Anticoagulant artificial blood vessel internal coating material and preparation method thereof

Abstract

The invention discloses an anticoagulant artificial blood vessel internal coating material and a preparation method thereof. The preparation method comprises the following steps: (1) preparing a double-effect chain extender; (2) stable heparin loading; and (3) preparing by a multi-stage anticoagulation mechanism process. After the anticoagulant artificial blood vessel inner coating material prepared by the invention is applied to the field of biological medicine, the expected effects mainly comprise: (1) a pre-modification core advantage: compared with an anticoagulant coating prepared by a post-modification strategy, uniform distribution of anticoagulant components can enable the coating to keep long-term effective anticoagulant performance; (2) anticoagulation performance: an in-vitro platelet adhesion experiment is adopted, and the prepared material can significantly inhibit platelet adhesion (the reduction rate gt; 78%); and (3) mechanical properties: the prepared coating material has excellent mechanical properties, the tensile strength is greater than or equal to 15 MPa, and the elongation at break is greater than 400%.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials technology, and in particular to an anticoagulant coating material for artificial blood vessels and its preparation method, which is mainly used to improve the long-term patency of small-diameter artificial blood vessels in vivo. Technical Background

[0002] Cardiovascular disease has become a major threat to human health, affecting a large number of people. In the treatment of cardiovascular diseases, implantable or interventional medical devices, such as artificial blood vessels, are frequently used. Autologous blood vessels are an ideal replacement for damaged blood vessels, but the source of autologous blood vessels is limited, and obtaining them can cause secondary trauma and complications for patients. Therefore, the demand for artificial blood vessels is constantly increasing. Current artificial blood vessel materials have certain issues regarding blood compatibility. For example, some materials are prone to inducing blood clotting, leading to thrombosis, which affects the patency and lifespan of the artificial blood vessel. While large-diameter artificial blood vessels generally have better long-term patency, thrombosis severely impacts the long-term patency rate of small-diameter artificial blood vessels (inner diameter < 6 mm). Optimizing the performance of small-diameter artificial blood vessels is of great clinical significance for cardiovascular surgery. For example, in coronary artery bypass grafting, a significant number of patients have small-diameter diseased coronary arteries, and the high thrombosis risk of existing small-diameter artificial blood vessels makes them unsuitable as an ideal choice. Overcoming the challenge of anticoagulation will bring hope to many patients with coronary heart disease, improve myocardial blood supply, reduce the risk of myocardial infarction, alleviate angina symptoms, and improve quality of life and long-term survival rates. Polyurethane materials, due to their excellent physical and mechanical properties and biocompatibility, have become one of the ideal choices for artificial blood vessels, but their anticoagulation performance still needs to be further improved through anticoagulation coatings.

[0003] Currently, the commonly used anticoagulant coating modification strategies for small-diameter artificial blood vessels are mainly divided into three categories: bio-inert coatings, bioactive coatings, and coatings with endothelial cell (EC)-specific growth factors. Bio-inert coatings refer to coatings that can prevent the interaction between blood and the device surface, especially the adsorption of non-specific proteins, such as grafting polyethylene glycol or zwitterionic polymers onto the surface of the artificial blood vessel material. Bioactive coatings refer to coatings containing components that can actively participate in or regulate physiological processes in the body, such as commonly used heparin, aspirin, and warfarin. These active ingredients can directly interfere with the coagulation process. Coatings with EC-specific growth factors refer to coatings that accelerate the endothelialization of artificial blood vessels by fixing or releasing factors that promote the specific growth of endothelial cells on the surface of the artificial blood vessel. Endothelial cells can prevent coagulation factors and platelets in the blood from directly contacting procoagulant substances within the blood vessel, thereby achieving an anticoagulant effect. Antonio et al. used a chemical grafting method to graft PEG with a certain density and chain length onto the surface of a material. The neutrally charged hydrophilic PEG polymer chains bind with water molecules and form a hydration layer on the surface, thereby resisting the non-specific adhesion of proteins and platelets and playing a dual role in anticoagulation and antibacterial action. Smith et al. constructed a stable polymer coating by modifying PU catheters with polysulfobetaine (polySB). The long chains of the zwitterionic polymer have an equal number of anionic and cationic groups. This structure makes them highly hydrophilic and can resist the non-specific adhesion of proteins and platelets. Leslie et al. formed a "slip" liquid film by chemically bonding flexible fluorinated carbon chains to interact with perfluorinated liquids, ultimately obtaining a slip surface that can effectively inhibit the adhesion of platelets and proteins. Feng et al. immobilized heparin on the surface of polycarbonate-type polyurethane (PCU) and formed a hydrophilic passivation layer as a spacer by grafting PEG onto the surface. This spacer effectively reduced the adhesion of proteins and platelets on the PCU surface and inhibited thrombus formation, ultimately preparing a heparin-PEG covalently grafted anticoagulant coating. These modification methods mostly employ post-modification, meaning that after the material has been synthesized, anticoagulant components are added to the surface of the material or its surface is modified through physical adsorption, chemical grafting, or other methods to impart anticoagulant properties. This invention employs pre-modification, introducing anticoagulant components or groups into the molecular structure of the material during the coating material synthesis process. Regarding anticoagulant performance, pre-modification, because the anticoagulant components are uniformly distributed throughout the molecular chains of the material, provides anticoagulant properties both internally and on the surface, potentially offering advantages in terms of the durability of the anticoagulant effect. Even with partial wear on the material surface during long-term use, the internal anticoagulant components can still function. This uniform distribution of anticoagulant components may make the anticoagulant properties of the material more stable and uniform, and will not cause rapid coagulation due to the lack of local anticoagulant components.Subsequent modifications to enhance anticoagulant properties primarily focus on the material's surface. Once the surface anticoagulant coating is damaged, the anticoagulant performance may significantly decrease. This invention aims to synthesize a highly efficient anticoagulant coating and apply it to small-diameter artificial blood vessels to improve their blood compatibility, increase the long-term patency rate of transplanted blood vessels, and provide higher-quality vascular replacement materials for cardiovascular disease treatment. Summary of the Invention

[0004] To address the aforementioned technical problems, the present invention aims to provide an anticoagulant artificial blood vessel inner coating material and its preparation method. This method can prepare an anticoagulant artificial blood vessel inner coating material that can be used to improve the long-term patency of small-diameter artificial blood vessels in vivo.

[0005] To achieve the above-mentioned technical objectives and effects, this invention provides a method for preparing an anticoagulant artificial blood vessel inner coating material, which is achieved through the following technical solution and mainly includes the following steps:

[0006] S1. Raw material preparation:

[0007] (1) Polyurethane matrix: It may be one or more of the following: polytetrahydrofuran glycol, polypropylene glycol, polyethylene glycol, polycaprolactone glycol, polyethylene adipate glycol, polyethylene oxide glycol, polypropylene glycol, polytrimethylene ether glycol, and polycarbonate glycol, and react with one or more of the following: toluene diisocyanate, diphenylmethane diisocyanate, hexamethylene diisocyanate, dicyclohexylmethane diisocyanate, naphthalene diisocyanate, terephthalate diisocyanate, and 1,4-cyclohexane diisocyanate to form a prepolymer;

[0008] The structural formulas of some of the oligomeric polyols involved are shown in the table below:

[0009]

[0010] The structural formulas of some of the diisocyanates involved are shown in the table below:

[0011]

[0012] (2) Functionalized chain extender: The monohydroxy esterification product of o-acetylsalicylic acid chloride and triethanolamine (SA-TEA) is introduced into the polyurethane chain as a chain extender to provide antiplatelet adhesion function.

[0013] (3) Covalent grafting of heparin: The heparin carboxyl group is activated by EDC / NHS and forms an amide bond with the amino group in the polyurethane chain to achieve stable loading;

[0014] S2. Process Preparation:

[0015] (1) Synthesis of functionalized chain extender (SA-TEA): Acetylsalicylic acid chloride: triethanolamine: triethylamine = 1:1.0-1.5:2-3 was added dropwise at 0℃, and the reaction was carried out at 25℃ for 6-8 h. The product was purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a white solid.

[0016] (2) Synthesis of polyurethane prepolymer: oligomeric polyol and diisocyanate are reacted at a molar ratio of 1:1.5-2.5 at 80-90℃ for 1-3 h to generate terminal-NCO prepolymer.

[0017] (3) Chain extension and heparin grafting: Add SA-TEA chain extender. The diamine chain extender can be one or more of the following: ethylenediamine, hexamethylenediamine, butanediamine, diethylenetriamine, 4,7,10-trioxadecadecane-1,13-diamine, 4,4'-diaminodiphenyl ether, isophorone diamine, etc., in one or more of the following solvents: dichloromethane, ethyl acetate, butyl acetate, acetone, ethanol, methanol, etc., and react at 25-30°C for 8-12 h. Add heparin solution (10 mg / mL, EDC / NHS activated) to the polyurethane system and react at 30-50°C for 3-4 h.

[0018] The structural formulas of some of the diamine chain extenders involved are shown in the table below:

[0019]

[0020] (4) Coating process: The composite solution is uniformly coated on the inner surface of the artificial blood vessel by dip-spray coating method, and then cured by vacuum drying (40-60℃, 12-24 h) and ultraviolet irradiation (wavelength 365 nm, 20-60 min) to form a stable anticoagulant coating.

[0021] The anticoagulant artificial blood vessel inner coating material prepared by this invention has the following beneficial effects: (1) Dual-effect chain extender: The composite product of o-acetylsalicylic acid chloride and triethanolamine (SA-TEA) is innovatively used as a chain extender. This molecule not only perfectly assumes the role of connecting polyurethane chain segments by traditional chain extenders, but more importantly, it directly integrates acetylsalicylic acid (the active ingredient of aspirin) with clear antiplatelet aggregation activity as a functional side group into the polyurethane molecular chain. This "intramolecular drug loading" strategy realizes the inherent and uniform distribution of anticoagulant function in the material body. (2) Stable heparin loading: Unlike the traditional physical blending method, an amide bond covalent fixation strategy is adopted. The carboxyl group of heparin is activated by EDC / NHS, so that it reacts with the amino group introduced in advance in the polyurethane chain to form a stable covalent amide bond. This chemical bonding method significantly improves the loading stability of heparin on the material, effectively avoids the loss of heparin under long-term blood flushing or complex in vivo environment, and ensures the durability of anticoagulant activity. (3) Multi-level anticoagulation mechanism: First, the hydrophilicity of the polyurethane substrate itself and components such as SA-TEA and heparin helps to form a hydration layer on the material surface, reducing non-specific protein adsorption. Second, covalently fixed heparin exerts a strong anticoagulant effect by catalyzing antithrombin III (ATIII), inhibiting multiple key coagulation factors in the coagulation cascade reaction; at the same time, the acetylsalicylic acid component in SA-TEA effectively inhibits platelet activation and aggregation. Finally, the uniform and dense coating itself constitutes a physical barrier, preventing platelets and coagulation factors from directly contacting and adhering to the surface of the artificial blood vessel substrate. (4) Core advantages of the pre-modification strategy: The anticoagulant components (acetylsalicylic acid, heparin) are chemically bonded to the interior of the polyurethane molecular chain during the material synthesis stage, rather than just modified on the surface. This allows the anticoagulant components to be evenly distributed in the coating body, and the internal function continues to be released even if the surface is worn; it completely solves the problem of the sudden drop in anticoagulant function caused by surface damage in the post-modified coating, ensuring the long-term patency of small-diameter blood vessels (inner diameter <6 mm).

[0022] The anticoagulant artificial blood vessel inner coating material prepared by this invention is expected to have the following main effects when applied in the biomedical field: (1) Core advantages of pre-modification: Compared with the anticoagulant coating prepared by post-modification strategy, the uniform distribution of anticoagulant components can enable the coating to maintain long-term effective anticoagulant performance. (2) Anticoagulant performance: Using in vitro platelet adhesion experiments, the prepared material can significantly inhibit platelet adhesion (reduction rate >78%). (3) Mechanical properties: The prepared coating material has excellent mechanical properties, with tensile strength ≥15 MPa and elongation at break >400%. Detailed Implementation

[0023] Example 1

[0024] Step 1. Synthesis of SA-TEA chain extender

[0025] According to the raw material ratio shown in Table 1, triethanolamine and triethylamine were dissolved in 50 mL of anhydrous DCM and cooled to 0°C in an ice bath. Under nitrogen protection, o-acetylsalicylic acid chloride (dissolved in 20 mL of DCM) was added dropwise to the above solution at a rate of 1 mL / min. After the addition was complete, the ice bath was removed, the temperature was raised to 25-30°C, and the reaction was carried out with magnetic stirring (500 rpm) for 6-8 h. The reaction progress was monitored by TLC (developing solvent: petroleum ether / ethyl acetate = 2:1, iodine colorimetric assay, target product Rf = 0.4). The reaction solution was washed twice with 50-100 mL of water, then washed with 50-100 mL of saturated brine. The organic phase was dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain a pale yellow oily crude product. The product was purified by column chromatography (silica gel 200-300 mesh, eluent gradient: pure petroleum ether → petroleum ether: ethyl acetate = 2:1), the target component was collected, and after concentration, 5.3 g of white crystals were obtained, with a yield of 68%.

[0026] Table 1. Proportions of raw materials for the synthesis of SA-TEA chain extender

[0027] Material Name Mass (g) Amount of substance (mmol) Equivalent ratio Volume (ml) Acetylsalicylic acid chloride 5 25.2 1.0 \ Triethanolamine 4.2 27.7 1.1 \ Triethylamine 7.6 75.6 3.0 \ Anhydrous dichloromethane \ \ \ 70

[0028] Step 2. Preparation of polyurethane prepolymer

[0029] According to the raw material ratio shown in Table 2, polycarbonate diol was added to a clean four-necked flask, and the temperature was raised to 60-70℃ under nitrogen protection. After the polycarbonate diol was completely melted, terephthalic diisocyanate was slowly added to the flask (20-30 min), the temperature was raised to 80-90℃, and the reaction was carried out with mechanical stirring (120 rpm) for 2-3 h to obtain isocyanate-terminated polyurethane prepolymer, which was then used directly in the next step.

[0030] Table 2. Raw material ratios for the preparation of polyurethane prepolymers

[0031] Material Name Mass (g) Amount of substance (mmol) Equivalent ratio Volume (ml) Polycarbonate diol (Mn=2000) 18.0 9.0 1.0 \ terephthalic diisocyanate 2.8 18.0 2.0 \

[0032] Step 3. Chain extension

[0033] According to the raw material ratio shown in Table 3, SA-TEA was slowly added to the prepolymer. After stirring at 40-50°C for 30 min, 80-100 mL of dichloromethane was added for dilution. After the prepolymer was completely dissolved, hexamethylenediamine was added dropwise to the reaction solution. Then, the mixture was stirred at room temperature (25-30°C) for 8-12 h to obtain a polyurethane system with complete chain extension, which could be directly used in the next step. The amount of polycarbonate diol used in step 2 was taken as 1 equiv, and the equivalent ratio of polycarbonate diol, SA-TEA, and hexamethylenediamine was 1:0.9:1.

[0034] Table 3. Chain extender feed ratio

[0035] Material Name Mass (g) Amount of substance (mmol) Equivalent ratio Volume (ml) prepolymer \ \ 1.0 \ SA-TEA chain extender 2.6 8.4 0.9 \ Hexamethylenediamine 1.1 9.5 1.0 \ Anhydrous dichloromethane \ \ \ 80

[0036] Step 4. Heparin activation and grafting

[0037] According to the raw material ratio shown in Table 4, dissolve heparin sodium in MES buffer, add EDC and NHS, and activate at room temperature for 30 min. Add the activated heparin solution dropwise to the chain-extended polyurethane system and react at 50°C for 4 h.

[0038] Table 4. Ratio of Heparin Activation and Grafting Raw Materials

[0039] Material Name Mass (g) Amount of substance (mmol) Equivalent ratio Volume (ml) Sodium heparin (molecular weight 15 kDa) 0.5 0.03 1.0 \ 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDC) 0.09 0.6 20.0 \ N-hydroxysuccinimide (NHS) 0.06 0.5 16.7 \ MES buffer (0.1 M, pH=6.0) \ \ \ 50

[0040] Step 5. Coating processing and curing

[0041] The polyurethane solution obtained in step 4 was uniformly coated onto the inner surface of the pretreated polyurethane artificial blood vessel substrate using an dip-spray coating method. The coating was first vacuum dried at 40-60°C for 12-24 h to fully remove the solvent. Then, it was photocrosslinked and cured by irradiation under UVA 365nm ultraviolet light for 20-60 min to form the final inner coating.

[0042] Example 2

[0043] Step 1. Synthesis of SA-TEA chain extender

[0044] The specific steps are the same as in Example 1.

[0045] Step 2. Preparation of polyurethane prepolymer

[0046] Polycaprolactone diol was added to a clean four-necked flask and heated to 60-70°C under nitrogen protection. After the polycaprolactone diol was completely melted, terephthalic diisocyanate was slowly added to the flask (20-30 min), and the temperature was raised to 80-90°C. The mixture was mechanically stirred (120 rpm) for 2-3 h to obtain an isocyanate-terminated polyurethane prepolymer, which was then used directly in the next step. The molar ratio of polycaprolactone diol to terephthalic diisocyanate was 1:2.

[0047] Step 3. Chain extension

[0048] SA-TEA was slowly added to the prepolymer, and the mixture was stirred at 40-50°C for 30 min. Then, 80-100 mL of ethyl acetate was added for dilution. After the prepolymer was completely dissolved, hexamethylenediamine was added dropwise to the reaction solution. The mixture was then stirred at room temperature (25-30°C) for 8-12 h to obtain a fully chain-extended polyurethane system, which was directly used in the next step. The amount of polycaprolactone diol used in step 2 was considered as 1 equiv, and the equivalent ratio of polycaprolactone diol, SA-TEA, and hexamethylenediamine was 1:0.9:1.

[0049] Step 4. Heparin activation and grafting

[0050] The specific steps are the same as in Example 1.

[0051] Step 5. Coating processing and curing

[0052] The specific steps are the same as in Example 1.

[0053] Example 3

[0054] Step 1. Synthesis of SA-TEA chain extender

[0055] The specific steps are the same as in Example 1.

[0056] Step 2. Preparation of polyurethane prepolymer

[0057] Polytetrahydrofuran diol was added to a clean four-necked flask and heated to 60-70°C under nitrogen protection. After the polytetrahydrofuran diol was completely melted, terephthalic diisocyanate was slowly added to the flask (20-30 min), and the temperature was raised to 80-90°C. The mixture was mechanically stirred (120 rpm) for 2-3 h to obtain an isocyanate-terminated polyurethane prepolymer, which was then used directly in the next step. The molar ratio of polytetrahydrofuran diol to terephthalic diisocyanate was 1:2.

[0058] Step 3. Chain extension

[0059] SA-TEA was slowly added to the prepolymer, and the mixture was stirred at 40-50°C for 30 min. Then, 80-100 mL of acetone was added for dilution. After the prepolymer was completely dissolved, hexamethylenediamine was added dropwise to the reaction solution. The mixture was then stirred at room temperature (25-30°C) for 8-12 h to obtain a polyurethane system with complete chain extension, which was directly used in the next step. The amount of polytetrahydrofuran diol used in step 2 was considered as 1 equiv, and the equivalent ratio of polytetrahydrofuran diol, SA-TEA, and hexamethylenediamine was 1:0.9:1.

[0060] Step 4. Heparin activation and grafting

[0061] The specific steps are the same as in Example 1.

[0062] Step 5. Coating processing and curing

[0063] The specific steps are the same as in Example 1.

[0064] Example 4

[0065] Step 1. Synthesis of SA-TEA chain extender

[0066] The specific steps are the same as in Example 1.

[0067] Step 2. Preparation of polyurethane prepolymer

[0068] Polycarbonate diol and polytetrahydrofuran diol were added to a clean four-necked flask and heated to 60-70°C under nitrogen protection. After the polycarbonate diol and polytetrahydrofuran diol were completely melted, terephthalic diisocyanate was slowly added to the flask (20-30 min), and the temperature was raised to 80-90°C. The mixture was mechanically stirred (120 rpm) for 2-3 h to obtain isocyanate-terminated polyurethane prepolymer, which was directly used in the next step. The molar ratio of polycarbonate diol to polytetrahydrofuran diol was 1:1. The molar ratio of oligomeric polyol (polycarbonate diol + polytetrahydrofuran diol) to terephthalic diisocyanate was 1:2.

[0069] Step 3. Chain extension

[0070] SA-TEA was slowly added to the prepolymer, and the mixture was stirred at 40-50°C for 30 min. Then, 80-100 mL of ethyl acetate was added for dilution. After the prepolymer was completely dissolved, isophorone diamine was added dropwise to the reaction solution. The mixture was then stirred at room temperature (25-30°C) for 8-12 h to obtain a polyurethane system with complete chain extension, which was directly used in the next step. The sum of the amounts of polycarbonate diol and polytetrahydrofuran diol (the two oligomeric polyols) in step 2 was considered as 1 equiv. The equivalent ratio of oligomeric polyol, SA-TEA, and isophorone diamine was 1:0.9:1.

[0071] Step 4. Heparin activation and grafting

[0072] The specific steps are the same as in Example 1.

[0073] Step 5. Coating processing and curing

[0074] The specific steps are the same as in Example 1.

[0075] Example 5

[0076] Step 1. Synthesis of SA-TEA chain extender

[0077] The specific steps are the same as in Example 1.

[0078] Step 2. Preparation of polyurethane prepolymer

[0079] Polycarbonate diol was added to a clean four-necked flask and heated to 60-70°C under nitrogen protection. After the polycarbonate diol was completely melted, diphenylmethane diisocyanate was slowly added to the flask (20-30 min), and the temperature was raised to 80-90°C. The mixture was mechanically stirred (120 rpm) for 2-3 h to obtain an isocyanate-terminated polyurethane prepolymer, which was then used directly in the next step. The molar ratio of polycarbonate diol to diphenylmethane diisocyanate was 1:2.

[0080] Step 3. Chain extension

[0081] SA-TEA was slowly added to the prepolymer, and the mixture was stirred at 40-50°C for 30 min. Then, 80-100 mL of ethyl acetate was added for dilution. After the prepolymer was completely dissolved, hexamethylenediamine was added dropwise to the reaction solution. The mixture was then stirred at room temperature (25-30°C) for 8-12 h to obtain a polyurethane system with complete chain extension, which was directly used in the next step. The amount of polycaprolactone diol used in step 2 was considered as 1 equiv, and the equivalent ratio of polycaprolactone diol, SA-TEA, and hexamethylenediamine was 1:0.9:1.

[0082] Step 4. Heparin activation and grafting

[0083] The specific steps are the same as in Example 1.

[0084] Step 5. Coating processing and curing

[0085] The specific steps are the same as in Example 1.

[0086] Example 6

[0087] Step 1. Synthesis of SA-TEA chain extender

[0088] The specific steps are the same as in Example 1.

[0089] Step 2. Preparation of polyurethane prepolymer

[0090] Polycarbonate diol was added to a clean four-necked flask and heated to 60-70°C under nitrogen protection. After the polycarbonate diol was completely melted, hexamethylene diisocyanate was slowly added to the flask (20-30 min), the temperature was raised to 80-90°C, and the mixture was mechanically stirred (120 rpm) for 2-3 h to obtain an isocyanate-terminated polyurethane prepolymer, which was then used directly in the next step. The molar ratio of polycarbonate diol to hexamethylene diisocyanate was 1:2.

[0091] Step 3. Chain extension

[0092] SA-TEA was slowly added to the prepolymer, and the mixture was stirred at 40-50°C for 30 min. Then, 80-100 mL of ethyl acetate was added for dilution. After the prepolymer was completely dissolved, propylenediamine was added dropwise to the reaction solution. The mixture was then stirred at room temperature (25-30°C) for 8-12 h to obtain a polyurethane system with complete chain extension, which was directly used in the next step. The amount of polycaprolactone diol used in step 2 was considered as 1 equiv, and the equivalent ratio of polycaprolactone diol, SA-TEA, and hexamethylenediamine was 1:0.9:1.

[0093] Step 4. Heparin activation and grafting

[0094] The specific steps are the same as in Example 1.

[0095] Step 5. Coating processing and curing

[0096] The specific steps are the same as in Example 1.

[0097] Comparative Example

[0098] It is largely the same as Example 1, except that the synthesis of SA-TEA chain extender and the grafting and activation of heparin are omitted.

[0099] Step 1. Preparation of polyurethane prepolymer

[0100] Polycarbonate diol was added to a clean four-necked flask, and the temperature was raised to 60-70°C under nitrogen protection. After the polycarbonate diol was completely melted, terephthalic diisocyanate was slowly added to the flask (20-30 min), and the temperature was raised to 80-90°C. The mixture was mechanically stirred (120 rpm) for 2-3 h to obtain isocyanate-terminated polyurethane prepolymer, which was then used directly in the next step. The molar ratio of polycarbonate diol to terephthalic diisocyanate was 1:2.

[0101] Step 2. Chain extension

[0102] Triethanolamine was slowly added to the prepolymer, and the mixture was stirred at 40-50°C for 30 min. Then, 80-100 mL of dichloromethane was added for dilution. After the prepolymer was completely dissolved, hexamethylenediamine was added dropwise to the reaction solution. The mixture was then stirred at room temperature (25-30°C) for 8-12 h to obtain a fully chain-extended polyurethane system, which was directly used in the next step. The amount of polycarbonate diol used in step 1 was considered as 1 equiv, and the equivalent ratio of polycarbonate diol, triethanolamine, and hexamethylenediamine was 1:0.9:1.

[0103] Step 3. Coating processing and curing

[0104] The polyurethane solution obtained in step 2 was uniformly coated onto the inner surface of the pretreated polyurethane artificial blood vessel substrate using an dip-spray coating method. The coating was first vacuum dried at 40-60°C for 12-24 h to fully remove the solvent. Then, it was photocrosslinked and cured by irradiation under UVA 365nm ultraviolet light for 20-60 min to form the final inner coating.

[0105] The mechanical strength test results are shown in the table below:

[0106] Example Tensile strength (MPa) Elongation at break (%) Comparative Example 17.5 420 Example 1 18.5 410 Example 2 16.0 490 Example 3 14.2 530 Example 4 17.8 460 Example 5 19.2 390 Example 6 16.8 440

[0107] The results of the platelet adhesion test are shown in the table below:

[0108] Example Platelet adhesion density (cells / μm²) Adhesion reduction rate (%) Comparative Example 28.5 / Example 1 4.1 85.6 Example 2 5.3 81.4 Example 3 6.0 78.9 Example 4 5.8 79.6 Example 5 5.5 80.7 Example 6 5.4 81.1

[0109] The above are merely preferred embodiments of the present invention and are not intended to limit the implementation methods and protection scope of the present invention. Those skilled in the art should recognize that any equivalent substitutions and obvious changes made based on the description and illustrations of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing an anticoagulant coating material for artificial blood vessels, characterized in that: Includes the following steps: S1. Raw material preparation: (1) Polyurethane matrix: It may be one or more of the following: polytetrahydrofuran glycol, polypropylene glycol, polyethylene glycol, polycaprolactone glycol, polyethylene adipate glycol, polyethylene oxide glycol, polypropylene glycol, polytrimethylene ether glycol, and polycarbonate glycol, and react with one or more of the following: toluene diisocyanate, diphenylmethane diisocyanate, hexamethylene diisocyanate, dicyclohexylmethane diisocyanate, naphthalene diisocyanate, terephthalate diisocyanate, and 1,4-cyclohexane diisocyanate to form a prepolymer; (2) Functionalized chain extender: The monohydroxy esterification product of o-acetylsalicylic acid chloride and triethanolamine (SA-TEA) is introduced into the polyurethane chain as a chain extender to provide antiplatelet adhesion function. (3) Covalent grafting of heparin: The heparin carboxyl group is activated by EDC / NHS and forms an amide bond with the amino group in the polyurethane chain to achieve stable loading; S2. Process Preparation: (1) Synthesis of functionalized chain extender (SA-TEA): Acetylsalicylic acid chloride: triethanolamine: triethylamine = 1:1.0-1.5:2-3 was added dropwise at 0℃, and the reaction was carried out at 25℃ for 6-8 h. The white solid was obtained by column chromatography. (2) Synthesis of polyurethane prepolymer: oligomeric polyol and diisocyanate are reacted at a molar ratio of 1:1.5-2.5 at 80-90℃ for 1-3 h to generate terminal-NCO prepolymer; (3) Chain extension and heparin grafting: Add SA-TEA chain extender, or one or more of the diamine chain extender, such as ethylenediamine, hexamethylenediamine, butanediamine, diethylenetriamine, 4,7,10-trioxadecano-1,13-diamine, 4,4'-diaminodiphenyl ether, or isophorone diamine, in one or more of the solvents dichloromethane, ethyl acetate, butyl acetate, acetone, ethanol, or methanol, and react at 25-30°C for 8-12 h; add heparin solution (10 mg / mL, EDC / NHS activated) to the polyurethane system and react at 30-50°C for 3-4 h. (4) Coating process: The composite solution is uniformly coated on the inner surface of the artificial blood vessel by dip-spray coating method, and then cured by vacuum drying (40-60℃, 12-24 h) and ultraviolet irradiation (wavelength 365 nm, 20-60 min) to form a stable anticoagulant coating.

2. The method for preparing the anticoagulant artificial blood vessel inner coating material according to claim 1, characterized in that: The structural formulas of the oligomeric polyols involved in the polyurethane matrix are shown in the table below:

3. The method for preparing the anticoagulant artificial blood vessel inner coating material according to claim 1, characterized in that: The diisocyanate structures involved in the polyurethane matrix are shown in the table below:

4. The method for preparing the anticoagulant artificial blood vessel inner coating material according to claim 1, characterized in that: In S2, the structural formula of the diamine chain extender is shown in the table below:

5. The anticoagulant artificial blood vessel inner coating material prepared by the method for preparing the anticoagulant artificial blood vessel inner coating material according to any one of claims 1 to 4.

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