Self-healing ready-to-use artificial blood vessel and use thereof

Abstract

The application belongs to the field of cardiovascular interventional medical instruments, and discloses a self-healing and puncture type artificial blood vessel and application. The self-healing and puncture type artificial blood vessel, wherein the intermediate layer is a self-healing polyurethane elastomer (SHPU), endows the artificial blood vessel with excellent mechanical strength, toughness and puncture resistance; the inner layer is an anticoagulant hydrogel layer (SBMA-IL), and the outer layer is an antibacterial hydrogel layer (SBMA@PVP-OL); the inner layer and the outer layer are covalently bonded to the inner and outer surfaces of the SHPU pipeline by using surface permeation-grafting crosslinking technology. The puncture type artificial blood vessel disclosed by the application has the performances of rapid self-healing, long-acting anticoagulation and high-efficiency antibiosis, and can effectively solve the problems of bleeding, thrombosis and infection existing in the current vascular access when used as a hemodialysis vascular access.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of cardiovascular interventional medical devices, and relates to a self-healing immediate puncture artificial blood vessel and application, in particular to an artificial blood vessel with the properties of rapid self-healing, long-acting anticoagulation and high-efficiency antibiosis. BACKGROUND

[0002] Although the maturation period of an artificial blood vessel arteriovenous fistula (AVG) is short, the needle hole of the artificial blood vessel cannot self-heal after dialysis needle puncture, and bleeding and its complications may occur. In order to improve the puncture resistance of the AVG, an immediate puncture artificial blood vessel (ECG) with self-closing performance emerges as the times require. The ECG introduces an intermediate layer with a self-closing function, and realizes rapid closure after puncture through the mechanical rebound of the intermediate layer, which can be used within 24-72 hours after implantation. Although these ECGs can effectively reduce post-puncture bleeding and related complications, there are still some problems to be solved:

[0003] (1) Passive hemostasis mechanism leads to incomplete closure of the puncture hole and bleeding. The sealing effect of the intermediate layer which relies on mechanical rebound to realize the sealing of the puncture hole is limited, which easily leads to bleeding. In addition, under high-frequency puncture, the layer structure is easy to be damaged by fatigue, which further aggravates the bleeding or fluid accumulation, promotes platelet aggregation, increases the risk of infection, and may induce false aneurysm due to local hemodynamic disorder, affecting the long-term stability and biological safety of the implanted material.

[0004] (2) Surface thrombosis or tube wall delamination leads to low long-term patency rate. Restenosis after ECG is the first complication of hemodialysis patients. The hydrophobic inner surface of the ECG easily promotes platelet adsorption, and the inner layer lacks self-closing function, so that the blood contacts the intermediate layer after puncture, increasing the risk of thrombosis. In addition, the ECG has weak interlayer bonding force, which is easy to delaminate after puncture, which easily induces thrombosis.

[0005] (3) Early postoperative infection leads to bacteremia and graft removal. Although the ECG can be used quickly after operation, its infection rate is high due to unhealed incision and limited tissue barrier. After the infection spreads along the subcutaneous tunnel, it can cause systemic infection and may lead to sepsis or anastomotic bleeding. Severe infection requires removal of the graft, and local infection can be controlled by antibiotics or partial resection, but treatment of drug-resistant bacterial infection is difficult.

[0006] Therefore, how to provide a high-performance self-healing immediate puncture artificial blood vessel is a technical problem to be solved by those skilled in the art. SUMMARY

[0007] Therefore, in view of the post-puncture bleeding, low long-term patency rate and high postoperative infection risk of the ECG, the present application provides a self-healing immediate puncture artificial blood vessel and application.

[0008] It should be noted that the development of high-performance ECG needs to be based on the three basic functional requirements of the inner surface anticoagulation, the middle layer anti-puncture and the outer surface antibacterial, and the reasonable construction of the three-layer composite structure. Its long-term effectiveness depends on the mechanical matching of each layer, the coating bonding strength and the functional synergy in the complex environment in the body (such as blood flow shear, blood vessel pulsation and repeated puncture), ensuring the feasibility of clinical transformation.

[0009] The present application aims to prepare a self-healing polyurethane (SHPU) pipeline with rapid self-healing in the blood-tissue dual-phase medium through the molecular structure design of polyurethane elastomer, covalently bond an anticoagulant hydrogel inner layer (SBMA-IL) and an antibacterial hydrogel outer layer (SBMA@PVP-OL) on the inner and outer surfaces of the SHPU pipeline respectively by using the surface permeation-grafting crosslinking technology (CN116003692B) explored in the previous research of the applicant, and construct a self-healing and immediate type artificial blood vessel (SH-ECG) with rapid self-healing, long-acting anticoagulation and high-efficiency antibacterial performance through the reasonable regulation and optimization of the multi-functional hierarchical composite structure and the interface interaction.

[0010] In order to achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows:

[0011] The first technical purpose of the present application is to provide a self-healing and immediate type artificial blood vessel, the pipe wall has a three-layer composite structure, the middle layer is a self-healing polyurethane elastomer (SHPU), the inner layer is an anticoagulant hydrogel layer (SBMA-IL), and the outer layer is an antibacterial hydrogel layer (SBMA@PVP-OL).

[0012] The diameter of the SH-ECG pipeline is 1.5-30 mm, the wall thickness is 50-2000 µm, the thickness of the middle layer is 20-1500 µm, the thickness of the inner layer is 10-200 µm, and the thickness of the outer layer is 10-300 µm.

[0013] The shape of the pipeline includes straight cylinder type, conical type, bifurcated type and stepped shape.

[0014] Optionally, the self-healing polyurethane is a polyurethane-urea with polydimethylsiloxane (PDMS) as the soft segment, diisocyanate and 3,3'-dithiodipropionyl hydrazine (DPH) as the hard segment.

[0015] Further, the diisocyanate is selected from one or more of isophorone diisocyanate (IPDI), 1,6-hexane diisocyanate (HDI), 4,4'-methylenebis(phenyl isocyanate) (MDI), 2,6-toluene diisocyanate (2,6-TDI), 2,4-toluene diisocyanate (2,4-TDI), and 4,4'-dicyclohexylmethane diisocyanate (HMDI).

[0016] Further, the molar ratio of the polydimethylsiloxane (PDMS), diisocyanate and 3,3'-dithiodipropionyl hydrazine (DPH) is 1:0.4-2:0.2-1.

[0017] Here, taking diisocyanate IPDI as an example, the preparation process of the self-healing polyurethane elastomer is as follows:

[0018] .

[0019] The self-healing polyurethane imparts excellent mechanical strength, toughness and puncture resistance to the material. Among them, the hydrophobic PDMS soft segment in the main chain not only provides high elasticity and realizes efficient closure, but also prevents water molecules from penetrating into the polymer network, thereby accelerating the synergistic self-healing process of the dynamic covalent bond (-S-S-) and high-density hydrogen bond in the hard segment. The self-healing mechanism is shown as follows:

[0020] .

[0021] The self-healing polyurethane elastomer is prepared into a self-healing polyurethane pipeline by extrusion molding, 3D printing and mold method, wherein the inner diameter of the pipeline is 1.5-30 mm, the pipeline wall thickness is 50-2000 µm, and the shape of the pipeline includes straight cylinder, cone, bifurcation and step.

[0022] Optionally, the anticoagulant hydrogel layer is a coating layer formed on the surface of the intermediate layer polyurethane substrate pre-activated by a surface initiator and simultaneously initiating grafting and crosslinking polymerization of the zwitterionic monomer and the water-soluble crosslinking agent in an aqueous solution; the aqueous solution contains the zwitterionic monomer, the water-soluble crosslinking agent and the water-soluble initiator;

[0023] The friction coefficient of the polymer coating in the aqueous medium is <0.005, and the surface Young's modulus is 10-60 kPa; and the zwitterionic monomer is at least one or more of methacryloyl ethyl sulfobetaine, 2-methacryloyloxyethyl phosphocholine and carboxybetaine methacrylate; the water-soluble crosslinking agent is a combination of chemical crosslinking agent and physical crosslinking agent; the chemical crosslinking agent is at least one or more of N,N-methylenebisacrylamide, N,N-bis(acryloyl) cystamine, ethylene glycol dimethacrylate and carboxybetaine dimethacrylate, and the physical crosslinking agent is selected from N-acryloyl glycine amide; the surface initiator is one of benzophenone, 4-methyl benzophenone, isopropyl thioxanthone, benzoyl peroxide or azobisisobutyronitrile; the water-soluble initiator is a photoinitiator or a thermal initiator, selected from one of Irgacure-2959, α-ketoglutaric acid, ammonium persulfate or potassium persulfate.

[0024] Optionally, the preparation process of the antibacterial hydrogel layer on the surface of the polyurethane substrate is as follows:

[0025] The outer surface coating layer is formed by immersing the surface coating layer in an iodine-ethanol solution, and the antibacterial coating layer is obtained by complexing NVP with iodine ions.

[0026] The zwitterionic monomer is at least one or more of methacryloyl ethyl sulfobetaine, 2-methacryloyloxyethyl phosphocholine, and carboxybetaine methacrylic acid ester.

[0027] The chemical crosslinking agent is at least one or more of N, N-methylenebisacrylamide (MBA), N, N-bis (acryloyl) cystamine (MSBA), ethylene glycol dimethacrylate (EBA), and carboxybetaine dimethacrylate (CBBA).

[0028] Further, the concentration of the zwitterionic monomer in the raw material of the antibacterial hydrogel layer is 5 wt%-10 wt%, the concentration of the vinyl pyrrolidone is 5 wt%-40 wt%, the chemical crosslinking agent accounts for 0 wt%-20 wt% of the mass of the vinyl pyrrolidone monomer, the physical crosslinking agent N-acryloyl glycine amide accounts for 0 wt%-50 wt% of the mass of the vinyl pyrrolidone monomer, and the water-soluble initiator accounts for 0.5 wt%-20 wt% of the mass of the vinyl pyrrolidone monomer; and the water-soluble initiator Irgacu-2959 accounts for 8 wt% of the mass of the vinyl pyrrolidone monomer.

[0029] After the outer surface coating layer is formed, the concentration of the immersed iodine-ethanol solution is 1 wt%-10 wt%, and the soaking time is 1-8 hours.

[0030] The self-healing mechanism of the inner and outer coating layers is as follows:

[0031] .

[0032] The second technical object of the present application is to provide an application of the puncture type artificial blood vessel with a three-layer composite structure as described above in cardiovascular interventional medical devices.

[0033] Alternatively, the puncture type artificial blood vessel with a three-layer composite structure can be used as a vascular graft, and more preferably as a vascular graft for hemodialysis.

[0034] Specifically, the self-healing ready-to-use artificial blood vessel can be used as a blood vessel graft for the following clinical purposes: arteriovenous access establishment for hemodialysis patients, small-diameter blood vessel replacement in coronary artery bypass graft surgery, and peripheral artery reconstruction, lower extremity ischemia treatment, or other long-term blood vessel reconstruction surgery scenarios.

[0035] Compared with the prior art, the beneficial effects of the present application are:

[0036] A "anticoagulant / puncture-resistant / antibacterial" multifunctional synergistic self-healing ready-to-use artificial blood vessel, the tube wall has a three-layer composite structure, the middle layer of self-healing polyurethane elastomer endows the material with excellent mechanical strength, toughness and puncture resistance; the inner layer of hydrogel rich in zwitterionic units endows the inner wall of the blood vessel with anticoagulant function, and also has self-healing property; the outer layer introduces complex iodine-containing vinyl pyrrolidone units (NVP) to play an antibacterial function by slow-release iodine, while the zwitterionic structure units and NVP provide bactericidal and antibacterial adhesion functions due to their high hydrophilicity.

[0037] 1) The current clinical use of ready-to-use artificial blood vessels (ECG) after dialysis needle puncture, the hemostasis process mainly relies on the mechanical rebound effect of the middle layer elastic film to realize the rapid closure of the needle hole, which is not a true sense of self-healing. This passive closure mechanism is prone to cause local fatigue and performance degradation of the elastic film after high-frequency puncture, making it unable to completely close the puncture site. In addition, the existing ECG generally lacks efficient anticoagulant and antibacterial functions.

[0038] The present application develops a new type of self-healing polyurethane material (SHPU), which has a dynamic self-healing network that can quickly complete reconstruction in seconds to minutes to repair damage under physiological environment, and has a mechanical strength matching that of natural blood vessels. A biomimetic super-lubricating zwitterionic hydrogel coating is constructed on the inner surface of the SHPU material, which can achieve long-acting anticoagulant function; an antibacterial coating of cross-linked copolymer hydrogel containing NVP, zwitterions, NAGA and chemical cross-linking structure units is constructed on the outer surface, and the sustained antibacterial performance is enhanced by the complexation of NVP and iodine. The SH-ECG, with the multifunctional synergistic effects of rapid self-healing, long-acting anticoagulant and high-efficiency antibacterial, provides a new safe, efficient and durable solution for the application of artificial blood vessels in hemodialysis.

[0039] 2) In the current clinical use of ready-to-use artificial blood vessels or related patents that have been published / authorized, the interlayer bonding mostly uses hot-pressing coating or electrospinning process (CN211096500U, CN119593139A), but due to poor material compatibility or weak fiber entanglement force, the interlayer bonding force is insufficient, which is prone to delamination under high-frequency puncture and blood flow scouring, affecting long-term patency and increasing the risk of thrombosis and infection, and also bringing great difficulty to the clinical fistula operation of doctors.

[0040] The application adopts surface permeation-grafting cross-linking technology to covalently bond zwitterionic hydrogel anticoagulant inner layer and antibacterial hydrogel outer layer on polyurethane pipeline, and prepares integrated self-healing instant puncture artificial blood vessel SH-ECG, which is stably combined through covalent bond between layers, ensures the functional stability and safety of the artificial blood vessel under high-frequency puncture and blood flow scouring, and also reduces the difficulty of clinical operation of doctors. BRIEF DESCRIPTION OF DRAWINGS

[0041] In order to more clearly illustrate the technical solutions of the embodiments of the present application or the prior art, the drawings needed to be used in the embodiments or the prior art description will be briefly introduced below. Obviously, the drawings in the following description are only embodiments of the present application, and other drawings can also be obtained according to the provided drawings without creative labor for those skilled in the art.

[0042] Figure 1 Three-layer structure and function of the self-healing instant puncture artificial blood vessel prepared in Example 1.

[0043] Figure 2 Self-healing polyurethane elastomer prepared in Example 1 1 H-NMR.

[0044] Figure 3 Stress-strain curves of samples with different PDMS-2000, IPDI, DPH ratios (P:I:D).

[0045] Figure 4 is the compliance and burst pressure of the self-healing polyurethane pipeline prepared in Example 1.

[0046] Figure 5 Self-healing process of the self-healing polyurethane elastomer prepared in Example 1 in PBS solution.

[0047] Figure 6 SEM images of the self-healing process of the self-healing polyurethane elastomer prepared in Example 1 in PBS solution after puncture and scratch.

[0048] Figure 7 SEM images of the cross section of the self-healing polyurethane pipeline after coating modification.

[0049] Figure 8 Iodine ion cumulative release curve of the outer layer antibacterial hydrogel coating with time.

[0050] Figure 9 Comparison chart of continuous sterilization performance of the pipeline surface before and after modification of the antibacterial coating.

[0051] Figure 10 SEM images of the hydrogel coating on the inner and outer surfaces at different times after puncture.

[0052] Figure 11 Analysis of the patency of the artificial blood vessel prepared in Example 1 implanted in the carotid artery of a pig for 9 months. DETAILED DESCRIPTION

[0053] The technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative work fall within the protection scope of the present application.

[0054] Herein, the term "embodiment" as "exemplary" in any embodiment described does not necessarily mean that the embodiment is superior or better than other embodiments. In the performance index test in the embodiments of the present application, unless otherwise specified, the conventional test method in the art is adopted. It should be understood that the terms described in the present application are only for describing the specific embodiments, and are not used to limit the disclosure of the present application.

[0055] Unless otherwise specified, the technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art to which the present application belongs; and the test methods and technical means not specially noted in the present application refer to the experimental methods and technical means commonly used by those skilled in the art.

[0056] In order to better illustrate the content of the present application, numerous specific details are given in the specific embodiments below. Those skilled in the art should understand that the present application can also be implemented without some specific details. In the embodiments, some methods, means, instruments, devices and the like which are well known to those skilled in the art are not described in detail, in order to highlight the main idea of the present application.

[0057] The technical features disclosed in the embodiments of the present application can be combined in any way without conflict, and the technical solutions obtained by the combination belong to the disclosure of the embodiments of the present application.

[0058] The present application discloses a preparation method of a self-healing and puncture type artificial blood vessel with a three-layer composite structure.

[0059] In order to better understand the present application, the present application will be further specifically described by the following embodiments, but it should not be understood as a limitation of the present application. Some non-essential improvements and adjustments made by those skilled in the art based on the above disclosure are also regarded as falling within the protection scope of the present application.

[0060] Example 1

[0061] Preparation of SH-ECG:

[0062] Preparation of self-healing polyurethane elastomer: 10 g of 3,3'-dimethylthiopropionate was first dissolved in 100 mL of anhydrous methanol, and then 16.18 g of an 80% mass fraction hydrazine hydrate solution was slowly added dropwise to the above solution. After reacting at room temperature for 24 h, the suspension was centrifuged to obtain a white product. The product was washed and dried with anhydrous methanol to obtain a white powder, 3,3-dithiodipropionyl hydrazine (DPH). Then, a linear self-healing poly (urethane-urea) elastomer (SHPU) was prepared using polydimethylsiloxane (PDMS-2000) as the soft segment, isophorone diisocyanate (IPDI) and 3, 3'-dithiodipropionyl hydrazine (DPH) as the hard segment.

[0063] By adjusting the molar ratio of PDMS-2000, IPDI and DPH, different self-healing polyurethanes were prepared. In this embodiment, the molar ratio of PDMS-2000, IPDI and DPH in the self-healing polyurethane prepared was 1:1.4:0.4, and the specific preparation method was as follows:

[0064] 5 g of PDMS was added to a three-necked flask, and nitrogen was introduced three times to remove air. The flask was heated to 100°C under vacuum and stirred for 2 h to remove moisture. Then, the temperature was lowered to 80°C, 0.796 g of IPDI and 0.04 g of catalyst dibutyltin dilaurate (DBTDL) were dissolved in 5 mL of toluene, and the mixture was slowly added dropwise to the three-necked flask under nitrogen. After 3 h of reaction, 0.238 g of DPH was dissolved in a mixture of 35 mL of N,N-dimethylacetamide (DMAc) and 30 mL of toluene, and the mixture was added dropwise to the above reaction system under nitrogen. The reaction was stirred for 4 h. After the reaction was completed, a certain viscosity and colorless transparent polymer solution was obtained. After the reaction system cooled to room temperature, the polymer solution was poured into a surface dish and dried in a 70°C oven for 12 h to remove the toluene and DMAc solvents, and a colorless transparent self-healing polyurethane elastomer was obtained.

[0065] Preparation of self-healing polyurethane pipeline: self-healing polyurethane elastomer can be prepared into a self-healing polyurethane pipeline by extrusion molding, 3D printing and mold method. The following takes 3D printing as an example.

[0066] The synthesized self-healing polyurethane elastomer samples were first cut into blocks, and then processed into 1.75 mm diameter wires using a micro-extruder for fused deposition modeling (FDM) 3D printing. The nozzle temperature of the micro-extruder was set to 140 °C, and the extrusion speed was 10 rpm. Using a computer design system, a FDM printer with a nozzle diameter of 0.4 mm was used to print a self-healing polyurethane elastomer pipeline with a diameter of 5 mm and a wall thickness of 200 µm to meet the needs of different indications scenarios. The chemical composition, mechanical properties, and self-healing properties of the prepared self-healing polyurethane elastomer pipeline are shown in Table 1 and Table 2: Figures 1-5 and Table 1:

[0067] Table 1 Performance of self-healing polyurethane pipeline prepared in Example 1

[0068]

[0069] Self-healing efficiency: ratio of original sample fracture strain after 2 minutes of repair to complete cut in 37 °C PBS solution

[0070] Preparation of internal surface anti-coagulation coating: according to the applicant's previously granted patent (CN116003692B), the prepared self-healing polyurethane elastomer pipeline was washed and completely dried using nitrogen flow. Then, one end of the pipeline was closed, and a benzophenone ethanol solution was poured into the other end, and soaked at 25 °C for 3 minutes. Then, the excess benzophenone and ethanol solution was recovered, washed, and dried using nitrogen.

[0071] Then, a zwitterionic polymer precursor solution was prepared. The specific steps were to dissolve methacrylic acid sulfobetaine (SBMA), N-acryloyl glycine amide (NAGA), chemical crosslinker carboxybetaine dimethyl acrylate (CBMAX), and photoinitiator Irgacure 2959 in deionized water. In the precursor solution, the SBMA content was 20wt%, the physical crosslinker NAGA accounted for 20% of the mass percentage of zwitterions; the chemical crosslinker CBMAX accounted for 10% of the mass percentage of zwitterions, and the photoinitiator Irgacure 2959 accounted for 10% of the mass percentage of zwitterions. Finally, one end of the pipeline with a benzophenone-activated surface was closed, and a zwitterionic polymer precursor solution was injected into the lumen of the pipeline from the other end, and a wavelength of 365 nm ultraviolet light was uniformly irradiated on the pipeline. Then, the adsorbate on the inner surface of the self-healing polyurethane elastomer pipeline was repeatedly washed with a large amount of deionized water to prepare SBMA-IL on the inner surface of the self-healing polyurethane elastomer pipeline. The treated sample was dried with nitrogen at room temperature.

[0072] Preparation of the outer surface antibacterial coating: After the outer surface of the tube was cleaned, it was dried with a nitrogen stream. Then the tube was sealed at both ends with clamps and immersed in a solution of benzophenone in ethanol for 5 min. The sample was then rinsed with deionized water and alcohol to remove unreacted benzophenone, and dried with N2. Then the tube was immersed in a prepolymer solution composed of N-vinyl pyrrolidone (NVP), NAGA, SBMA, N, N’ -methylene bisacrylamide (MBA) and a photoinitiator (Irgacu-2959) and polymerized under 365 nm ultraviolet light to form a hydrogel polymer on the surface of the tube. The concentration of the zwitterionic monomer in the prepolymer solution was 8 wt %, the concentration of vinyl pyrrolidone was 20 wt %, the chemical crosslinking agent accounted for 7 wt % of the mass of the vinyl pyrrolidone monomer, the physical crosslinking agent N-acryloyl glycine amide accounted for 25 wt % of the mass of the vinyl pyrrolidone monomer, and the water-soluble initiator accounted for 8 wt % of the mass of the vinyl pyrrolidone monomer. After the outer surface coating was formed, the tube with the above-mentioned outer surface hydrogel coating was immersed in a 5 wt % iodine ethanol solution for 6 h, wherein I2 existed in the form of H + I3 - and was complexed and stably attached to the surface of the hydrogel coating by forming hydrogen bonds with the amide groups in the hydrogel coating. To remove free iodine on the substrate, it was first washed with ethanol 3 times, then immersed in n-heptane for 24 h, and continuously washed until the washing liquid was colorless and no free iodine was detected by ultraviolet-visible spectroscopy (UV-Vis). SBMA@PVP-OL was prepared on the outer surface of the self-healing polyurethane elastomer tube. Then, the prepared SH-ECG was dried under a nitrogen stream and sterilized by H2O2 low temperature plasma, and finally packaged.

[0073] Examples 2-5

[0074] According to the method of Example 1, the operation was the same as Example 1, except that the soft and hard segment ratio of the polyurethane used in the intermediate layer (PDMS-2000: IPDI: DPH, hereinafter referred to as P: I: D) was changed. The tensile strength, burst pressure, compliance, suture strength, and self-healing efficiency of the polyurethane with different soft and hard segment ratios and the natural blood vessels were measured. As shown in Table 2.

[0075] Table 2 Performance of self-healing polyurethane tubes prepared in Examples 2-5 with different ratios of soft and hard segments

[0076]

[0077] As can be seen from Table 2, with the increase of hard segment content, the tensile strength, burst pressure and suture strength of the material are increased, but the compliance and self-healing efficiency are decreased. When PDMS-2000: IPDI: DPH = 1: 1.4: 0.4, the mechanical properties of the pipeline match the natural blood vessels, and the self-healing efficiency reaches 85% ± 2%, which meets the use requirements of artificial blood vessels.

[0078] Examples 6-10

[0079] According to the method of Example 1, the operation is the same as Example 1, except that the type of diisocyanate is changed, and the physical and chemical properties of the self-healing polyurethane pipeline prepared by different types of diisocyanate are measured.

[0080] Table 3 Performance of self-healing polyurethane pipeline prepared by different types of diisocyanate in Examples 6-10

[0081]

[0082] IPDI: isophorone diisocyanate; HDI: 1, 6-hexane diisocyanate; MDI: 4, 4'-methylene bis (phenyl isocyanate); 2, 6-TDI: 2, 6-toluene diisocyanate; 2, 4-TDI: 2, 4-toluene diisocyanate; HMDI: 4, 4'-dicyclohexyl methane diisocyanate

[0083] As can be seen from Table 3, with the introduction of benzene ring or the increase of steric hindrance effect in diisocyanate, the tensile strength, suture strength and burst pressure of the material are increased, the compliance is decreased, and the self-healing efficiency is decreased.

[0084] Examples 11-12

[0085] According to the method of Example 1, the operation is the same as Example 1, except that the type of zwitterionic monomer in the outer layer antibacterial coating is changed, and the thickness, hydrophilicity, lubricity, surface Young's modulus, protein, bacterial adhesion amount and antibacterial performance of the hydrogel coating composed of different types of zwitterionic monomers are measured.

[0086] Table 4 Performance of outer coating prepared by different types of zwitterionic monomers

[0087]

[0088] T: coating thickness; CF: coating friction coefficient; WA: surface water contact angle; E: surface Young's modulus; Ad pro : protein adsorption amount; Ad bac : platelet adhesion amount; Ad pla-10 : platelet adhesion amount after shearing in PBS solution for 10 days; IZD: inhibition zone diameter.

[0089] As shown in Table 4, although the zwitterionic monomers used are different (SBMA, CBMA, MPC), the prepared outer hydrogel coating layers have similar ranges of thickness, coefficient of friction, water contact angle, surface Young's modulus, protein adsorption amount, platelet adhesion amount, and antibacterial properties, indicating that different types of zwitterionic monomers can be used to construct an outer antibacterial coating layer with good hydrophilicity, lubricity, and anti-protein / bacterial adhesion properties.

[0090] Examples 13-15

[0091] According to the method of Example 1, the operation is the same as that of Example 1, except that the type of chemical crosslinking agent in the outer antibacterial coating layer is changed, and the thickness, hydrophilicity, lubricity, surface Young's modulus, protein, bacterial adhesion amount, and antibacterial properties of the hydrogel coating layer composed of different types of chemical crosslinking agents are measured.

[0092] Table 5 Performance of outer coating layers prepared using different types of chemical crosslinking agents

[0093]

[0094] As shown in Table 5, although the types of chemical crosslinking agents used are different (MBA, MSBA, EBA, CBBA), the prepared outer hydrogel coating layers have similar ranges of coating thickness, coefficient of friction, water contact angle, surface Young's modulus, protein adsorption amount, platelet adhesion amount, and diameter of the inhibition zone, indicating that different types of chemical crosslinking agents have little effect on the overall performance of the coating layer, and can be used to construct an outer antibacterial coating layer system with good overall performance.

[0095] Examples 16-34

[0096] According to the method of Example 1, the operation is the same as that of Example 1, except that the contents of SBMA, NVP, NAGA, and chemical crosslinking agent in the outer antibacterial coating layer are changed, and the thickness, hydrophilicity, lubricity, surface Young's modulus, protein, bacterial adhesion amount, mechanical stability, iodine ion release time, and antibacterial properties of the outer antibacterial coating layer composed of different contents of monomers and crosslinking agents are measured.

[0097] Table 6 Performance of outer antibacterial coating layers composed of different contents of monomers and crosslinking agents

[0098]

[0099] WA0: surface water contact angle before the accelerated fatigue test; WA1: surface water contact angle after the accelerated fatigue test; CF0: surface coefficient of friction before the accelerated fatigue test; CF1: surface coefficient of friction after the accelerated fatigue test; IIRT: iodine ion release time.

[0100] As can be seen from Table 6, with the increase of SBMA content, the hydrophilicity, lubricity and anti-bioadhesion performance of the coating are all enhanced, and the thickness of the coating also shows an increasing trend. This is mainly due to the excellent hydrophilicity of SBMA, which can significantly improve the swelling rate of the coating. At the same time, the increase of SBMA content also makes the network structure of the coating more flexible, and the overall stiffness decreases, which is manifested as the decrease of the surface Young's modulus of the coating. However, when the content of SBMA is too high, due to the insufficient mechanical strength of the coating, its structural stability decreases, and local shedding is prone to occur after the accelerated fatigue test, thereby causing significant changes in the hydrophilicity and lubricity of the coating. It is worth noting that the iodine ion release time (IIRT) and the inhibition zone diameter (IZD) have no obvious correlation with the content of SBMA, indicating that the change of the content of SBMA has little effect on the antibacterial persistence and antibacterial intensity of the coating.

[0101] With the increase of N-vinylpyrrolidone (NVP) content, the hydrophilicity, lubricity, anti-bioadhesion performance, antibacterial performance and iodine ion release time of the obtained coating all show an increasing trend, and the thickness of the coating increases synchronously. The thickness growth is mainly due to the excellent hydrophilicity of polyvinylpyrrolidone (PVP), which significantly improves the swelling ability of the coating. The mechanism of the enhancement of the antibacterial performance and the extension of the iodine ion release time lies in that the increase of NVP content increases the density of amide groups in the coating, which can form more stable hydrogen bond interactions with I2·H + I3 - complexes, enhancing the complex stability of iodine and delaying its release, effectively improving the antibacterial persistence and intensity of the coating. In addition, the increase of NVP content also makes the network structure inside the coating tend to be flexible, reducing the overall stiffness, which is manifested as the decrease of the surface Young's modulus. However, when the content of NVP is too high, due to the decrease of the mechanical strength of the coating, its structural stability is weakened, and local shedding is prone to occur under the condition of accelerated fatigue, thereby causing significant changes in the hydrophilicity and lubricity of the coating.

[0102] With the increase of the content of the physical crosslinking agent N-acryloylglycine (NAGA), the mechanical properties and mechanical stability of the prepared coating are significantly enhanced, and the thickness of the coating decreases. This phenomenon is mainly due to the introduction of physical crosslinking points mainly in the form of multiple hydrogen bonds by NAGA in the coating network, thereby limiting the excessive swelling of the coating and improving the compactness and mechanical strength of the coating structure. On the other hand, with the continuous increase of the content of NAGA, the hydrophilicity and lubricity of the coating decrease, and the anti-bioadhesion performance shows a downward trend. This is because the amide groups and amino acid-like structures in the NAGA molecule have certain bioactivity and are easy to interact with proteins and bacterial surface molecules through hydrogen bonds or electrostatic interactions, thereby promoting their adsorption on the surface of the coating. It is worth noting that the change of the content of NAGA has little effect on the antibacterial performance and iodine ion release behavior of the coating, and its mechanism mainly reflects the regulation of the network structure rather than the influence on the complexing ability of iodine ions.

[0103] With the increase of the content of the chemical crosslinking agent CBMAX, the mechanical properties and mechanical stability of the coating are improved within a certain range. However, when the content of CBMAX is too high, the mechanical stability of the coating decreases, mainly because the excessive chemical crosslinking leads to an increase in the brittleness of the coating, which is easy to crack or fall off. In addition, too high content of the crosslinking agent will significantly reduce the hydrophilicity and lubricity of the coating, thereby causing an increase in the amount of platelet adhesion, which may have an adverse effect on biocompatibility. Experimental results show that there is no significant difference in iodine ion release time (IIRT) and inhibition zone diameter (IZD) under different CBMAX content conditions, indicating that the content of CBMAX has little effect on the antibacterial performance and iodine release behavior of the coating.

[0104] Examples 35-45

[0105] According to the method of Example 1, the operation is the same as that of Example 1, except that the concentration of the iodine-ethanol solution used for impregnation and the soaking time are changed after the formation of the outer surface coating, and the thickness, surface Young's modulus, protein and bacterial adhesion amount, iodine ion sustained release time and self-healing efficiency of the outer antibacterial coating are measured, as shown in Table 7.

[0106] Table 7 Performance of the outer antibacterial coating composed of different concentrations of iodine-ethanol solution and soaking time

[0107]

[0108] The experimental results show that, within a certain range, with the increase of the concentration of iodine solution and the extension of the soaking time, the loading capacity of iodine ions in the coating is correspondingly improved, resulting in the enhancement of the iodine ion release time (IIRT) and the antibacterial performance. However, when the concentration of iodine solution reaches a high level or the soaking time is too long, the complexing sites of the coating and iodine ions tend to be saturated, and the further complexing ability of iodine is limited. Therefore, continuing to increase the concentration of iodine solution or extending the soaking time no longer has a significant impact on the antibacterial performance of the coating and the release behavior of iodine ions.

[0109] In addition, the characterization method of the self-healing and wear-resistant artificial blood vessel with a three-layer composite structure prepared by the present application is as follows:

[0110] (1) Tensile strength test: In this experiment, a general material testing system (Instron, Norwood, MA, USA) equipped with a 2519-104 type sensor was used to evaluate the tensile strength of the sample. The test content included the ultimate tensile strength and the radial loading-unloading behavior. During the test, the sample was installed between two groups of parallel hooks composed of stainless steel wires with a diameter of 1 mm along the radial direction, and the test was carried out under the action of radial tension. A mechanical sensor with a 50 N range was used, and the loading rate was set to 2 mm / min until the sample was broken.

[0111] (2) Self-healing efficiency: The self-healing polyurethane artificial blood vessel sample was cut into a long strip-shaped test piece with a size of 50 mm × 10 mm and immersed in a 37°C phosphate buffered saline (PBS) solution for 10 minutes to achieve pre-hydration treatment. Then, the test piece was fractured along its width direction and quickly aligned the cutting interface to achieve preliminary closure. The sample was continued to be immersed in PBS for 2 minutes after the interface was kept in contact, and then the tensile property test was carried out to evaluate the self-healing ability of the material.

[0112] Needle test and scratch test: The sample was cut along the longitudinal direction and then pre-treated in a 37°C phosphate buffered saline (PBS) solution. Then, a syringe needle was used to make multiple holes and scratches on the surface of the sample to simulate mechanical damage. After the damage treatment was completed, the sample was continued to be kept in the 37°C PBS solution, and sampling was carried out at the set time point to observe its self-healing behavior. To prevent the self-healing process from continuing after sampling, the sample was immediately cooled to −20°C and freeze-dried after each sampling, effectively terminating the self-healing reaction. All samples treated at different time points were observed and analyzed under a scanning electron microscope (SEM) to evaluate the repair effect of the scratches and holes and other damages.

[0113] (3) Compliance test: The compliance test device consists of a programmable syringe pump and a pressure monitoring gauge, which is used to regulate and record the deformation behavior of the lumen structure under different internal pressures. By adjusting the injection and withdrawal rate of the syringe pump, precise control of the pressure in the closed fluid circuit is achieved. During the test, the change in diameter of the sample is measured using a vernier caliper. The compliance is characterized by the relative radial expansion degree under unit pressure difference, and the calculation formula is as follows:

[0114] ;

[0115] where P1 is the low pressure value, P2 is the high pressure value, and the unit is mmHg. RP1 and RP2 represent the diameters at pressures P1 and P2, respectively. The compliance is expressed as the percentage change in diameter per 100 mmHg.

[0116] (4) Burst pressure test: After the sample is fully swollen in phosphate buffered saline (PBS) to the equilibrium state, it is connected to the pressure loading device. Then, PBS solution is injected into the sample lumen at a constant rate of 50 mmHg / s, so that the internal pressure continues to rise and tends to be stable. The internal pressure change is monitored in real time during the pressurization process, and the instantaneous pressure value corresponding to the rupture of the sample is recorded as the burst pressure of the material.

[0117] (5) Suture strength test: Choose suture with type 8-0, penetrate the blood vessel wall from the end of the artificial blood vessel to the inner 2mm to form a fixed point. Then, a constant tensile load is applied to the suture at a rate of 50 mm / min until the suture completely penetrates the artificial blood vessel wall. The maximum tensile force required during this process is recorded, which is used as the suture strength indicator of the artificial blood vessel.

[0118] (6) Fatigue resistance test: To evaluate the fatigue resistance of the artificial blood vessel, the pulsatile accelerated fatigue test method is used. Under the condition of constant temperature 37℃, the artificial blood vessel sample is connected to the pulsatile fatigue test device (model: INVS-06, manufacturer: CARE Measurement & Control Co., Ltd), and physiological saline is injected into the lumen as the circulating medium. By applying a periodic pulse load with a frequency of 50 Hz and a pressure range of 80-160 mmHg, the sample is continuously operated to 380 million cycles. Before and after the test, the diameter and compliance of the sample are measured and compared to determine its fatigue resistance under long-period dynamic loading.

[0119] (7) Analysis of the surface morphology and thickness of the coating: Field emission scanning electron microscopy (Model: HITACHI S-4800, manufacturer: Hitachi) was used to observe and characterize the surface morphology and cross-sectional thickness of the sample coating. To improve the electrical conductivity of the sample and obtain clear images, the sample surface was treated with a metal coating for about 60 seconds under inert gas (argon) protection before scanning. Subsequently, high-resolution images of the coating surface and cross-section were obtained under imaging parameters of an acceleration voltage setting of 3 kV and a working distance control within the range of 10-15 mm, to evaluate the microstructure characteristics and thickness uniformity.

[0120] (8) Protein adhesion test: The determination of protein adsorption amount was performed by BCA protein quantification method, and the reagent used was BCA protein detection kit. This method is based on the following principle: in an alkaline environment, the peptide bond in the protein can reduce Cu + to Cu + , and the generated Cu + ions can form a purple complex with two molecules of BCA (bis-aminocyclohexane tetraacetic acid). This complex has a strong absorption peak at a wavelength of 562 nm, and the absorbance value is linearly related to the protein concentration. In this experiment, the model protein used was bovine serum albumin (BSA). According to the requirements of the kit instructions, standard BSA solutions with different concentration gradients were prepared, with a concentration range of 0, 2.5, 5, 10, 20, 40, and 200 μg / mL, and the optical absorption values of each standard solution at 562 nm were measured. The standard curve was plotted with absorbance as the abscissa and protein concentration as the ordinate, which was used for subsequent quantitative analysis of protein adsorption in samples.

[0121] (9) Surface Young's modulus test: A desktop nanoindentation testing device (Model: PIUMA) was used to determine the surface mechanical properties of the zwitterionic polymer coating modified on the substrate surface, with the specific test index being the Young's modulus. During the test, a spherical indenter with a radius of 48.5 mm was selected, and the coating sample previously soaked in PBS solution was subjected to loading detection. The test area was 100 μm × 100 μm, and data collection was performed by a 5 × 5 matrix method with a point spacing of 20 μm, achieving fine scanning and evaluation of the Young's modulus distribution in the area.

[0122] (10) Surface friction coefficient test: A CSM friction and wear tester was used to determine the friction coefficient of the sample surface. Before testing, the sample was pre-soaked in deionized water at a constant temperature of 25°C to ensure that it was in a stable wet state. During the test, a glass ball with a diameter of 3 mm was used as the loading probe, which was moved on the sample surface at a sliding speed of 30 mm / min, with a sliding stroke set to 20 mm. The friction coefficient was calculated by taking the ratio of the real-time recorded friction force to the applied normal load (800 μN).

[0123] (11) Platelet adhesion test: Firstly, the peripheral blood was treated by using commercial platelet separation kit to separate platelet-rich plasma (PRP) from the fresh whole blood collected from New Zealand white rabbits. The treated sample and PRP were co-incubated at 37°C for 2 hours to complete the process of platelet contacting with the material surface. Then, the sample was divided into non-washing group and PBS washing group, and was fixed in 2.5% glutaraldehyde fixing solution for 2 hours. After fixation, the sample was dehydrated by gradient ethanol solution with concentrations of 50%, 60%, 70%, 80%, 90% and 100% for 30 minutes for each gradient. After dehydration, all samples were naturally dried at room temperature for 24 hours. The dried sample was observed by scanning electron microscope (SEM, model: HITACHI S-4800, Hitachi Company). By analyzing the morphology of platelets on the surface of the non-washing group, the influence of the material surface on platelet activation was evaluated. At the same time, the number of residual platelets in the washing group was observed to determine the anti-platelet adhesion performance of the coating.

[0124] (12) Anti-bacterial performance / anti-bacterial adhesion performance test: Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus were selected as pathogenic bacteria models. The artificial blood vessels with the outer surface modified with the anti-bacterial coating were immersed in a 24-well plate containing 1 mL of E. coli or S. aureus suspension (1 × 10 8 CFU / mL), and incubated in a 37°C constant temperature incubator for 12 hours. After removing the bacterial solution, the surface was washed with PBS solution for 3 times to remove the bacteria not adhered to the surface, and then immersed in a PBS solution containing 4% glutaraldehyde and stored at 4°C overnight. Then, the sample was dehydrated by gradient ethanol with concentrations of 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% and 100% for 20 minutes for each gradient. Finally, the bacterial adhesion on the surface of the catheter was observed by scanning electron microscope to determine the anti-bacterial adhesion effect of the coating.

[0125] In order to quantitatively evaluate the anti-bacterial adhesion effect of the coating, 1 mL of bacterial suspension (1 × 10 8 CFU / mL) was co-cultured with the artificial blood vessels after ultraviolet sterilization for 30 minutes at 37°C constant temperature incubator for 12 hours. Then, all the catheters were washed with sterile PBS for 3 times to remove the loosely adhered bacteria. Next, all the samples were treated with ultrasonic wave in 2 mL of sterile PBS solution to separate the firmly adhered bacteria on the surface of the sample. After repeating the above process for 5 times, 10 mL of PBS containing bacteria was collected. After diluting the bacteria to an appropriate concentration, the bacteria were inoculated on LB agar plate and cultured in a 37°C constant temperature incubator for 12 hours. The number of bacterial colonies was determined by plate counting method to compare and evaluate the anti-bacterial adhesion effect of the coating.

[0126] Since the iodine ions in the coating are complexed by hydrogen bonds, the iodine element can be released in vivo to kill bacteria, so the bactericidal effect of the system in vitro is evaluated.

[0127] 100 μL of E. coli or S. aureus suspension (1 x 10 8 CFU / mL) was inoculated into LB agar medium, and then the sample after ultraviolet sterilization for 30 min was placed on the medium and cultured in a 37°C constant temperature incubator for 12 h, and the formation of the inhibition zone was observed.

[0128] To quantitatively determine the bactericidal effect of the coating, the sample after ultraviolet sterilization for 30 min was immersed in 1 mL of E. coli or S. aureus suspension (1 x 10 8 CFU / mL), and after 12 hours of culture in a 37°C constant temperature shaker, the sample was removed, the co-cultured suspension was moderately diluted, and then inoculated onto LB agar plates and cultured in a 37°C constant temperature incubator for 12 h. Plate counting method was used to determine the number of colonies formed to evaluate the in vitro bactericidal effect of the coating.

[0129] (13) Pig carotid artery end-to-end anastomosis experiment: 3-4 month-old male Bama pigs weighing 55-75 kg were selected as experimental animals. Induced anesthesia was performed by intramuscular injection of ketamine (dose: 20 mg / kg) and thiopental (dose: 2 mg / kg), and then fentanyl and propofol were injected through the ear vein to maintain general anesthesia. The animal used a 7mm tracheal tube to connect a positive pressure ventilator for respiratory support during the operation, and the oxygen supply rate was set to 1.2 L / min.

[0130] During the operation, the skin of the neck was first incised and the target carotid artery was separated, then the proximal and distal segments were clamped with two hemostatic forceps, the middle segment was cut off, and the artificial blood vessel was end-to-end anastomosed with the cut end of the carotid artery using 6-0 monofilament suture. After the operation was completed, the muscle layer, subcutaneous tissue and skin were sutured layer by layer using absorbable monofilament suture. The material was taken out 9 months after the operation for histological analysis to evaluate the biological response of the implanted body.

[0131] After the implantation of the artificial blood vessel, non-invasive detection was performed using Doppler ultrasound imaging to evaluate the blood flow patency. The detection used a veterinary digital color Doppler ultrasound diagnostic system (SIUI Apogee 3100V, China) and selected the superficial structure imaging mode. According to the anatomical positioning of the carotid artery and the synchronous pulse wave, the implantation site of the artificial blood vessel was determined. The ultrasound examination obtained three-dimensional color flow images, pulse synchronous signals and real-time blood flow velocity data; among them, the red and blue colors in the Doppler flow spectrum indicate the antegrade and retrograde directions of blood flow, respectively.

[0132] Specifically, Figure 2 The stress-strain curve of the self-healing polyurethane elastomer prepared in Example 1 1 H-NMR. It can be seen that δ = 4.21 ppm and δ = 9.07 ppm are proton peaks on the primary and secondary amines, respectively, and δ = 2.4 ppm and δ = 2.89 ppm also appear two sets of methylene proton peaks, and the area ratio of the four sets of peaks is 2:1:2:2. Analysis determines that the designed healing polyurethane elastomer is successfully prepared. Figure 2

[0133] The stress-strain curve of the sample with different PDMS-2000, IPDI, DPH ratios (P:I:D). From Figure 3 It can be seen that when PDMS-2000: IPDI: DPH = 1: 2: 1, the maximum breaking stress of the material can reach 10 Mpa, and the strain is close to 650%, indicating that it has high toughness and strength. With the decrease of hard segment content, the maximum breaking stress of the material decreases, but the toughness rises. Figure 3 Figure 4 is the compliance and burst pressure of the self-healing polyurethane pipeline prepared in Example 1. From

[0134] It can be seen that when the ratio of PDMS-2000: IPDI: DPH is 1:1.2:0.2, the mechanical properties of the self-healing polyurethane pipeline meet the use requirements of artificial blood vessels. Figure 4

[0135] Figure 6 The SEM diagram of the self-healing process of the self-healing polyurethane elastomer prepared in Example 1 in PBS solution after puncture and scratch. From Figure 6 It can be seen that in the PBS solution at 37℃, after being completely cut off, the SHPU has basically completed self-repairing after only 2 minutes, indicating that it has the characteristics of self-repairing in a fast liquid environment.

[0136] Figure 7 The SEM diagram of the cross section of the self-healing polyurethane pipeline after coating modification. From Figure 7 It can be seen that the SBMA-IL anticoagulant coating and the SBMA@PVP-OL antibacterial coating can uniformly modify the inner and outer surfaces of the polyurethane elastomer pipeline, and form a close combination with the substrate without gaps.

[0137] Figure 8 The curve of the cumulative release amount of iodine ions of the outer layer antibacterial hydrogel coating with time. From Figure 8 It can be seen that the outer layer antibacterial coating can maintain the release of iodine ions for more than one week, while the early infection after the artificial blood vessel arteriovenous fistula surgery usually occurs in 5-7 days after the surgery, which can meet the clinical anti-infection demand.

[0138] Figure 9 The comparison diagram of the continuous sterilization performance of the pipeline surface before and after the modification of the antibacterial coating. From​Figure 9 It can be seen that the outer layer of antibacterial coating has good sterilization effect.

[0139] Figure 10 SEM images of the water gel coating on the inner and outer surfaces at different times after puncture. From left to right, top row: 0 min, 5 min, 10 min, 20 min, 30 min, 60 min, 120 min, 240 min, 480 min, 720 min, 1440 min. Figure 10 It can be seen that the inner and outer layer coatings can basically complete self-healing within 20 minutes after puncture.

[0140] Figure 11 Analysis of the patency of the artificial blood vessel prepared in Example 1 implanted in the carotid artery of a pig for 9 months. From left to right, top row: 0 min, 5 min, 10 min, 20 min, 30 min, 60 min, 120 min, 240 min, 480 min, 720 min, 1440 min. Figure 11 It can be seen that the artificial blood vessel can maintain patency for a long time after being implanted in the body.

[0141] The above description of disclosed embodiments enables one of ordinary skill in the art to make or use the application. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein can be applied to other embodiments without departing from the spirit or scope of the application. Accordingly, the application is not to be limited to these embodiments shown herein but is to be accorded the broadest scope consistent with the principles and novel features disclosed herein.

Claims

1. A self-healing ready-to-use vascular graft, characterized in that, The pipe wall has a three-layer composite structure, the middle layer is a self-healing polyurethane elastomer SHPU, the inner layer is an anti-coagulation hydrogel layer SBMA-IL, and the outer layer is an antibacterial hydrogel layer SBMA@PVP-OL. The pipe has a diameter of 1.5-30 mm, a wall thickness of 50-2000 µm, a middle layer thickness of 20-1500 µm, an inner layer thickness of 10-200 µm, and an outer layer thickness of 10-300 µm. The shape of the pipe includes straight cylinder, cone, bifurcation, and step. The preparation process of the antibacterial hydrogel layer on the polyurethane substrate surface is as follows: The grafting cross-linking polymerization of the zwitterionic monomer and the water-soluble cross-linking agent is simultaneously initiated on the surface of the middle layer polyurethane substrate activated by a surface initiator and in an aqueous solution, and the coating layer formed on the substrate surface; the aqueous solution contains the zwitterionic monomer, the water-soluble cross-linking agent, and a water-soluble initiator; The friction coefficient of the polymer coating in the water medium is <0.005, and the surface Young's modulus is 10-60 kPa; The chemical crosslinker is at least The water-soluble cross-linking agent is a combination of a chemical cross-linking agent and a physical cross-linking agent; the physical cross-linking agent is selected from N-acryloyl glycine amide; - methylene bisacrylamide, The water-soluble initiator is a photoinitiator or a thermal initiator, and is selected from one of Irgacure-2959, α-ketoglutaric acid, ammonium persulfate, and potassium persulfate. - one or several of bis(acryloyl)cystamine, ethylene glycol dimethacrylate, carboxybetaine dimethacrylate. The self-healing polyurethane is a polyurethane-urea with polydimethylsiloxane (PDMS) as a soft segment, diisocyanate and 3,3'-dithiodipropionyl hydrazine (DPH) as hard segments.

2. The self-healing ready-to-use vascular graft of claim 1, wherein, The diisocyanate is selected from one or more of isophorone diisocyanate (IPDI), 1,6-hexane diisocyanate (HDI), 4,4'-methylene bis(phenyl isocyanate) (MDI), 2,6-toluene diisocyanate (2,6-TDI), 2,4-toluene diisocyanate (2,4-TDI), and 4,4'-dicyclohexylmethane diisocyanate (HMDI).

3. The self-healing ready-to-use vascular graft of claim 2, wherein, The molar ratio of the polydimethylsiloxane (PDMS), diisocyanate, and 3,3'-dithiodipropionyl hydrazine (DPH) is 1:0.4-2:0.2-1.

4. The self-healing ready-to-use vascular graft of claim 2, wherein, The anti-coagulation hydrogel layer is a grafting cross-linking polymerization of a zwitterionic monomer and a water-soluble cross-linking agent simultaneously initiated on the surface of a middle layer polyurethane substrate activated by a surface initiator and in an aqueous solution, and the coating layer formed on the substrate surface; the aqueous solution contains the zwitterionic monomer, the water-soluble cross-linking agent, and a water-soluble initiator; 5. The self-healing ready-to-use vascular graft of claim 1, wherein, The friction coefficient of the polymer coating in the water medium is <0.005, and the surface Young's modulus is 10-60 kPa; The water-soluble cross-linking agent is a combination of a chemical cross-linking agent and a physical cross-linking agent; the physical cross-linking agent is selected from N-acryloyl glycine amide; The water-soluble initiator is a photoinitiator or a thermal initiator, and is selected from one of Irgacure-2959, α-ketoglutaric acid, ammonium persulfate, and potassium persulfate. ​ 6. The self-healing ready-to-use vascular graft of claim 1, wherein, The concentration of the amphoteric ion monomer in the raw material of the antibacterial hydrogel layer is 5 wt%-10 wt%, the concentration of the vinyl pyrrolidone is 5 wt%-40 wt%, the chemical crosslinking agent accounts for 0 wt%-20 wt% of the mass of the vinyl pyrrolidone monomer, the physical crosslinking agent N-acryloyl glycine amide accounts for 0 wt%-50 wt% of the mass of the vinyl pyrrolidone monomer, and the water-soluble initiator Irgacu-2959 accounts for 8 wt% of the mass of the vinyl pyrrolidone monomer; After the formation of the outer surface antibacterial coating, the concentration of the impregnated iodine-ethanol solution is 1 wt%-10 wt%, and the soaking time is 1-8 hours.

7. Use of the self-healing ready-to-use artificial blood vessel according to claim 1 in the preparation of cardiovascular interventional medical devices.

8. Use according to claim 7, characterized in that, The self-healing ready-to-use artificial blood vessel is used as a vascular graft.

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