A vascular stent covering and a preparation method thereof

Abstract

The present application relates to a kind of vascular stent covering and its preparation method, belong to vascular stent technical field.The present application uses the composite construction strategy of "woven tube + electrospinning film", with high-strength PTFE woven tube as macroscopic support skeleton, improve the defect that pure electrospinning film mechanical property is poor;While through the synergic control of weaving process parameter, woven tube setting process and subsequent sintering process, on the one hand, eliminate the residual internal stress of PTFE woven tube, on the other hand, promote electrostatic spinning fiber to occur shrinkage melting, tightly cover and infiltrate the gap of woven monofilament, form the composite combination structure of micro mechanical interlocking and interface melting bonding between electrospinning film and PTFE woven tube, so that the obtained vascular stent covering has dual performance advantages, the microporous structure of airflow-assisted electrospinning nanofiber can realize blood resistance and give material good cell compatibility, and PTFE woven skeleton provides reliable mechanical support for overall covering.

Description

Technical Field

[0001] This invention belongs to the field of vascular stent technology, and particularly relates to a vascular stent coating and its preparation method. Background Technology

[0002] Peripheral artery disease is a leading cause of death and disability worldwide, seriously threatening the health of the human circulatory system. Vascular stents are the core interventional devices for the clinical treatment of this disease, and the performance of their cover material directly determines the therapeutic effect and long-term safety of the stent. Currently, the most widely used stent cover material in clinical commercial applications is expanded polytetrafluoroethylene (ePTFE). This material, with its excellent chemical inertness, corrosion resistance, and basic cellular compatibility, can adapt to the complex physiological environment within the body, meeting the fundamental requirements for the clinical application of vascular stents and becoming the mainstream cover material for vascular stents.

[0003] However, long-term clinical application has shown that expanded polytetrafluoroethylene (ePTFE) covered stents still have unavoidable technical shortcomings that limit their long-term therapeutic effects. Traditional ePTFE covered stents have a dense structure and a simple surface topology, which cannot provide a favorable microenvironment for the adhesion, proliferation, and infiltration of vascular endothelial cells, resulting in a slow endothelialization process after stent implantation. Simultaneously, the incompletely endothelialized covered surface remains continuously exposed to the blood environment, easily inducing platelet aggregation and adhesion, significantly increasing the long-term risk of in-stent thrombosis, and potentially leading to postoperative complications such as restenosis. This is a key bottleneck problem that urgently needs to be addressed in current clinical interventional vascular treatment.

[0004] To overcome the limitations of traditional expanded polytetrafluoroethylene (ePTFE) coatings, electrospinning technology has been increasingly applied to the modification and preparation of ePTFE coatings, becoming a popular research direction for vascular stent coating materials. Compared to traditional coating preparation processes, electrospinning technology can produce porous coatings with high porosity and biomimetic micro / nanofiber structures. This structure is highly similar to the extracellular matrix of natural human blood vessels, effectively guiding cell infiltration and growth, and accelerating the endothelialization process on the stent surface. This structurally solves the core problem of difficult endothelialization in traditional coatings, providing a new technological path for the development of high-performance vascular stent coatings.

[0005] Leveraging the technological advantages of electrospinning, the industry has successively developed various processes for preparing polytetrafluoroethylene (PTFE) nanofiber tubular membranes and artificial blood vessels. Current mainstream technologies use polyethylene oxide (PE) as a sacrificial template, combined with a PTFE spinning system, to prepare porous fiber membranes through a core process of electrospinning combined with high-temperature sintering. Simultaneously, by optimizing the receiving substrate and molding process, the tubular membranes are shaped and prepared. These include various technical solutions such as direct spinning with a metal mandrel, forming assisted by a mesh scaffold, using metal braided tubes as receiving carriers, and composite forming of flat membrane rolls. These solutions optimize membrane performance from dimensions such as tubular forming structure, inner surface morphology, and overall elasticity, promoting the industrialization and upgrading of electrospun PTFE membranes.

[0006] Although existing improved processes can successfully fabricate structurally complete polytetrafluoroethylene nanofiber tubular membranes, effectively improving the biomimetic structure and cell adaptability of traditional membranes, these electrospun membranes still have fundamental performance defects. The membranes are essentially stacked pure electrospun fibers, with the fibers bonded only by the weak melting effect after high-temperature sintering, lacking a high-strength cross-linked support structure, resulting in low overall mechanical strength. Human blood vessels experience continuous blood pulsation and periodic circumferential stress. Under long-term dynamic physiological loads, the single electrospun fiber structure cannot withstand continuous mechanical tension and impact, easily leading to membrane deformation and loosening. In severe cases, damage and cracking can occur, significantly shortening stent lifespan and increasing the risk of postoperative vascular injury, bleeding, and stent failure, thus limiting the clinical application of this type of biomimetic membrane stent.

[0007] Based on this, the present invention is proposed. Summary of the Invention

[0008] To address the aforementioned technical problems, this invention provides a vascular stent coating and its preparation method. It employs a composite construction strategy of "braided tube + electrospun membrane," using a high-strength PTFE braided tube as the macroscopic support framework to improve the poor mechanical properties of pure electrospun membranes. Simultaneously, through the synergistic control of braiding process parameters, braided tube shaping process, and subsequent sintering process, residual internal stress in the PTFE braided tube is eliminated, while the electrospun fibers shrink and melt, tightly encapsulating and penetrating the gaps between the braided monofilaments. This forms a composite structure of microscopic mechanical interlocking and interfacial fusion bonding between the electrospun membrane and the PTFE braided tube, giving the resulting vascular stent coating dual performance advantages. The micro / nanofiber porous structure formed by airflow-assisted electrospinning achieves blood flow obstruction and prevents leakage, while imparting good cell compatibility to the material. The PTFE braided framework provides reliable mechanical support for the overall coating.

[0009] The first objective of this invention is to provide a method for preparing a vascular stent graft, comprising the following steps: S1. Polytetrafluoroethylene (PTFE) yarn is braided on the surface of the mandrel. After the braiding is formed, the mandrel is removed after shaping and cooling to obtain a polytetrafluoroethylene braided tube. S2. A first electrospun film is formed on the surface of the receiver by an airflow-assisted electrospinning process using a spinning solution. The polytetrafluoroethylene braided tube described in S1 is then placed on the surface of the receiver carrying the first electrospun film. A second electrospun film is formed on the surface of the polytetrafluoroethylene braided tube using an airflow-assisted electrospinning process. After sintering and cooling, the receiver is removed to obtain the vascular stent coating. The spinning solution includes polyethylene oxide, polytetrafluoroethylene (PTFE), and a solvent.

[0010] In one embodiment of the present invention, in S1, the diameter of the polytetrafluoroethylene filament is 0.05mm-0.07mm.

[0011] In one embodiment of the present invention, in S1, the braiding angle is 55°-65°; the polytetrafluoroethylene filaments are interwoven on the surface of the mandrel through braiding to form a tubular mesh skeleton.

[0012] In one embodiment of the present invention, in S1, the shaping is carried out by heating to 360°C-372°C at a rate of 2.8°C / min-3.2°C / min and holding at that temperature for 5min-15min; the shaping causes the polytetrafluoroethylene filaments to undergo micro-melting cross-linking at the braiding intersections.

[0013] In one embodiment of the present invention, in S2, the mass fraction of polyethylene oxide (PEO) in the spinning solution is 0.8%-1.2%, and the mass fraction of polytetrafluoroethylene (PTFE) is 33.5%-34.5%.

[0014] In one embodiment of the invention, in S2, the diameter of the receiving element is smaller than the diameter of the mandrel.

[0015] In one embodiment of the present invention, in S2, the airflow-assisted electrospinning process of the first electrospun membrane and the second electrospun membrane is independently as follows: voltage is 10kV, air pressure is 0.08MPa-0.12MPa, receiver rotation speed is 380rpm-420rpm, receiver moving distance is 120mm-160mm, receiving distance is 22cm-28cm, needle moving speed is 28mm / s-32mm / s, spinning solution feed rate is 3mL / h-4mL / h, and spinning time is 10min-30min; the thickness of the electrospun membrane is adjusted by controlling the spinning time.

[0016] In one embodiment of the present invention, in S2, the environmental conditions for the airflow-assisted electrospinning are as follows: temperature is 25℃-35℃, and relative humidity is 15%-25%.

[0017] In one embodiment of the present invention, in S2, the sintering is carried out by heating to 320°C-340°C at a rate of 4.8°C / min-5.2°C / min and holding at that temperature for 10min-20min; through sintering, the electrospun fibers and braided monofilaments form a mechanical interlock and undergo local melting and bonding.

[0018] A second objective of this invention is to provide a vascular stent coating prepared by the method described.

[0019] The technical solution of the present invention has the following advantages compared with the prior art: (1) The preparation method of the present invention adopts a shaping process for PTFE braided tubes, and precisely controls the temperature window for micro-melting cross-linking of braided nodes, so as to eliminate residual internal stress of braided tubes and avoid damaging the structure of the braided tube body. Combined with the subsequent sintering process of electrospun tube + braided tube composite structure, the fine electrospun fibers are induced to shrink and melt by high temperature thermal drive, so that they tightly wrap and penetrate into the gaps between braided monofilaments, forming a composite interface with mechanical interlocking superposition and local melting bonding at the microscale, which effectively improves the technical problem of interlayer delamination between electrospun film and braided skeleton.

[0020] (2) The inner and outer surfaces of the vascular stent membrane described in this invention retain a microporous structure. A dense interlocking interface is formed between the electrospun membrane and the braided tube skeleton. The stent relies on the PTFE braided tube skeleton to provide reliable mechanical support on the one hand, and on the other hand, it uses the electrospun membrane to achieve blood flow prevention and seepage prevention, while constructing a blood contact interface with high porosity and excellent cell compatibility.

[0021] (3) The vascular stent covering described in this invention can take into account the thinner wall thickness, sufficient tensile strength and appropriate tensile elongation. Its mechanical properties match those of natural blood vessels. It is non-cytotoxic and can effectively support the adhesion and proliferation of fibroblasts and endothelial cells. It is suitable for long-term implantation of vascular stent coverings in the body. Attached Figure Description

[0022] To make the content of this invention easier to understand, the invention will be further described in detail below with reference to specific embodiments and accompanying drawings, wherein: Figure 1 The images show the microstructure of the vascular stent coating prepared in Example 1 of this invention; where (a) is the microstructure of the outer surface, (b) is the microstructure of the inner surface, and (c) is the microstructure of the cross section. Figure 2 The images show the microstructure of the braided skeleton of the vascular stent covering of the present invention; wherein, (a) is the microstructure of the braided tube intersection node of Example 1, and (b) is the microstructure of the braided tube intersection node of Comparative Example 4. Figure 3 The stress-strain curves of the vascular stent grafts in Embodiment 1 and Comparative Examples 1-2 of the present invention are shown. Figure 4 The OD values ​​and cell proliferation rates of L929 cells cultured in the vascular stent-coated extract of Example 1 of the present invention at different culture days are shown. Figure 5 The images are fluorescence inverted microscope images of L929 cells cultured in PTFE filament extract for different number of days according to Example 1 of this invention. Detailed Implementation

[0023] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, so that those skilled in the art can better understand and implement the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. It should be understood that the specific embodiments are only used to explain the present invention, but the embodiments are not intended to limit the present invention.

[0024] In this invention, unless otherwise stated, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0025] In this invention, unless otherwise stated, the term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0026] In this invention, unless otherwise specified, the experimental methods used in the embodiments of this invention are conventional methods, and the materials and reagents used are commercially available unless otherwise specified.

[0027] In this invention, unless otherwise stated, the polyethylene oxide (PEO) used in the examples has a Mw of approximately 5,000,000 Da and was purchased from Shanghai Maclean Biochemical Technology Co., Ltd., with the product number P101347-250g.

[0028] In this invention, unless otherwise stated, the polytetrafluoroethylene (PTFE) dispersion used in the examples was purchased from Shanghai McLean Biochemical Technology Co., Ltd., with product number P816262-500g.

[0029] Example 1 The vascular stent grafting and its preparation method in this embodiment specifically include the following steps: Preparation of S1 and PTFE braided tubing: PTFE yarn with a diameter of 0.06 mm was selected and braided on a stainless steel mandrel with a diameter of 8 mm. The braiding machine parameters were adjusted to make the braiding angle 60°. After the braiding was completed, the two ends of the sample were tied and placed horizontally in a muffle furnace for shaping. The temperature was raised to 370°C at a rate of 3°C / min and held for 10 min. After that, the sample was allowed to cool naturally to room temperature with the furnace. Then the mandrel was removed to obtain the PTFE braided tube. S2. Preparation of vascular stent grafts S21. Preparation of spinning solution: Place 3.75g of 4% polyethylene oxide (PEO) aqueous solution in a beaker, add 8.08g of 60% polytetrafluoroethylene (PTFE) dispersion, and then slowly add 2.45g of deionized water. Stir continuously at 1500rpm for 1h to obtain the spinning solution. S22. Preparation of the first electrospun membrane: A coaxial needle (17G outer needle connected to the air tube, 21G inner needle connected to the syringe containing the spinning solution) was selected. A stainless steel rod with a diameter of 6mm was used as the receiving device and rotated at 400rpm. The moving distance of the receiving device was set to 140mm, the receiving distance to 25cm, and the needle moving speed to 30mm / s. A 10kV high voltage was connected, the air pressure was controlled to be 0.1MPa, and the feeding rate of the spinning solution was 3.5mL / h. The airflow-assisted electrospinning was carried out for 20min under the environmental conditions of a temperature of about 30℃ and a relative humidity of about 20% to obtain the first electrospun membrane. S23. Preparation of vascular stent coating: A PTFE braided tube is placed on the surface of a stainless steel rod receiving device with a pre-formed first electrospun membrane. Electrospinning is performed again using the same process parameters as for the preparation of the first electrospun membrane to form a second electrospun membrane on the outside of the PTFE braided tube. Subsequently, the stainless steel rod with the sample is placed in a muffle furnace for sintering. The temperature is increased to 330°C at a rate of 5°C / min and held for 15 min. After the sample is cooled to room temperature with the furnace, it is removed from the stainless steel rod to obtain the vascular stent coating.

[0030] Comparative Example 1 The basic principle is the same as in Example 1, except that PTFE braided tubing was not introduced into the vascular stent graft.

[0031] Comparative Example 2 The basic principle is the same as in Example 1, except that the first and second electrospun membranes are not introduced into the vascular stent cover.

[0032] Comparative Example 3 The process is basically the same as in Example 1, except that sintering is not performed in S2.

[0033] Comparative Example 4 The process is basically the same as in Example 1, except that in S1, the temperature is increased to 355°C at a rate of 3°C / min and held for 30 minutes.

[0034] Test Example 1 The microstructure of the vascular stent graft prepared in Example 1 was characterized using scanning electron microscopy, and the results are as follows: Figure 1 As shown. From Figure 1 It can be seen that the outer surface of the vascular stent cover maintains a continuous and complete micro-nanofiber stacking morphology, retaining a well-connected micro-nanopore network structure; the inner surface and cross-sectional morphology of the cover show that after high-temperature sintering, the fine electrospun fibers shrink and partially melt, and the fibers can tightly wrap the braided monofilaments of the PTFE braided tube and embed themselves in the gaps between the braided monofilaments, forming a mechanically interlocked, superimposed, and partially melted cross-linked composite interface between the electrospun fiber layer and the PTFE braided tube matrix, thus achieving a strong interfacial bond between the electrospun membrane and the PTFE braided support structure.

[0035] Test Example 2 The microstructure of the finished vascular stent coatings prepared in Example 1 and Comparative Example 4 was characterized using scanning electron microscopy. During sample preparation, the electrospun membrane on the surface was peeled off, followed by microstructure characterization. The results are as follows: Figure 2 As shown. From Figure 2 As can be seen, after the shaping treatment at 370℃ for 10 minutes in Example 1, sufficient local micro-melting occurred at the cross-node position of the PTFE braided tube, and adjacent braided monofilaments fused and bonded to each other, locking the braided node structure. However, the heat treatment condition of 355℃ for 30 minutes in Comparative Example 4 did not enter the effective temperature window for micro-melting cross-linking of the PTFE braided tube nodes. There were no obvious melting and bonding traces at the cross-node position of the braided tube skeleton, and the braided monofilaments only physically overlapped each other, with the node position in a state of free sliding.

[0036] Test Example 3 Referring to the standard YY 0500-2004 Cardiovascular Implants and Artificial Blood Vessels, tensile mechanical properties tests were performed on the vascular stent grafts prepared in Example 1 and Comparative Examples 1-3. 6cm long vascular stent graft specimens were cut, and the inner diameter D and wall thickness d of each specimen were measured using vernier calipers. The tensile speed was set to 50mm / min, and the clamping distance was L=20mm. Each group of specimens was tested in parallel three times, and the arithmetic mean was taken. The breaking strength F and the displacement ΔL at fracture were recorded. The tensile properties were then analyzed according to the formula... Calculation formula for fracture strength T The elongation at break E was calculated, and the results are as follows: Figure 3 As shown in Table 1: Table 1

[0037] from Figure 3 As shown in Table 1, the vascular stent graft in Example 1 possesses both excellent tensile strength and elongation at break, achieving a synergistic balance between high tensile strength and high compliance. This is because a composite structure combining an electrospun layer and a PTFE braided tube was constructed, with the two structures complementing each other: under low stress conditions in the initial stretching stage, the electrospun membrane bears the tension, while the braided skeleton can undergo free deformation simultaneously, ensuring the material's high elongation characteristics; as the tensile stress increases, the high-strength braided skeleton takes over as the main load-bearing phase, while secondary high-temperature sintering allows the electrospun fibers to penetrate into the braided skeleton to form an interlocking cross-linked network, constraining excessive slippage of the braided threads, thereby simultaneously improving the overall tensile strength of the graft and adapting to the dynamic mechanical requirements of vascular pulsation in vivo.

[0038] Comparing Example 1 and Comparative Example 1, it can be seen that Comparative Example 1, which uses only pure electrospun membrane, has significantly deteriorated overall mechanical properties, insufficient tensile strength, and a substantial decrease in deformation capacity. This is because the pure electrospun membrane relies solely on the random stacking of micro- and nanofibers, lacking a high-strength woven skeleton as mechanical support. The bonding between fibers is weak, making it prone to plastic deformation under external force, resulting in poor structural stability and difficulty in withstanding the continuous impact of hemodynamics in vivo. Furthermore, deformation and tearing are also likely to occur during the demolding process after sample preparation.

[0039] Comparing Example 1 and Comparative Example 2, it can be seen that Comparative Example 2 is a pure PTFE braided tube. Although it has good tensile strength, the elongation at break of the material is significantly worse. This is because only the braided skeleton is retained, and the electrospun coating layer with a porous fiber structure is missing. The flexible buffering effect brought by the electrospun fibers is lacking, resulting in a decrease in overall compliance. At the same time, the pore size of the braided tube itself is too large, and it does not have a flow-blocking and sealing effect. It cannot be directly used as a flow-blocking coating for vascular stents, resulting in application defects such as blood leakage.

[0040] Comparing Example 1 and Comparative Example 3, it can be seen that Comparative Example 3, without secondary sintering treatment, suffers from compromised overall mechanical integrity of the composite coating, making it impossible to obtain stable and effective tensile mechanical test results. This is because without a high-temperature sintering process, the PTFE particles in the electrospun fibers cannot undergo fusion bonding to achieve sufficient mechanical strength. Furthermore, the electrospun membrane is difficult to form a mechanically interlocked and fusion-crosslinked interface with the braided skeleton, resulting in weak interfacial bonding between the electrospun membrane and the braided tube. During sample demolding and under stress, interlayer peeling and separation easily occur, and the composite structure cannot form an effective whole, thus losing its composite reinforcement effect.

[0041] Test Example 4 The cytotoxicity of PTFE threads was tested according to the standard of GB / T 16886.5-2017 Medical Device Biological Evaluation Part 5: In Vitro Cytotoxicity Tests. A routine cell culture control group was set up. L929 cells were cultured in the sample extraction solution for 1, 3, and 5 days, respectively. The OD absorbance of cells at each time point was measured using a CCK-8 assay kit, and the cell proliferation rate was calculated. Simultaneously, cell adhesion, spreading, and growth morphology at different culture time points were observed using a fluorescence inverted microscope. The results are as follows: Figures 4-5 As shown. From Figures 4-5 It can be seen that as the culture time increased from 1 day to 5 days, the OD absorbance value of L929 cells gradually increased, corresponding to an increasing trend in cell proliferation rate with the extension of culture time. At 1 day of culture, the cell proliferation rate was 96.42±0.25%, with a cytotoxicity rating of grade 1. At 3 days of culture, the cell proliferation rate reached 101.58±3.21%, and at 5 days of culture, the cell proliferation rate was 107.00±0.51%, with a cytotoxicity rating of grade 0. The fluorescence morphology results corroborated the quantitative detection results; on day 1 of culture, most of the cells within the field of view... L929 cells successfully adhered to the culture vessel, exhibiting a typical spindle-shaped morphology with only a very small number of free, unattached cells. By day 3, the cell number had significantly increased, and the cells were growing well. By day 5, the cell number increased rapidly again, with dense cell distribution and cross-linking and fusion observed. This indicates that the PTFE filaments have extremely low cytotoxicity, can support effective adhesion, spreading, and proliferation of L929 cells, and possess excellent in vitro cell compatibility, meeting the basic biosafety requirements for clinical applications of vascular stent grafts.

[0042] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A method for preparing a vascular stent coating, characterized in that, Includes the following steps: S1. Polytetrafluoroethylene (PTFE) yarn is braided on the surface of the mandrel. After the braiding is formed, the mandrel is removed after shaping and cooling to obtain a PTFE braided tube. S2. A first electrospun film is formed on the surface of the receiver by an airflow-assisted electrospinning process. The polytetrafluoroethylene braided tube described in S1 is sleeved on the surface of the receiver carrying the first electrospun film. A second electrospun film is formed on the surface of the polytetrafluoroethylene braided tube by an airflow-assisted electrospinning process. After sintering and cooling, the receiver is removed to obtain the vascular stent coating. The spinning solution includes polyethylene oxide, polytetrafluoroethylene, and a solvent.

2. The method for preparing a vascular stent coating according to claim 1, characterized in that, In S1, the diameter of the polytetrafluoroethylene filament is 0.05mm-0.07mm.

3. The method for preparing a vascular stent coating according to claim 1, characterized in that, In S1, the weaving angle of the weaving is 55°-65°.

4. The method for preparing a vascular stent coating according to claim 1, characterized in that, In S1, the shaping is achieved by heating to 360℃-372℃ at a rate of 2.8℃ / min-3.2℃ / min and holding at that temperature for 5min-15min.

5. The method for preparing a vascular stent coating according to claim 1, characterized in that, In S2, the spinning solution contains 0.8%-1.2% polyethylene oxide and 33.5%-34.5% polytetrafluoroethylene.

6. The method for preparing a vascular stent coating according to claim 1, characterized in that, In S2, the diameter of the receiving element is smaller than the diameter of the mandrel.

7. The method for preparing a vascular stent coating according to claim 1, characterized in that, In S2, the airflow-assisted electrospinning process of the first electrospun membrane and the second electrospun membrane is independently as follows: voltage is 10kV, air pressure is 0.08MPa-0.12MPa, receiver rotation speed is 380rpm-420rpm, receiver moving distance is 120mm-160mm, receiving distance is 22cm-28cm, needle moving speed is 28mm / s-32mm / s, spinning solution feed rate is 3mL / h-4mL / h, and spinning time is 10min-30min.

8. The method for preparing a vascular stent coating according to claim 1, characterized in that, In S2, the environmental conditions for airflow-assisted electrospinning are as follows: temperature is 25℃-35℃, and relative humidity is 15%-25%.

9. The method for preparing a vascular stent coating according to claim 1, characterized in that, In S2, the sintering is carried out by heating to 320℃-340℃ at a rate of 4.8℃ / min-5.2℃ / min and holding at that temperature for 10min-20min.

10. A vascular stent coating prepared by the method of any one of claims 1-9.

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