Preparation method of ready-to-penetrate artificial blood vessel containing silicone rubber elastomer middle layer

Abstract

The invention relates to the field of medical apparatus and instruments, and particularly discloses a preparation method of an instant-penetrating artificial blood vessel containing a silicone rubber elastomer interlayer, which comprises the following steps: preparing a three-layer instant-penetrating artificial blood vessel on a multi-size tubular receiver layer by layer by adopting an electrostatic spinning technology; wherein the middle layer of the three-layer artificial blood vessel adopts a two-channel electrostatic spinning technology, and two-component room-temperature / medium-temperature addition type filling reinforcing silicon rubber is synthesized to serve as a silicon rubber elastomer; wherein the inner layer and the outer layer of the three-layer artificial blood vessel are prepared by adopting thermoplastic polyurethane as a raw material and performing electrostatic spinning treatment. The ready-to-wear three-layer artificial blood vessel prepared by the invention has excellent physical and mechanical properties and biocompatibility, and a special middle-layer silica gel structure is adopted as a core, so that a puncture needle eye can be retracted, a puncture point can be immediately contracted and closed to stop bleeding after puncture and needle withdrawal, exosmosis of serum is avoided, occurrence of postoperative limb edema is reduced, and the bleeding risk is reduced.

Description

Technical Field

[0001] The invention belongs to the field of medical devices, and in particular relates to a method for preparing a ready-to-wear artificial blood vessel containing a silicone rubber elastomer intermediate layer. Background Art

[0002] In recent years, the application of immediate puncture artificial blood vessels is a major progress in the field of artificial blood vessel materials for hemodialysis. Vascular access is the lifeline of hemodialysis patients. Establishing a smooth, effective and lasting vascular access is a prerequisite for hemodialysis patients and determines their survival and quality of life. The first choice for establishing vascular access is autologous arteriovenous fistula (AVF), followed by graft arteriovenous fistula (AVG), and finally central venous catheter (CVC). However, AVF and traditional AVG require a long maturation period, and repeated central venous catheterization is prone to cause serious complications-central venous stenosis. Ordinary artificial blood vessels can only be punctured and used about 2-4 weeks after surgery. The reason is that after ordinary artificial blood vessels are punctured, needle holes will be left on the blood vessel wall. The wall of the artificial blood vessel can only rely on the surrounding tissue to compress and stop bleeding, and cannot repair the needle holes by itself. About 3-4 weeks after surgery, when the subcutaneous tissue and the artificial blood vessel grow closely together, the bleeding can be stopped by pressure from the outside of the skin after puncture. Premature puncture can easily lead to subcutaneous hematoma and pseudoaneurysm formation. Different from traditional artificial blood vessels, the puncture-type artificial blood vessels reduce the risk of bleeding from the puncture needle eye through the special structural design of their tube wall. There is no need to wait for 2 weeks for the artificial blood vessels to heal with the subcutaneous tissue fibers. Dialysis can be performed immediately after surgery. Its greatest significance is to reduce the use of hemodialysis catheters during the transition period, thereby protecting the patient's central venous resources. Human blood vessels are divided into three layers. The endothelial cells of the inner membrane can secrete bioactive substances, the middle membrane plays an elastic and supporting role, and the outer membrane can secrete proteins and transport nutrients. The puncture-type artificial blood vessels simulate the structure and function of human blood vessels and adopt a three-layer structural design. The core adopts a special middle-layer silicone structure to avoid serum extravasation, reduce the occurrence of postoperative limb edema, and retract the puncture needle eye. After the puncture needle is removed, the puncture point immediately contracts and closes to stop bleeding, reducing the risk of bleeding.

[0003] Among the various methods for preparing artificial blood vessels, electrospinning artificial blood vessels have obvious advantages. On the one hand, electrospinning technology is easy to prepare small-caliber artificial blood vessels (SDBVs). The inner diameter and thickness of the product can be adjusted by controlling the size of the receiving device and the spinning time, and the blending or compounding of different materials can be designed to give the product different properties. On the other hand, electrospinning technology can prepare continuous ultrafine fibers with a large specific surface area, which is conducive to mimicking the natural extracellular matrix (ECM) in the human body, providing environmental conditions for cell adhesion, proliferation and differentiation, and can promote ECM secretion to a certain extent. The biocompatibility of materials made by other processes is better. Electrospinning technology is a very promising tissue engineering technology. It can prepare polymer fiber scaffolds that meet the requirements of ECM construction and promote cell adhesion, proliferation and growth. Summary of the invention

[0004] In view of the deficiencies in materials and functions of existing products, the present invention aims to provide a ready-to-wear artificial blood vessel containing a silicone rubber elastomer intermediate layer and a preparation method thereof.

[0005] Based on the above purpose, the present invention adopts the following technical solution: The first aspect of the present invention provides a method for preparing a ready-to-wear artificial blood vessel containing a silicone rubber elastomer intermediate layer, comprising the following steps: using electrospinning technology to prepare a three-layer ready-to-wear artificial blood vessel layer by layer; wherein a solution electrospinning technology is used to electrospin a thermoplastic polyurethane tube on a multi-sized tubular receptor as the inner layer of the artificial blood vessel; The middle layer of the artificial blood vessel adopts double-channel electrostatic spinning technology to synthesize a two-component room temperature / medium temperature addition type filling and reinforcing silicone rubber as the middle layer of the artificial blood vessel; The outermost layer of the artificial blood vessel is prepared by using thermoplastic polyurethane as raw material on the surface of the silicone rubber layer using electrostatic spinning technology to obtain a three-layer tubular model, and then subjected to high-temperature treatment and secondary vulcanization to obtain a ready-to-wear three-layer artificial blood vessel.

[0006] More preferably, before the electrospinning of the innermost layer of polyurethane material, a layer of release agent is coated on the multi-size controllable receiver roller to facilitate subsequent demoulding.

[0007] More preferably, the demoulding agent is selected from medical vaseline paraffin or silicone oil for lubrication, or a layer of polytetrafluoroethylene is sprayed to make the contact interface inert, or a layer of water-soluble polyvinyl alcohol is coated to achieve water-soluble lubrication during demoulding.

[0008] Preferably, the inner diameter of the three-layer, ready-to-wear artificial blood vessel prepared by electrospinning is 3 mm, 4 mm, 5 mm, and 6 mm, the wall thickness is about 2 mm, the outer diameter ratio is (1-1.05):1, and the outer diameter variation range is controllable within 0.25 mm.

[0009] Preferably, the inner and outer polyurethane layers are both made by electrospinning a spinning solution; the environmental conditions during the electrospinning process are a vacuum environment with a humidity of 35%±5% and a vacuum degree not exceeding 0.1MPa or a normal pressure environment with a temperature of 25±5°C.

[0010] Preferably, the inner and outer polyurethane layer spinning solutions are mainly prepared with thermoplastic polyurethane as solute, N,N-dimethylformamide and tetrahydrofuran as solvents, and the above as raw materials.

[0011] More preferably, in the spinning solution, the mass fraction of thermoplastic polyurethane is 10% to 30%; and the mass ratio of N,N-dimethylformamide to tetrahydrofuran is 1:1.

[0012] More preferably, in the spinning solution, the molecular weight of the thermoplastic polyurethane is 50,000-150,000 Da.

[0013] More preferably, the molecular weight of the thermoplastic polyurethane in the spinning solution is 100000 Da. The use of thermoplastic polyurethane with this molecular weight is beneficial to improving the mechanical properties of blood vessels, and its electrostatic spinning process and fiber uniformity are optimal.

[0014] Preferably, the electrospinning parameters for preparing the inner and outer polyurethane layers are: voltage 10-15 kV, injection speed 10-30 µL / min, reciprocating distance 15-20 cm, receiver roller speed 600-800 rmp, and receiving distance 18-25 cm.

[0015] Preferably, the middle layer silicone rubber elastomer is a two-component room temperature / medium temperature addition type filled and reinforced silicone rubber, which is made by dual-channel electrospinning technology; the environmental conditions during the electrospinning process are a vacuum environment with a humidity of 35%±5% and a vacuum degree not exceeding 0.1MPa or a normal pressure environment with a temperature of 0~100°C.

[0016] More preferably, the spinning solution for preparing the intermediate layer silicone rubber elastomer is mainly composed of base polymer, filler, crosslinking agent, vulcanization activator, functional additive, reaction inhibitor and the like as raw materials, and organic substances such as dichloromethane and toluene as solvent.

[0017] More preferably, the spinning solution is divided into two components, A and B, the crosslinking agent and the vulcanization activator are dispersed in the A and B rubber solutions respectively, and the remaining raw materials are equally divided into the same solvent to prepare A and B spinning solutions; in the spinning solution, the mass fraction of the mixed rubber is 20%~50%.

[0018] More preferably, the base polymer in the silicone rubber spinning solution is side / terminal polymethylvinylsiloxane raw rubber with a molecular weight ranging from several thousand to 100,000-200,000. The vinyl content in the polymethylvinylsiloxane raw rubber is controlled within a certain range according to the desired properties of the vulcanized rubber.

[0019] More preferably, the solid filler in the silicone rubber spinning solution is selected from reinforcing fillers such as hydrophobic silica reinforcing fillers such as precipitated / fumed white carbon black, silica aerogel, etc., volume-increasing fillers such as montmorillonite, carbon black and titanium dioxide, etc., and liquid fillers such as silicone resin.

[0020] More preferably, the crosslinking agent in the silicone rubber spinning solution is polymethyl hydrogen siloxane containing ≡SiH groups at the end or side positions.

[0021] More preferably, the amount ratio of the base polymer to the crosslinking agent in the total rubber material of components A and B is determined by the molar ratio of the silicon vinyl group in the raw rubber to the silicon hydrogen group in the crosslinking agent ( ) determines the selection range. .

[0022] More preferably, the vulcanization activator in the silicone rubber spinning solution is various organic or inorganic catalysts that promote vulcanization efficiency, such as transition metals (such as platinum, rhodium, palladium, nickel, etc.) and their compounds or complexes, typically platinum catalysts, i.e. various forms of platinum and its compounds and complexes, complexes formed by chloroplatinic acid and olefins, cycloalkanes, alcohols, aldehydes, ethers, etc. As an example. In terms of metal platinum, the minimum amount of platinum catalyst should be 1×10 of the total amount of base rubber and crosslinking agent. -7 However, considering the possibility of platinum poisoning due to impure system, the actual dosage is generally 1×10 -6 ~2×10 -5 .

[0023] More preferably, the functional additives in the silicone rubber spinning solution are thickeners for increasing adhesion to the substrate, antibacterial agents for increasing the antibacterial property and biocompatibility of silicone rubber, etc. Among them, internally added thickeners include titanate, silicon boron thickeners and silane coupling agents and their compound additions; bulk modified antibacterial agents include metal ion inorganic antibacterial agents, antibiotics, organic antibacterial agents such as quaternary ammonium salts, and composite antibacterial agents.

[0024] More preferably, the reaction inhibitor in the silicone rubber spinning solution is an acetylene alcohol compound, a nitrogen-containing compound, an organic peroxide, etc. The general addition amount is 1%-5% of the mass of the base rubber.

[0025] More preferably, the electrospinning parameters for preparing the intermediate layer silicone rubber elastomer are: after A and B dual channels are connected in series, the spinning voltage is 6~12 kV, the injection speed is 20~100 µL / min, the reciprocating distance is 15~20 cm, the receiver roller speed is 600~800 rmp, and the receiving distance is 18~25 cm.

[0026] In the step S3, when the elastic layer after electrospinning of the intermediate layer silicone rubber is in an incompletely vulcanized state, the outermost layer of the artificial blood vessel is prepared on the surface of the silicone rubber layer using electrospinning technology using thermoplastic polyurethane as a raw material.

[0027] Among them, the incompletely vulcanized state refers to the situation when the vulcanization time or the vulcanization temperature does not reach the complete vulcanization conditions, and the surface becomes sticky and tacky. At this time, the surface of the incompletely vulcanized silicone rubber still has a certain fluidity and adhesion, and can form a good mechanical interlocking and chemical cross-linking with the polyurethane fiber.

[0028] Because the silicone rubber is not fully vulcanized, the polymer chains have not been completely cross-linked and have a certain adhesion ability, allowing the polyurethane to penetrate the surface of the silicone rubber, thereby enhancing the adhesion between the two. In the subsequent environmental changes (such as high-temperature secondary vulcanization) of the incompletely vulcanized silicone rubber, cross-linking reactions may continue to occur. This dynamic cross-linking process can generate more cross-linking points between the polyurethane and the silicone rubber, further enhancing the interface strength.

[0029] As is understood in the art, the outermost layer of polyurethane is prepared in time when the elastomeric layer after the electrospinning of the intermediate layer of silicone rubber is in an incompletely vulcanized state. After the electrospinning of the outermost layer of polyurethane is completed, it is placed in a vacuum high-temperature drying oven for secondary vulcanization at a temperature of 90~120°C and a vacuum degree not exceeding 0.1MPa.

[0030] More preferably, the three-layer, ready-to-wear artificial blood vessel will shrink radially and / or longitudinally during high-temperature secondary vulcanization, and the degree of shrinkage is preferably about 0% to 20%, and is closely related to its thickness.

[0031] The second aspect of the present invention provides a ready-to-wear artificial blood vessel product containing a silicone rubber elastomer intermediate layer prepared by the preparation method described in the first aspect.

[0032] Compared with the prior art, the present invention has the following beneficial effects: (1) The ready-to-wear artificial blood vessel prepared by the present invention has a three-layer structure, with the inner and outer layers being thermoplastic polyurethane and the middle being an elastic silicone layer. Since the silicone layer has good toughness and elasticity, the elastic retraction of the silicone after puncture and needle removal can stop bleeding. Therefore, this artificial blood vessel with a special structure can be punctured within 24 hours after surgery. The earliest puncture time in the currently available data is 2 hours after surgery. With its unique material properties, the ready-to-wear artificial blood vessel greatly reduces the occurrence of postoperative edema and the risk of puncture bleeding, allowing it to be punctured and dialyzed immediately after surgery, meeting the requirements of patients who do not want to undergo intubation for transitional dialysis, and is a boon for patients with poor vascular conditions who cannot undergo intubation for transitional dialysis.

[0033] (2) The ready-to-wear artificial blood vessel prepared by the present invention uses TPU as the inner and outer layer materials of the blood vessel. The TPU fiber is elastic and has an elastic modulus very close to that of human arteries, and has better compliance than ePTFE artificial blood vessels. In addition, the microphase separation structure of PU makes it have better biocompatibility and better anti-thrombotic effect. Therefore, the product performance and morphology obtained by using electrospinning technology to make TPU as the inner and outer polymer materials of the ready-to-wear artificial blood vessel is the best.

[0034] (3) The wearable artificial blood vessel containing a silicone rubber elastomer intermediate layer prepared by the present invention has axial and circumferential bidirectional stretchable and retractable elasticity, and its mechanical properties match those of natural blood vessels in the human body. It also has a high porosity and specific surface area, and can simulate the extracellular matrix structure of natural blood vessels to meet the current market demand for artificial blood vessels. In one embodiment, the strain of the wearable artificial blood vessel containing a silicone rubber elastomer intermediate layer prepared by the present invention can reach 400%; in another embodiment, the axial tensile strength of the wearable artificial blood vessel containing a silicone rubber elastomer intermediate layer prepared by the present invention can reach 10MPa, the elongation can reach 500%, and the stress-strain tensile curve presents a "J" shape, showing excellent mechanical properties that exceed those of natural blood vessels. In addition, the process parameters such as the thickness and inner diameter of the artificial blood vessel in the preparation method of the present invention are adjustable, and it has broad application prospects in the field of tissue engineering.

[0035] (4) The ready-to-wear artificial blood vessel containing a silicone rubber elastomer intermediate layer prepared by electrospinning of the present invention is a tubular model obtained by spinning and demolding using a size-controllable roller as a receiver. There are no problems such as the need to glue the seams of rolled tubes. The material is uniform and not layered, and no external adhesive is used, which makes the mechanical properties of the product more uniform and stable.

[0036] (5) The preparation method of the present invention keeps the spinning environment under vacuum conditions or at a constant temperature of 60°C during the spinning process, so that the organic solvent evaporates rapidly during the spinning process to obtain a fluffy and porous TPU tubular model, thereby ensuring that the small-caliber artificial blood vessel of the present invention will not be decomposed by small molecules or released by toxic organic solvents during subsequent high-temperature treatment. The method has the characteristics of low pollution, low energy consumption, green environmental protection, easy availability of raw materials, convenient and efficient operation, etc. The entire preparation process does not have high requirements on equipment, which is conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 This is a stress-strain tensile curve of the ready-to-wear artificial blood vessel prepared in an embodiment of the present invention.

[0038] Figure 2 This is a microscopic scanning electron microscope image of the inner surface of the ready-to-wear artificial blood vessel in an embodiment of the present invention.

[0039] Figure 3 This is a microscopic scanning electron microscope image of the outer surface of the ready-to-wear artificial blood vessel in an embodiment of the present invention.

[0040] Figure 4 This is a microscopic scanning electron microscope image of a cross-section of a ready-to-wear artificial blood vessel in an embodiment of the present invention.

[0041] Figure 5 This is a microscopic scanning electron microscope image of the longitudinal section of the ready-to-wear artificial blood vessel in an embodiment of the present invention.

[0042] Figure 6 This is a real picture of the ready-to-wear artificial blood vessel prepared in the example of the present application.

[0043] Figure 7 The microscopic morphology of electrospinning of each polymer raw material in the embodiments of the present invention under an optical microscope. DETAILED DESCRIPTION

[0044] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below through embodiments in combination with the accompanying drawings. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0045] It should be noted that, in the absence of conflict, the embodiments and features in the embodiments of the present application can be combined with each other. The present application will be described in detail below with reference to the accompanying drawings and in combination with the embodiments.

[0046] Example 1: Study on the influence of the thickness of the inner layer of the polyurethane on the mechanical properties of the artificial blood vessel in the preparation method of the artificial blood vessel containing the silicone rubber elastomer intermediate layer In order to explore the influence of the material preparation conditions and vulcanization state of the artificial blood vessels layer by layer on the physical and mechanical properties of the overall blood vessel model, the inventors conducted the following experiments, namely, Example 1-1, Example 1-2, Example 1-3, and Example 1-4, and the corresponding polyurethane electrospinning solution injection volumes were 2.5mL, 4mL, 5mL, and 2.5mL, respectively. The axial and circumferential mechanical properties of the artificial blood vessels were tested using the Gaotie AI-7000-SU1 universal testing machine. The results are as follows: Figure 1 And as shown in Table 1.

[0047] Example 1-1 This embodiment provides a ready-to-wear artificial blood vessel containing a silicone rubber elastomer intermediate layer, and a preparation method thereof comprises the following steps: (1) Preparation of TPU electrospinning solution: 8.8 g TPU (molecular weight 100000 Da) solid was dissolved in a solvent with a DMF:THF ratio of 1:1, i.e., 15.6 g DMF and 15.6 g THF, so that the mass concentration of the TPU solution was 22 wt%, and the solution was heated in a closed water bath with stirring at 80 °C.

[0048] (2) Electrospinning process of TPU as the inner layer of three-layer artificial blood vessels: the voltage was set to 12 Kv, the injection volume was controlled at 4.0-5.0 mL, the injection speed was 20 µL / min, the reciprocating distance was 150 mm, the reciprocating speed was 300 mm / min, the receiver roller speed was 350 rpm, the receiver was a metal rod with a diameter of 4 mm, and a layer of medical white vaseline was coated on the surface of the receiver as a release agent. The receiving distance was 180 mm, the temperature setting value was 25±2°C, the humidity setting value was 40%, and the electrospinning obtained a TPU single-layer tube with a thickness of 0.6±0.1 mm.

[0049] (3) Preparation of the A / B component rubber of the two-component room temperature / medium temperature addition-type filling and reinforcing silicone rubber and its electrospinning solution: Solution A is prepared by dissolving 12 g of vinyl silicone oil (viscosity 10,000 Pa·s, vinyl content 0.13%) and 1.8 g of hydrogenated silicone oil (hydrogen content 1.18%) in 15 mL of dichloromethane and dispersing them evenly by ultrasonication; Solution B is prepared by dissolving 12 g of vinyl silicone oil (viscosity 10,000 Pa·s, vinyl content 0.13%), 0.1 g of a homemade Castaplatin catalyst and 0.3 g of a homemade acetylene alcohol inhibitor (20%wt) in 15 mL of dichloromethane and dispersing them evenly by ultrasonication.

[0050] (4) Dual-channel electrospinning process of two-component addition-type liquid silicone rubber as the middle layer of three-layer artificial blood vessels: The syringe filled with A / B electrospinning solution was set as a dual-channel, and the two syringe needles were connected in series. The voltage was set to 8 kV, and the injection volume of A / B tubes was controlled at about 4.0 mL. The injection speed was 50 µL / min, the reciprocating distance was 150 mm, and the reciprocating speed was 300 mm / min. Electrospinning was continuously performed on the receiver roller surface of the above-mentioned TPU single-layer tube. The receiver roller speed was 350 rpm, the receiving distance was 180 mm, the temperature setting value was 60±2°C, and the humidity setting value was 40%. The electrospinning middle layer obtained a TPU-LSR double-layer tube with a thickness of 0.8±0.1 mm.

[0051] (5) Electrospinning process of TPU as the outermost layer of three-layer artificial blood vessel: After the spinning of the middle layer of silicone rubber is completed, the surface vulcanization degree is observed in real time, and the vulcanization temperature is controlled not to be higher than the complete vulcanization temperature, so that the silicone rubber is in a sticky and tacky state and not completely cured, and the third layer of TPU is electrospun promptly and quickly. The electrospinning solution and environmental conditions are the same as those in steps (1) and (2). The electrospinning outermost layer obtains a TPU-LSR-TPU three-layer artificial blood vessel with a thickness of 1.2±0.1mm.

[0052] (6) Sample post-processing and mechanical properties testing: The obtained three-layer artificial blood vessel model is placed in a vacuum high-temperature drying oven for secondary vulcanization for 1 h at a temperature of 90-120°C and a vacuum degree not exceeding 0.1 MPa. After demolding, a ready-to-wear artificial blood vessel containing a silicone rubber elastomer intermediate layer can be obtained. After three parallel samples are stably prepared, mechanical properties tests are carried out in accordance with the requirements of the standard "YYT 0500-2021 Cardiovascular Implants, Vascular Prostheses, Vascular Grafts and Vascular Patches".

[0053] The surface and cross-section of the ready-to-wear artificial blood vessel containing the silicone rubber elastomer intermediate layer were tested using a SEM scanning electron microscope. Figure 2-5 The microstructure diagrams of the inner / outer surface and the cross / longitudinal section of the ready-to-wear artificial blood vessel with a silicone rubber elastomer intermediate layer are shown respectively. Figure 6 This is a photo of the three-layer artificial blood vessel prepared. Figure 2 and Figure 3 It can be seen that the fibers on the inner and outer surfaces of the TPU layer obtained by electrospinning are smooth and have uniform diameter distribution. The inner surface fiber diameter is smaller than the outer surface fiber and has a higher porosity, which has a positive effect on early endothelial cell adhesion, late cell proliferation and cell activity. Figure 4 , Figure 5 and Figure 6It can be seen that the cross-section of the ready-to-wear artificial blood vessel containing a silicone rubber elastomer middle layer prepared by the present invention is composed of three layers of materials, the inner and outer layers of TPU are in the form of nanofibers, the middle layer is a smooth silicone rubber elastomer, and the layers are tightly bonded without stratification.

[0054] Example 1-2 The contents of a ready-to-wear artificial blood vessel containing a silicone rubber elastomer intermediate layer are substantially the same as those of Example 1-1, except that the injection volume of the TPU electrospinning solution in step (2) is controlled at 3.5±0.1 mL, and a TPU single-layer tube with a thickness of 0.4±0.1 mm is obtained by electrospinning.

[0055] Examples 1-3 The contents of a ready-to-wear artificial blood vessel containing a silicone rubber elastomer intermediate layer are substantially the same as those of Example 1-1, except that the injection volume of the TPU electrospinning solution in step (2) is controlled at 2.5±0.1 mL, and a TPU single-layer tube with a thickness of 0.25±0.1 mm is obtained by electrospinning.

[0056] Examples 1-4 The contents of a wearable artificial blood vessel containing a silicone rubber elastomer intermediate layer are basically the same as those of Example 1-1, except that: after the spinning of the intermediate layer of silicone rubber in step (5) is completed, the surface vulcanization degree is observed and the vulcanization time is extended to 3 hours, and the high-temperature secondary vulcanization operation in step (6) is advanced to after the second layer of silicone rubber is electrospun. When the surface is in a fully vulcanized state where it is non-sticky to the touch and has good elasticity and flexibility and can be restored to its original shape when pressed, the third layer of TPU is electrospun. The electrospinning solution and environmental conditions are the same as those in steps (1) and (2). The electrospinning outermost layer obtains a TPU-LSR-TPU three-layer artificial blood vessel with a thickness of 1.2±0.1 mm.

[0057] During the tensile strength test, due to the insufficient adhesion between the 2nd and 3rd layers of materials, the materials were deformed and misaligned during the stretching process, and the three layers of blood vessels were stratified and ruptured prematurely. The stratification phenomenon was used as the end point of the tensile test. The test results are shown in Table 1.

[0058] Table 1 Effect of polyurethane inner layer thickness on mechanical properties of artificial blood vessels

[0059] It can be seen from Table 1 that as the thickness of the polyurethane inner layer decreases, the axial tensile strength and elongation of the TPU inner tube in the ready-to-wear artificial blood vessel containing a silicone rubber elastomer intermediate layer prepared by the present invention both show a trend of gradual increase. Considering the improvement of preparation efficiency and performance, it is more preferred that the injection amount of the TPU electrospinning solution is controlled at 2.5 mL, and the process steps of preparing the third layer of polyurethane in time during incomplete vulcanization and then performing high-temperature secondary vulcanization are strictly followed as the optimal preparation conditions. At this time, the axial tensile strength of the inner TPU tube is 9.91 MPa, and the elongation is 748.29%, showing characteristics matching those of natural blood vessels, and the product effect of the three-layer blood vessel still being tightly adhered between layers under external force stretching can be achieved without using a viscosity enhancer.

[0060] Example 2 The content of a wearable artificial blood vessel containing a silicone rubber elastomer intermediate layer is basically the same as that of Example 1-1, except that: in step (4), in the preparation method of a two-component addition-type liquid silicone rubber as a three-layer artificial blood vessel intermediate layer, different dual-channel electrospinning voltages, injection speeds, and receiving distances are set to explore the morphology of electrospun silicone rubber fibers. More preferably, the spinning environment and conditions are A / B dual-channel syringe needles connected in series, the voltage is set to 8 kV, the injection volume of the A / B tubes is controlled at about 4.0 mL, the injection speed is 50 µL / min, the reciprocating distance is 150 mm, the reciprocating speed is 300 mm / min, the receiver roller speed is 350 rmp, the receiving distance is 180 mm, the temperature setting value is 60±2°C, and the humidity setting value is 40%. Figure 7 Figure 5 shows the microscopic morphology of electrospinning of various polymers under an optical microscope. Figures a to d show the spinning morphology of two-component high-temperature vulcanized liquid silicone rubber after gradually optimizing the parameters, which gradually transforms from droplet shape to fiber shape. Figure e shows the wreath-shaped electrospinning jet path of TPU. Figure f shows the nanofiber morphology of TPU electrospinning.

[0061] Example 3 The contents of a ready-to-wear artificial blood vessel containing a silicone rubber elastomer intermediate layer are basically the same as those of Example 1-1, except that in step (3), the types and ratios of the rubber materials in the A / B two-component spinning solution are designed and adjusted. The specific formula is shown in Table 2, and different intermediate layers of silicone rubber are obtained and applied to artificial blood vessels for mechanical property testing.

[0062] Table 2 Two-component addition high temperature vulcanized liquid silicone rubber formula

[0063] Table 3 Effect of the middle layer silicone rubber formula on the mechanical properties of the double-layer artificial blood vessel

[0064] As can be seen from Table 3, the experiment shows that the adjustment of the formula of the intermediate layer silicone rubber has a significant effect on the axial tensile strength and elongation of the ready-to-wear artificial blood vessel containing a silicone rubber elastomer intermediate layer prepared by the present invention, among which the axial tensile strength and elongation of the TPU-A35-1 artificial blood vessel are the best, which are 3.45 MPa and 321.22% respectively, and its mechanical properties are far better than the average level of natural blood vessels.

[0065] In summary, the wearable artificial blood vessel containing a silicone rubber elastomer intermediate layer prepared by the present invention has mechanical properties and silicone rubber retraction elasticity far superior to those of natural human blood vessels, and has a high porosity and specific surface area, which can simulate the extracellular matrix structure of natural blood vessels to meet the current market demand for artificial blood vessels, and effectively overcome the deficiencies in the prior art, and has a high industrial utilization value. The above embodiments serve to illustrate the substantive content of the present invention, but do not limit the protection scope of the present invention. The modification or equivalent substitution of the technical solution of the present invention by ordinary technicians in this field does not deviate from the essence and protection scope of the technical solution of the present invention.

Claims

1. A method for preparing a ready-to-wear artificial blood vessel containing a silicone rubber elastomer intermediate layer, characterized in that: The three-layer ready-to-wear artificial blood vessel is prepared layer by layer using electrospinning technology, including the following steps: S1 uses solution electrospinning technology to electrospin thermoplastic polyurethane tubes in multi-sized tubular receivers as the inner layer of artificial blood vessels; S2 uses dual-channel electrospinning technology to synthesize two-component room temperature / medium temperature addition-type filling and reinforcing silicone rubber for use as the silicone rubber elastomer for the middle layer of artificial blood vessels; S3 The outermost layer of the artificial blood vessel is prepared by using thermoplastic polyurethane as raw material on the surface of the incompletely vulcanized silicone rubber layer using electrospinning technology; S4 The three-layer tubular object is subjected to secondary vulcanization at high temperature to prepare a ready-to-wear three-layer artificial blood vessel containing a silicone rubber elastomer middle layer.

2. The method for preparing the three-layer, ready-to-wear artificial blood vessel according to claim 1, characterized in that: The inner diameter of the prepared three-layer ready-to-wear artificial blood vessel is 3 mm to 6 mm, the wall thickness is 2 mm to 4 mm, and the outer diameter variation range is controllable within 0.1 mm to 0.25 mm.

3. The method for preparing the three-layer, ready-to-wear artificial blood vessel according to claim 1, characterized in that: The inner and outer polyurethane layers are both made by electrospinning a spinning solution; the environmental conditions during the electrospinning process are a vacuum environment with a humidity of 35%±5% and a vacuum degree not exceeding 0.1MPa or a normal pressure environment with a temperature of 25±5°C.

4. The method for preparing the three-layer, ready-to-wear artificial blood vessel according to claim 3, characterized in that: The spinning solution of the inner and outer polyurethane layers is mainly prepared with thermoplastic polyurethane, N,N-dimethylformamide and tetrahydrofuran as raw materials; in the spinning solution, the mass fraction of thermoplastic polyurethane is 10% to 30%.

5. The method for preparing the three-layer, ready-to-wear artificial blood vessel according to claim 3, characterized in that: Preparation of inner and outer polyurethane layers The electrospinning parameters are as follows: voltage 10-15 kV, injection speed 10-30 µL / min, reciprocating distance 15-20 cm, receiver roller speed 600-800 rmp, and receiving distance 18-25 cm.

6. The method for preparing a three-layer, ready-to-wear artificial blood vessel according to claim 1, characterized in that: The middle layer silicone rubber elastomer is a two-component room temperature / medium temperature addition type filled and reinforced silicone rubber, which is made by dual-channel electrospinning technology; the environmental conditions during the electrospinning process are a vacuum environment with a humidity of 35%±5% and a vacuum degree not exceeding 0.1MPa or a normal pressure environment with a temperature of 0~100°C.

7. The method for preparing a three-layer, ready-to-wear artificial blood vessel according to claim 6, characterized in that: The spinning solution for preparing the intermediate layer silicone rubber elastomer is mainly composed of side vinyl silicone oil or terminal vinyl silicone oil as a base polymer, filler, cross-linking agent hydrogen silicone oil, vulcanization activator, and reaction inhibitor as raw materials, and dichloromethane or toluene is used as solvent; the spinning solution is divided into two components A and B, firstly, the vinyl silicone oil, filler and reaction inhibitor are mixed evenly and then divided into two equal parts into A and B tubes, then the cross-linking agent is added to the A tube, and the vulcanization activator is added to the B tube, and the rubber materials in the A and B tubes are respectively dissolved in an organic solvent so that the mass fraction of the mixed rubber material is 20%~80%, thereby obtaining an electrospinning solution for preparing the intermediate layer silicone rubber elastomer.

8. The method for preparing the three-layer, ready-to-wear artificial blood vessel according to claim 7, characterized in that: Preparation of the middle layer silicone rubber elastomer The electrospinning parameters are as follows: A and B dual channels are connected in series, the spinning voltage is 6-12 kV, the injection speed is 50-100 µL / min, the reciprocating distance is 15-20 cm, the receiver roller speed is 600-800 rmp, and the receiving distance is 18-25 cm.

9. The method for preparing a three-layer, ready-to-wear artificial blood vessel according to any one of claims 2 to 8, characterized in that: In step S3, when the elastic layer after electrospinning of the intermediate layer silicone rubber is in an incompletely vulcanized state, the electrospinning technology is promptly used on the surface of the silicone rubber layer to prepare the outermost layer of the artificial blood vessel using thermoplastic polyurethane as a raw material.

10. A three-layer, ready-to-wear artificial vascular product, prepared by the preparation method according to any one of claims 1 to 9.

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