Polymer for long-acting anticoagulant antibacterial coating of small-caliber artificial blood vessel and preparation method of polymer

Abstract

The invention discloses a polymer for a long-acting anticoagulant antibacterial coating of a small-caliber artificial blood vessel and a preparation method of the polymer, and the preparation method comprises the following steps: dissolving hydroxyl-terminated diol SN-diOH and diisocyanate in a first solvent, and carrying out prepolymerization reaction under the protection of inert gas to obtain a prepolymer; a phosphoric acid / second solvent mixed solution and a chain extender capable of forming multiple hydrogen bonds are simultaneously and separately dropwise added into the prepolymer for chain extension reaction, a dichloromethane solution is continuously dropwise added into the prepared solution for precipitation, methyl tert-butyl ether is added for continuous precipitation, and ultrasonic super-crushing is performed; and standing, layering liquid and solid, adding petroleum ether into the clear liquid, carrying out vacuum drying on the precipitate to obtain a powdery polymer, dissolving, extruding into isopropanol, soaking and purifying, and carrying out vacuum drying. The synthesis method is simple, the yield is high, and the obtained polymer for the long-acting anticoagulant antibacterial coating has important application prospects in the aspect of small-caliber artificial blood vessels for arteriovenous fistulization and cardiac coronary artery and peripheral blood vessel bypass therapy.

Description

Technical Field

[0001] The present invention belongs to the field of polymer synthesis, and particularly relates to a polymer for a long-acting anticoagulant and antibacterial coating of a small-diameter artificial blood vessel and a preparation method thereof. Background Art

[0002] In recent years, the prevalence and mortality of cardiovascular diseases have been remaining high worldwide. When cardiovascular diseases develop to a certain extent, vascular transplantation is the most effective treatment method. Autologous blood vessels from patients are an ideal source. However, due to limited quantity and the fact that patients often suffer from other potential diseases, the effect of transplantation is not satisfactory. Therefore, the development of artificial blood vessel grafts has important clinical application value. At present, large- and medium-diameter artificial blood vessels have achieved initial effects in clinical applications and there are commercial products, but small-diameter artificial blood vessels often face some transplantation failures caused by thrombosis, intimal hyperplasia and infection. This is mainly because there is a risk of bacterial contamination during surgical operations and the use of instruments, which may lead to local infection and even systemic infection, and even cause death. At the same time, during use, since blood-contact devices are in direct contact with blood, there are risks of activating the coagulation cascade and platelets, etc., and then thrombus is formed on the material surface, ultimately leading to treatment failure and even endangering the life safety of patients.

[0003] Currently, antibiotics and antibacterial agents are mostly used clinically to deal with bacterial infections, and anticoagulants and antiplatelet drugs are used to inhibit thrombus formation. However, the long-term use of antibiotics and the like can cause bacterial drug resistance and other complications of the body, and anticoagulant drugs can also cause complications such as uncontrollable systemic bleeding and multiple organ dysfunction. Therefore, endowing small-diameter artificial blood vessels with antibacterial and anticoagulant properties by certain means is of great significance for reducing the occurrence of related complications during clinical applications.

[0004] Antifouling coatings can reduce the adhesion of platelets, proteins and blood cells on the material surface, and at the same time reduce the probability of thrombus occurrence. Antifouling coatings include superhydrophobic and hydrophilic coatings, which are of great significance in reducing non-specific adhesion, thereby reducing the formation of biofilms and thrombi. Currently, various hydrophilic polymers such as polyethylene glycol (PEG) and zwitterionic polymers can reduce the adhesion of plasma proteins, cells and bacteria by forming a hydrated layer on the material surface. Zwitterionic polymers with equal amounts of oppositely charged ions are ideal candidates for promoting hydrophilic surfaces because they can form a stronger hydrated layer on the material surface through electrostatically induced hydration, i.e., ionic solvation effect, and have more excellent and stable anticoagulant and antibacterial properties compared with PEG.

[0005] As a new type of polymer material, zwitterionic polymers are electrically neutral, and their chemical structures include equal amounts of cationic and anionic groups. Among them, polybetaine zwitterionic polymers are a common type of this kind of polymer. This kind of polymer is named because its structure is similar to that of betaine. Its positive charge groups are mostly quaternary ammonium groups, and the negative charge groups are phosphate groups, sulfonate groups or carboxylate groups, etc. The sulfonic acid group is an active group for natural anticoagulation and promoting endothelialization, and plays an important anticoagulant role in the coating; the positively charged cationic group in the quaternary ammonium salt molecule can undergo electrostatic interaction with the negatively charged group on the bacterial cell membrane, destroying the cell wall structure of the bacteria, causing the outflow of the contents of the bacterial cells, and ultimately leading to the death of the bacteria, achieving the antibacterial effect. Therefore, by preparing monomers with different densities of sulfonic acid groups and quaternary ammonium salts and using these monomers to prepare zwitterionic polymers, the controllability of the anticoagulant and antibacterial coating effects of small-caliber artificial blood vessels can be achieved. Summary of the Invention

[0006] Aiming at the above-mentioned deficiencies of the prior art, the main purpose of the present invention is to provide a preparation method of a polymer for a long-acting anticoagulant and antibacterial coating of a small-caliber artificial blood vessel. The obtained polymer is a polymer with sulfonic acid groups, quaternary ammonium salts and groups capable of forming multiple hydrogen bonds with known densities, which can be firmly attached to the small-caliber artificial blood vessel, significantly improve the biocompatibility and antibacterial property of the artificial blood vessel substrate material, endow the small-caliber artificial blood vessel with long-acting anticoagulation and antibacterial functions, and improve its clinical application effect.

[0007] The present invention also provides a polymer for a long-acting anticoagulant and antibacterial coating of a small-caliber artificial blood vessel, which is prepared by the preparation method of the polymer for a long-acting anticoagulant and antibacterial coating of a small-caliber artificial blood vessel.

[0008] The present invention mainly solves three technical problems:

[0009] One is to solve the problem of the single function of traditional coatings. The sulfonic acid groups contained in the polymers of the present invention are active groups for natural anticoagulation and promoting endothelialization, playing an important anticoagulant role. The positively charged cationic groups in the quaternary ammonium salt molecules can achieve antibacterial effects by destroying the cell wall structure of bacteria.

[0010] The second is to solve the problem of uncontrollable functionalization of traditional anticoagulant and antibacterial coatings. The present invention uses monomers with different densities of sulfonic acid groups and quaternary ammonium salts, and introduces the monomers into the molecular main chain through bulk copolymerization to synthesize polymers, so as to achieve controllable time for the anticoagulant and antibacterial coatings of small-caliber artificial blood vessels to play their functions.

[0011] The third is to solve the problem of weak binding force between traditional coatings and substrates. The groups capable of forming multiple hydrogen bonds in the polymers of the present invention move towards the substrate after deposition in an aqueous environment, enhancing the hydrogen bond interaction between the coating and the substrate. Through the interaction of multiple hydrogen bonds with the substrate material, it can be persistently and firmly attached to the surface of the small-caliber artificial blood vessel substrate material.

[0012] The above object of the present invention can be achieved by the following solutions:

[0013] The present invention provides a preparation method of a polymer for a long-acting anticoagulant and antibacterial coating of a small-caliber artificial blood vessel, comprising the following steps:

[0014] S1: Dissolve a hydroxyl-terminated diol SN-diOH and a diisocyanate in a first solvent, and carry out a prepolymerization reaction under the protection of an inert gas to obtain an anticoagulant and antibacterial coating prepolymer;

[0015] S2: Prepare a phosphoric acid / second solvent mixed solution, and simultaneously and separately drop it and a chain extender capable of forming multiple hydrogen bonds into the anticoagulant and antibacterial coating prepolymer obtained in step S1, and carry out a chain extension reaction at 12-60 °C for 18-36 h;

[0016] S3: After the reaction is completed, continuously drop a dichloromethane solution into the solution obtained in step S2 for precipitation under ventilation conditions, then add methyl tert-butyl ether for further precipitation, and then carry out ultrasonic treatment to break up large pieces of solid; let it stand, the liquid and the solid are separated, add petroleum ether to the clear liquid, pump out the excess organic reagents with an oil pump, and vacuum-dry the precipitate to obtain a powdery polymer;

[0017] S4: Soak and purify with isopropanol for 24 h, and vacuum-dry at 60 °C for 48 h; redissolve with DMSO, extrude it into isopropanol for soaking and purifying for 24 h, and vacuum-dry at 60 °C for 48 h; repeat this step more than 3 times to obtain the product.

[0018] Preferably, in step S1, the hydroxyl-terminated diol SN-diOH is a diol compound substituted with an ammonium salt and a sulfonic acid group, and is selected from one or more of the diol compounds shown in the following formulas 4-I-1, 4-II-1, 4-III-1, 4-IV-1, 4-V-1; the diisocyanate is selected from one or more of 1,4-butane diisocyanate (BDI), 1,6-hexane diisocyanate (HDI), L-lysine diisocyanate (LDI), and isophorone diisocyanate (IPDI); the first solvent and the second solvent are selected from one or more of ethyl acetate, butyl acetate, acetone, butanone, cyclohexanone, isophorone, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and N-methylpyrrolidone (NMP);

[0019]

[0020] Preferably, in step S1, the mass-volume concentration of the solution formed by dissolving the hydroxyl-terminated diol SN-diOH and the diisocyanate as solutes in the first solvent is 1% - 8%.

[0021] Preferably, in step S1, the prepolymerization reaction temperature is 12-80°C, and the prepolymerization reaction time is 0.5-4 h.

[0022] Preferably, in step S2, in the phosphoric acid / second solvent mixed solution, the volume ratio of phosphoric acid to the second solvent is 1:40-100; the second solvent is selected from one or more of acetone, DMF, DMSO, and NMP; the chain extender capable of forming multiple hydrogen bonds is selected from one or more of imidazolidinyl urea, ureido-4-pyridone UPy, 2,4-diamino-6-hydroxypyrimidine, and dimethylglyoxime.

[0023] Preferably, in step S3, the ultrasonic time is 0.5-2 h, and the vacuum drying temperature is 80°C.

[0024] Preferably, in step S4, isopropanol soaking and motor stirring are carried out simultaneously, and the stirring speed is 300-500 rpm; the mass-volume concentration of the powdery polymer solution prepared when DMSO is redissolved is 6%-20%.

[0025] Preferably, the molar ratio of the hydroxyl-terminated diol SN-diOH, diisocyanate, and chain extender is 1:2:0.1-1.

[0026] The present invention also provides a polymer for a long-acting anticoagulant and antibacterial coating of a small-caliber artificial blood vessel, which is prepared by the preparation method of the polymer for a long-acting anticoagulant and antibacterial coating of a small-caliber artificial blood vessel described in any one of the above.

[0027] Preferably, the polymer for a long-acting anticoagulant and antibacterial coating of a small-caliber artificial blood vessel is a water-strongly adhesive polyurethane with a controllable density of anticoagulant and antibacterial active sites. When synthesizing the polymer, the monomer-active components can be regulated, and the components can be anticoagulant and antibacterial molecules.

[0028] The present invention also provides the application of the polymer for a long-acting anticoagulant and antibacterial coating of a small-caliber artificial blood vessel in the preparation of a small-caliber artificial blood vessel for arteriovenous fistula, coronary heart artery, and peripheral vascular bypass. By combining the artificial blood vessel preparation technology with the polymer for a long-acting anticoagulant and antibacterial coating of a small-caliber artificial blood vessel, a small-caliber artificial blood vessel with long-acting anticoagulant and antibacterial functions is prepared, and the original and preset three-dimensional structure is maintained during the coating process.

[0029] During the process of synthesizing the polymer for a long-acting anticoagulant and antibacterial coating of a small-caliber artificial blood vessel in the present invention, there are at least the following technical improvements:

[0030] (1) By bulk copolymerization, the ammonium salt and sulfonic acid group-substituted diol compounds are block-copolymerized onto the main chain of the coating polymer molecule, with controllable anticoagulant and antibacterial durations.

[0031] (2) During the synthesis process, the mass volume concentration of the terminal hydroxyl diol SN-diOH and the diisocyanate as solutes dissolved in the first solvent is ensured to be 1% to 8%, the volume ratio of phosphoric acid to the second solvent is 1:40 to 100, the prepolymerization temperature is 12 to 80°C, and the prepolymerization time is 0.5 to 4 hours, so as to obtain a long-acting anticoagulant and antibacterial polymer with a stable molecular structure and good biocompatibility, which has no hypersensitivity reaction to the human body during transplantation surgery and has affinity with the blood and surrounding tissues in the human body.

[0032] (3) A polymer for long-lasting anticoagulant and antibacterial coating with high adhesion in wet state is obtained by using a specific chain extender.

[0033] (4) After the chain extension is completed, a series of treatments are performed to obtain a powdered polymer, which is then subjected to post-treatment and repeated for more than 3 times to obtain an anticoagulant and antibacterial powdered polymer with a stable molecular structure.

[0034] Compared with the prior art, the present invention has at least the following beneficial effects:

[0035] 1. The soft segment terminal hydroxy diol SN-diOH used in the present invention is a diol compound substituted with ammonium salts and sulfonic acid groups. By embedding diols substituted with different ammonium salts and sulfonic acid groups into the main chain of the polymer molecule, the anticoagulation and antibacterial duration of the polymer can be controlled. This is different from the commonly used surface chemical grafting or physical blending technology that is uncontrollable and prone to functional failure, and can achieve controllable anticoagulation and antibacterial duration effects of the polymer without causing acute thrombosis, and has efficient anticoagulation and antibacterial effects.

[0036] 2. The anticoagulant and antibacterial effects of the polymer synthesized by the present invention can be achieved by regulating the proportion of the synthesized monomer compounds. The artificial blood vessels using the polymer can maintain the original pore size, porosity, and pore structure indicators, and will not destroy the functions of the active groups in the monomer molecules, which is conducive to the preset anti-platelet flocculation, and promotes the migration and growth of vascular hosts such as endothelial cells, so as to achieve the therapeutic effect of the artificial blood vessels during use. This artificial blood vessel functional polymer with good tissue compatibility, strong adhesion in wet state and good microscopic morphology and the synthesis method provide a simple and effective technical idea for the development of high-performance artificial blood vessels in the preparation of cerebrovascular, cardiovascular, and peripheral vascular products.

[0037] 3. The synthesis method of the present invention is simple and has a high yield. By regulating the cationic active sites and the density of the sulfonic acid groups, a polymer for a long-acting anticoagulant and antibacterial active coating is obtained. It has important application prospects, especially in the preparation of small-caliber artificial blood vessels for arteriovenous fistula, coronary artery and peripheral vascular bypass treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 It is the molecular structural formula of several terminal hydroxy diols SN-diOH.

[0039] Figure 2 Reaction mechanism diagram of the polymer (4-IV-1-KNKJ-ZP) for the long-acting anticoagulant and antibacterial coating synthesized in Example 1.

[0040] Figure 3 NMR spectrum of 4-IV-1-KNKJ-ZP synthesized in Example 1.

[0041] Figure 4 SEM image of the coating on the inner surface of the electrospun polyurethane nanofiber small-diameter artificial blood vessel with 4-IV-1-KNKJ-ZP synthesized in Example 1. Detailed implementation manners

[0042] The present invention will be described in detail below with reference to the accompanying drawings and specific embodiments.

[0043] Example 1

[0044] This example provides a preparation method of a polymer for a long-acting anticoagulant and antibacterial coating of a small-diameter artificial blood vessel. The chemical structure of the hydroxyl-terminated diol SN-diOH monomer with anticoagulant and antibacterial activities used is as Figure 1 shown, and the steps are as follows:

[0045] The molar ratio of 4-IV-1, HDI, and ureido-4-pyridone UPy is 1:2:1. The hydroxyl-terminated diol 4-IV-1 and HDI are dissolved in DMSO to form a mixed solution with a mass-volume concentration of 3%. Under nitrogen protection, the reaction temperature is set to 40 °C, and the prepolymerization reaction is carried out for 4 h to obtain a prepolymer for the anticoagulant and antibacterial coating for standby.

[0046] Prepare a mixture with a volume ratio of phosphoric acid to DMSO of 1:100, and simultaneously and separately drop it and ureido-4-pyridone UPy into the prepolymer for the anticoagulant and antibacterial coating. The chain extension reaction is carried out at 60 °C for 36 h; after the reaction is completed, dichloromethane solution is continuously dropped into the finally prepared solution for precipitation in a fume hood, and then methyl tert-butyl ether is added for further precipitation, and then ultrasonic treatment is carried out for 1 h to break up the large pieces of solid; after standing, when the liquid and solid are separated, petroleum ether is added to the clarified liquid, and the excess organic reagents are pumped out by an oil pump, and the precipitate is dried in a vacuum drying oven at 80 °C to obtain a powdery polymer.

[0047] Then, it is soaked in isopropanol and purified by electric stirring at a speed of 500 rpm for 24 h, vacuum dried at 60 °C for 48 h, and then dissolved in DMSO again according to the requirement of a mass-volume concentration of 20% of the powdery polymer / DMSO, extruded into isopropanol for soaking and purification for 24 h, and vacuum dried at 60 °C for 48 h. This step is repeated 5 times, and finally vacuum freeze-dried to obtain a polymer (4-IV-1-KNKJ-ZP) for a long-acting anticoagulant and antibacterial coating with a stable molecular structure. Its reaction mechanism and NMR spectrum are as Figure 2 and 3as shown

[0048] Example 2

[0049] The molar ratio of 4-IV-1, LDI and imidazolidinyl urea is 1:2:1. Dissolve the hydroxyl-terminated diol 4-IV-1 and LDI in DMF to form a mixed solution with a mass-volume concentration of 5%. Set the reaction temperature to 45°C under nitrogen protection and carry out a prepolymerization reaction for 3 h to obtain the anticoagulant and antibacterial coating prepolymer for standby.

[0050] Prepare a solution with a volume ratio of phosphoric acid to DMSO of 1:80, and simultaneously and separately drop it and ureido-4-pyridone UPy into the anticoagulant and antibacterial coating prepolymer. Carry out a chain extension reaction at 60°C for 36 h; after the reaction, continuously drop dichloromethane solution into the finally obtained solution for precipitation in a fume hood, then add methyl tert-butyl ether for further precipitation, and then carry out ultrasonic treatment for 1 h to crush the large pieces of solid; let it stand. After the liquid and solid are separated, add petroleum ether to the clear liquid, pump out the excess organic reagents with an oil pump, and dry the precipitate in a vacuum drying oven at 80°C to obtain a powdery polymer.

[0051] Then soak it in isopropanol and purify it by electric stirring at 400 rpm for 24 h, dry it in vacuum at 60°C for 48 h. Then, according to the requirement of a mass-volume concentration of 20% of the powdery polymer / DMSO, dissolve it again with DMSO, extrude it into isopropanol for soaking and purification for 24 h, and dry it in vacuum at 60°C for 48 h. This step is repeated 5 times, and finally vacuum freeze-dry to obtain 4-IV-1-KNKJ-ZP.

[0052] Comparative Example 1

[0053] This comparative example provides a preparation method of a polymer for a long-acting anticoagulant and antibacterial coating. The chemical structural formula of the hydroxyl-terminated diol SN-diOH monomer with anticoagulant and antibacterial activity used is as Figure 1 shown. The steps are basically the same as those in Example 1, except that the hydroxyl-terminated diol SN-diOH monomer used is 4-Ⅲ-1, and the synthesized polymer for the long-acting anticoagulant and antibacterial coating shows stronger antibacterial and anticoagulant effects, as shown in Table 1.

[0054] Comparative Example 2

[0055] This comparative example provides a preparation method of a polymer for a long-acting anticoagulant and antibacterial coating, which is basically the same as that in Example 1, except that the chain extender used is imidazolidinyl urea, and the synthesized polymer for the anticoagulant and antibacterial coating shows weaker adhesion, as shown in Table 1.

[0056] Comparative Example 3

[0057] This comparative example provides a method for preparing a polymer for a long-acting anticoagulant and antibacterial coating, which is basically the same as Example 1, except that the terminal hydroxyl diol SN-diOH monomer used is 4-II-1, and the synthesized anticoagulant and antibacterial polymer exhibits strong anticoagulant performance, as shown in Table 1.

[0058] Comparative Example 4

[0059] This comparative example provides a method for preparing a polymer for a long-acting anticoagulant and antibacterial coating, which is basically the same as Comparative Example 3, except that the chain extender used is dimethylglyoxime, and the synthesized anticoagulant and antibacterial polymer exhibits weak adhesion, as shown in Table 1.

[0060] Performance Test

[0061] The polymers for long-acting anticoagulant and antibacterial coatings prepared in the examples and comparative examples were respectively subjected to antibacterial zone test, platelet quantification test and bond strength test, and the surface coating morphology of the polymer on the small-caliber artificial blood vessel of polyurethane nanofibers was observed by SEM, as Figure 4 shown.

[0062] Antibacterial zone quantification test:

[0063] The synthesized polymer was cast into a PTFE mold to prepare a circular membrane with a diameter of 14 cm, and sterilized by ultraviolet light irradiation. The pH of the prepared LB broth and LB agar was adjusted to 7.0, and high-temperature sterilization was carried out at 120 °C for 20 min. The sterilized LB agar was poured into a sterile petri dish while it was hot, and the petri dish was inverted after cooling. The bacterial strain was transferred to LB broth under sterile conditions and cultured in a constant temperature shaker at 37 °C for 12 h. Take about 20 μL of the bacterial culture solution, smear it on the surface of the petri dish containing the solid medium, and evenly smear the bacterial solution in one direction with a spreading rod. Gently place the circular polymer membranes of each group on the petri dish in the designated space, place them in a constant temperature shaker for 12 h, take pictures, and calculate the inhibition zone (cm) with Image J software.

[0064] Platelet adhesion amount test:

[0065] Use a plastic vacuum blood collection tube containing 3.2% sodium citrate solution to draw rabbit blood from the marginal ear vein of healthy New Zealand white rabbits at a ratio of 9:1 (v / v). Rich platelet plasma (PRP, containing 2×10 per milliliter) was obtained by centrifugation at 1200 rpm for 15 min. 7Platelets). The steps of platelet adhesion test are as follows: Coat the synthesized polymer onto a round cover glass with a diameter of 14 mm, soak it in 75% ethanol for 20 min for cleaning and sterilization, then wash it several times with deionized water, and place it into a 24-well cell culture plate. Add 500 μL of PRP to each well, and slowly shake and process it at 37 °C for 2 hours. Then, gently wash it 10 times with PBS buffer solution to ensure that the unadhered blood components are washed away. Next, immerse the sample into a 4% paraformaldehyde solution and fix it at 4 °C for 2 hours. Dehydrate it by the gradient ethanol solution gradient method (20%, 40%, 60%, 80%, 90%, 95%, 100%), and soak it for 12 minutes each time. After the dehydrated sample is volatilized and dried in a fume hood, sputter it with gold, and observe the platelet adhesion on the membrane surface by SEM. In addition, use a lactate dehydrogenase (LDH) kit (LDH, Clontech Laboratories) to quantitatively test the platelet adhesion amount.

[0066] Bond strength test:

[0067] Select pig skin as the model for studying the adhesiveness of the hydrogel. First, scrape off the fat layer in the pig skin until the dermis layer is exposed, and cut the pig skin into small pieces with a width of 1 cm × 3 cm. Apply the synthesized anticoagulant and antibacterial polymer aqueous solution with a mass-volume concentration of 25% on a 1 cm × 1 cm area of one piece of pig skin, stagger and stack another piece of pig skin of the same size, and apply a weight of 50 g for 1 hour (to ensure the completion of bonding). Then, fix the 1 cm parts at both ends of the sample on a material tensile testing machine (HY-940FS) for radial uniaxial tension test. The sensor load range is 0 - 200 N, and the tensile speed is 1 mm / min.

[0068] Table 1

[0069]

[0070]

[0071] As shown in Table 1, by controlling the density of ammonium salt and sulfonic acid group on the terminal hydroxyl diol SN-diOH monomer and the type of chain extender, a polymer with significant antibacterial and anticoagulant effects and wet adhesion performance is obtained by bulk copolymerization. It can stably and long-lastingly regulate the vascular graft microenvironment in situ, quickly resist platelet and bacteria adhesion, and achieve long-term patency and no infection after small-diameter artificial vascular grafting.

[0072] The above is the preferred embodiment of the present invention, but the present invention should not be limited to the content disclosed in this embodiment. Therefore, all equivalent or modified implementations completed without departing from the spirit disclosed by the present invention fall within the protection scope of the present invention.

Claims

1. A method for preparing a polymer for a long-acting anticoagulant and antibacterial coating of a small-caliber artificial blood vessel, characterized in that: The steps include: S1: SN-diOH, a terminal hydroxyl diol, and diisocyanate are dissolved in a first solvent, and a prepolymerization reaction is carried out under the protection of an inert gas to obtain an anticoagulant and antibacterial coating prepolymer; S2: preparing a phosphoric acid / second solvent mixed solution, and dropping the mixed solution and a chain extender capable of forming multiple hydrogen bonds into the anticoagulant and antibacterial coating prepolymer separately, and performing a chain extension reaction at 12-60° C. for 18-36 hours; S3: After the reaction is completed, a dichloromethane solution is continuously added dropwise to the reaction solution obtained in step S2 under ventilation conditions for precipitation, and methyl tert-butyl ether is added for further precipitation, and then large pieces of solid are broken up by ultrasound; the mixture is allowed to stand for separation of liquid and solid, petroleum ether is added to the clarified liquid, excess organic reagents are removed, and the precipitate is vacuum dried to obtain a powdered polymer; S4: immerse in isopropanol for purification for 24 hours, and vacuum dry at 60°C for 48 hours; dissolve in DMSO again, squeeze out and immerse in isopropanol for purification for 24 hours, and vacuum dry at 60°C for 48 hours; repeat this step more than 3 times to obtain.

2. The method for preparing a polymer for a long-acting anticoagulant and antibacterial coating for a small-caliber artificial blood vessel according to claim 1, characterized in that: In step S1, the terminal hydroxy diol SN-diOH is selected from one or more of the diol compounds shown in formulas 4-Ⅰ-1, 4-Ⅱ-1, 4-Ⅲ-1, 4-Ⅳ-1, and 4-Ⅴ-1; The diisocyanate is selected from one or more of 1,4-butanediisocyanate, 1,6-hexamethylenediisocyanate, L-lysine diisocyanate, and isophorone diisocyanate; The first solvent and the second solvent are selected from one or more of ethyl acetate, butyl acetate, acetone, butanone, cyclohexanone, isophorone, dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone; 3. The method for preparing a polymer for a long-acting anticoagulant and antibacterial coating for a small-caliber artificial blood vessel according to claim 1, characterized in that: In step S1, the mass volume concentration of the solution formed by dissolving the terminal hydroxyl diol SN-diOH and the diisocyanate as solutes in the first solvent is 1% to 8%.

4. The method for preparing a polymer for a long-acting anticoagulant and antibacterial coating for a small-caliber artificial blood vessel according to claim 1, characterized in that: In step S1, the prepolymerization temperature is 12 to 80° C., and the prepolymerization time is 0.5 to 4 hours.

5. The method for preparing a polymer for a long-acting anticoagulant and antibacterial coating for a small-caliber artificial blood vessel according to claim 1, characterized in that: In step S2, in the phosphoric acid / second solvent mixed solution, the volume ratio of phosphoric acid to the second solvent is 1:40 to 100; the second solvent is selected from one or more of acetone, dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone; the chain extender capable of forming multiple hydrogen bonds is selected from one or more of imidazolidinyl urea, ureido-4-pyridone UPy, 2,4-diamino-6-hydroxypyrimidine, and dimethylglyoxime.

6. The method for preparing a polymer for a long-acting anticoagulant and antibacterial coating for a small-caliber artificial blood vessel according to claim 1, characterized in that: In step S3, the ultrasonic time is 0.5 to 2 hours, and the vacuum drying temperature is 80°C.

7. The method for preparing a polymer for a long-acting anticoagulant and antibacterial coating for a small-caliber artificial blood vessel according to claim 1, characterized in that: In step S4, isopropanol immersion and motor stirring are performed simultaneously, and the stirring speed is 300-500 rpm; the mass volume concentration of the powdered polymer solution prepared when DMSO is redissolved is 6%-20%.

8. The method for preparing a polymer for a long-acting anticoagulant and antibacterial coating for a small-caliber artificial blood vessel according to claim 1, characterized in that: The molar ratio of the terminal hydroxy diol SN-diOH, the diisocyanate and the chain extender is 1:2:0.1-1.

9. A polymer for a long-lasting anticoagulant and antibacterial coating of a small-caliber artificial blood vessel, characterized in that: The invention is prepared by the method for preparing a polymer for a long-acting anticoagulant and antibacterial coating for small-caliber artificial blood vessels as described in any one of claims 1 to 8.

10. Use of the polymer for the long-acting anticoagulant and antibacterial coating of small-caliber artificial blood vessels according to claim 9 in the preparation of small-caliber artificial blood vessels for arteriovenous fistula, coronary artery and peripheral vascular bypass.

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