a mixture thereof. 3. The anticoagulant surface modification method of artificial implant according to claim 1 or 2, characterized in that the artificial implant is an artificial blood vessel, a blood vessel, a polymer film or a porous stent, or is made of glass , ceramics, silicon, various metals, or various polymer materials in various shapes of biomedical devices. 4. The method for modifying the anticoagulant surface of artificial implants according to claim 1, characterized in that the organic solvent for dissolving the silicone rubber is an alkane solvent. 5. The anticoagulant surface modification method of artificial implant according to claim 4, characterized in that the alkane solvent is n-hexane. 6. The anticoagulant surface modification method of artificial implant according to claim 1, characterized in that the volume concentration of the silicone rubber solution is 0.1-100v/v%. 7. The anticoagulant surface modification method of artificial implant according to claim 1, characterized in that the polyanion is heparin, heparan sulfate, sodium alginate, sodium polystyrene sulfonate, glucose sulfate, cartilage sulfate One or a mixture of sodium polyacrylate and polymethacrylic acid. 8. The anticoagulant surface modification method of artificial implant according to claim 1, characterized in that said polycation is diphenylamine-4-diazo resin or substituted diphenylamine diazo resin. 9. The anticoagulant surface modification method of artificial implant according to claim 8, characterized in that the substituted diphenylamine diazo resin is 3-methoxydiphenylamine-4-diazo resin, N-formazine In base diphenylamine-4-diazo resin, 2-nitrodiphenylamine-4-diazo resin, 2-sulfonic acid diphenylamine-4-diazo resin, N-methyldiphenylamine-2-diazo resin One or a mixture of several. 10. The method for modifying the anticoagulant surface of artificial implants according to claim 1, characterized in that the thickness of the anticoagulant surface ultra-thin film is 1-1000 nm.

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