WO2022193576A1 - Ptfe管状覆膜支架及其制备方法 - Google Patents

Ptfe管状覆膜支架及其制备方法 Download PDF

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WO2022193576A1
WO2022193576A1 PCT/CN2021/118144 CN2021118144W WO2022193576A1 WO 2022193576 A1 WO2022193576 A1 WO 2022193576A1 CN 2021118144 W CN2021118144 W CN 2021118144W WO 2022193576 A1 WO2022193576 A1 WO 2022193576A1
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ptfe
tubular
stent
fiber membrane
peo
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PCT/CN2021/118144
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English (en)
French (fr)
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赵荟菁
骆宇
孟凯
张克勤
龚霄雁
薛志恒
刘浩
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苏州大学
苏州茵络医疗器械有限公司
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    • D—TEXTILES; PAPER
    • D04—BRAIDING; LACE-MAKING; KNITTING; TRIMMINGS; NON-WOVEN FABRICS
    • D04H—MAKING TEXTILE FABRICS, e.g. FROM FIBRES OR FILAMENTARY MATERIAL; FABRICS MADE BY SUCH PROCESSES OR APPARATUS, e.g. FELTS, NON-WOVEN FABRICS; COTTON-WOOL; WADDING ; NON-WOVEN FABRICS FROM STAPLE FIBRES, FILAMENTS OR YARNS, BONDED WITH AT LEAST ONE WEB-LIKE MATERIAL DURING THEIR CONSOLIDATION
    • D04H1/00—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres
    • D04H1/70—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres
    • D04H1/72—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres the fibres being randomly arranged
    • D04H1/728—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres the fibres being randomly arranged by electro-spinning
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D1/00—Treatment of filament-forming or like material
    • D01D1/02—Preparation of spinning solutions
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/0007—Electro-spinning
    • D01D5/0015—Electro-spinning characterised by the initial state of the material
    • D01D5/003—Electro-spinning characterised by the initial state of the material the material being a polymer solution or dispersion
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/0007—Electro-spinning
    • D01D5/0015—Electro-spinning characterised by the initial state of the material
    • D01D5/003—Electro-spinning characterised by the initial state of the material the material being a polymer solution or dispersion
    • D01D5/0038—Electro-spinning characterised by the initial state of the material the material being a polymer solution or dispersion the fibre formed by solvent evaporation, i.e. dry electro-spinning
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/0007—Electro-spinning
    • D01D5/0061—Electro-spinning characterised by the electro-spinning apparatus
    • D01D5/0076—Electro-spinning characterised by the electro-spinning apparatus characterised by the collecting device, e.g. drum, wheel, endless belt, plate or grid
    • D01D5/0084—Coating by electro-spinning, i.e. the electro-spun fibres are not removed from the collecting device but remain integral with it, e.g. coating of prostheses
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
    • D01F6/00—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof
    • D01F6/02—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from homopolymers obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • D01F6/08—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from homopolymers obtained by reactions only involving carbon-to-carbon unsaturated bonds from polymers of halogenated hydrocarbons
    • D01F6/12—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from homopolymers obtained by reactions only involving carbon-to-carbon unsaturated bonds from polymers of halogenated hydrocarbons from polymers of fluorinated hydrocarbons
    • D—TEXTILES; PAPER
    • D04—BRAIDING; LACE-MAKING; KNITTING; TRIMMINGS; NON-WOVEN FABRICS
    • D04H—MAKING TEXTILE FABRICS, e.g. FROM FIBRES OR FILAMENTARY MATERIAL; FABRICS MADE BY SUCH PROCESSES OR APPARATUS, e.g. FELTS, NON-WOVEN FABRICS; COTTON-WOOL; WADDING ; NON-WOVEN FABRICS FROM STAPLE FIBRES, FILAMENTS OR YARNS, BONDED WITH AT LEAST ONE WEB-LIKE MATERIAL DURING THEIR CONSOLIDATION
    • D04H1/00—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres
    • D04H1/40—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres from fleeces or layers composed of fibres without existing or potential cohesive properties
    • D04H1/42—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres from fleeces or layers composed of fibres without existing or potential cohesive properties characterised by the use of certain kinds of fibres insofar as this use has no preponderant influence on the consolidation of the fleece
    • D04H1/4282—Addition polymers
    • D04H1/4318—Fluorine series
    • D—TEXTILES; PAPER
    • D04—BRAIDING; LACE-MAKING; KNITTING; TRIMMINGS; NON-WOVEN FABRICS
    • D04H—MAKING TEXTILE FABRICS, e.g. FROM FIBRES OR FILAMENTARY MATERIAL; FABRICS MADE BY SUCH PROCESSES OR APPARATUS, e.g. FELTS, NON-WOVEN FABRICS; COTTON-WOOL; WADDING ; NON-WOVEN FABRICS FROM STAPLE FIBRES, FILAMENTS OR YARNS, BONDED WITH AT LEAST ONE WEB-LIKE MATERIAL DURING THEIR CONSOLIDATION
    • D04H1/00—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres
    • D04H1/70—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres
    • D04H1/76—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres otherwise than in a plane, e.g. in a tubular way
    • D—TEXTILES; PAPER
    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
    • D06C—FINISHING, DRESSING, TENTERING OR STRETCHING TEXTILE FABRICS
    • D06C7/00—Heating or cooling textile fabrics
    • D—TEXTILES; PAPER
    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
    • D06C—FINISHING, DRESSING, TENTERING OR STRETCHING TEXTILE FABRICS
    • D06C7/00—Heating or cooling textile fabrics
    • D06C7/02—Setting
    • D—TEXTILES; PAPER
    • D10—INDEXING SCHEME ASSOCIATED WITH SUBLASSES OF SECTION D, RELATING TO TEXTILES
    • D10B—INDEXING SCHEME ASSOCIATED WITH SUBLASSES OF SECTION D, RELATING TO TEXTILES
    • D10B2509/00—Medical; Hygiene
    • D10B2509/06—Vascular grafts; stents

Definitions

  • the invention relates to the technical field of vascular covered stents, in particular to a PTFE tubular covered stent and a preparation method thereof.
  • This technology uses a stent-graft to completely isolate the parent artery and the pseudoaneurysm cavity, and blood flows through the stent-graft and cannot enter the aneurysm cavity.
  • Endovascular stent graft therapy has the advantages of less trauma, faster recovery and fewer complications, and is currently widely used in the treatment of aneurysms and other diseases.
  • the stent-graft for endoluminal isolation is a combination of a metal stent and a covering, which not only retains the function of the metal stent, but also has the characteristics of the covering material.
  • the covering parts are made of polyester woven fabric, ePTFE, polyurethane, etc., these
  • the film prepared from the material has defects in blood compatibility, structural stability, etc., and it is easy to cause problems such as thrombosis or intimal hyperplasia.
  • Electrospinning technology is a simple and versatile process that can prepare fibers with diameters ranging from several nanometers to several micrometers, with high specific surface area and porosity, easy to mimic the composition and structure of the extracellular matrix, and is conducive to cell growth and proliferation. .
  • electrospinning technology there are few studies on the preparation of vascular stent-grafts by electrospinning technology.
  • the technical problem to be solved by the present invention is to provide a PTFE tubular covered stent prepared by electrospinning.
  • the covered stent has good mechanical properties and water permeability, the hemolysis rate is lower than 5%, and the blood compatibility is good. It can support the cell adhesion and proliferation of HUVECs without cytotoxicity, which provides a reference for the subsequent application of endoluminal isolation.
  • the present invention provides the following technical solutions:
  • a first aspect of the present invention provides a method for preparing a PTFE tubular covered stent, comprising the following steps:
  • the PTFE/PEO tubular fiber membrane is prepared by the method of electrospinning by using the metal mandrel jacket braided tube as the receiving device;
  • a metal stent as a receiving device to receive a tubular TPU electrospun membrane on the metal stent by electrospinning; then cover the sintered tubular PTFE fiber membrane over the TPU electrospun membrane, and then coat the tubular PTFE fiber membrane
  • the heat-shrinkable tube is put on, and the temperature of the heat-shrinkable tube is heated to melt the TPU electrospun membrane, so that the tubular PTFE fiber membrane is bonded to the metal stent, thereby obtaining the PTFE tubular covered stent.
  • the purpose of sintering the PTFE/PEO tubular fiber membrane is to remove PEO in the fiber membrane, and at the same time, the PTFE particles are melted to fill the voids existing in PEO, and finally a complete and continuous PTFE fiber membrane with certain strength is obtained.
  • the spinning solution used is an electrostatic spinning solution of PTFE/PEO, and the mass ratio of PTFE to PEO in the spinning solution is 99:1-97:3, preferably 97:3.
  • step S1 the parameters of the electrospinning are: the voltage is 12-20kV, the injection speed is 6-15 ⁇ L/min, the receiving distance is 15-22cm, the rotating speed of the receiving device is 200-600r/min, and the relative The humidity is (35 ⁇ 5)-(45 ⁇ 5)%, and the temperature is (18 ⁇ 3)-(25 ⁇ 3)°C.
  • the sintering temperature is 360-400° C., preferably 380° C.
  • the sintering time is 5-15 minutes, preferably 10 minutes.
  • the metal stent is a nickel-titanium alloy stent.
  • the TPU binder is obtained by dissolving TPU powder in DMF, and its concentration is 18%-25%, preferably 20wt%.
  • the temperature for heating the shrinkable tube is 140-160°C, preferably 150°C.
  • the second aspect of the present invention provides the PTFE tubular covered stent prepared by the method described in the first aspect.
  • the thickness of the PTFE tubular stent-graft is 0.08-0.14 mm, preferably 0.1 mm.
  • a third aspect of the present invention provides an application of the PTFE tubular covered stent described in the second aspect as a blood vessel stent.
  • the PTFE tubular covered stent of the invention has good mechanical properties and water permeability, the hemolysis rate is lower than 5%, and the blood compatibility is good. In vitro cell experiments showed that the PTFE tubular covered stent could support HUVECs cell adhesion and proliferation without cytotoxicity.
  • the PTFE tubular covered stent has potential application value in the field of tissue engineering.
  • Fig. 1 is the preparation flow chart of PTFE tubular covered stent
  • Figure 3 is a thermal analysis diagram: (a): DSC curve of PTFE particles; (b): TG curve of PTFE particles, PEO powder, PTFE/PEO precursor film and film after sintering at 380°C;
  • Figure 4 is the infrared spectrum of the PTFE/PEO precursor film before sintering and the PTFE film after sintering at 380°C;
  • Fig. 5 is (a): stress of PTFE membrane under different sintering temperature and different sintering time; (b): strain;
  • Figure 6 is the MTT chart of the proliferation of HUVECs cultured on the materials of each group for 1, 3, and 7 days;
  • Figure 7 is a laser confocal image of HUVECs cultured on 1, 3 and 7 days of materials in each group;
  • Figure 8 is the SEM images of HUVECs cultured on 1, 3 and 7 days of each group of materials.
  • test materials used are as follows:
  • PTFE Polytetrafluoroethylene dispersion emulsion
  • PEO polyethylene oxide
  • M w 5,000,000Da, Suzhou Great Medical Technology Co., Ltd.
  • elastic polyurethane TPU, BASF, Germany
  • N,N-dimethylformamide DMF, Suzhou Ketong Biomedical Technology Co., Ltd.
  • glutaraldehyde C 5 H 8 O 2 , Shanghai Sinopharm Chemical Reagent Co., Ltd.
  • FBS Gibco, USA
  • Phosphate buffer solution PBS, Coring, USA
  • Dimethyl sulfoxide DMSO, Sigma, USA
  • Trypsin EDTA, Gibco, USA
  • Fluorescein diacetate FDA, Sigma, USA
  • double antibody penicillin, Gibco, USA
  • human umbilical vein endothelial cells UUVECs
  • thiazole blue MTT, Shanghai Ruji Biotechnology Development
  • the spinning solution was introduced into a 5 mL syringe, and a mandrel (4 mm in diameter) wrapped with a stainless steel braided sleeve was used as a receiving device for electrospinning (JDS02 electrospinning machine, Changsha Nayi Instrument Technology Co., Ltd.), set
  • the electrospinning parameters were: the voltage was 15kV, the injection speed was 8 ⁇ L/min, the receiving distance was 20cm, the speed of the receiving device was 400r/min, the relative humidity was (40 ⁇ 5)%, and the temperature was (23 ⁇ 3)°C.
  • the stainless steel braided sleeve sample covered with PTFE/PEO fiber membrane was put into a vacuum oven (DZF-6020B, Tianjin Gongxing Laboratory Instrument Co., Ltd.), dried in vacuum at 60 °C for 10 h, and then removed. moisture in the fiber membrane. After drying, the samples were immediately transferred to a box furnace (MF-1200C, Anhui Beyike Equipment Technology Co., Ltd.), and sintered at different sintering temperatures and sintering times to explore the effect of different sintering conditions on the preparation of films. Impact. After sintering, the film is removed from the stainless steel braided sleeve, which is a tubular PTFE film.
  • the stent-graft was prepared by brushing with TPU solution, and the specific operations were as follows:
  • TPU adhesive 20wt% TPU solution, namely TPU adhesive.
  • WGLL-125BE type electric heating constant temperature blast drying oven Tianjin Test Instrument Co., Ltd.
  • Example 2 TPU electrospinning method is used to prepare the covered stent, and the specific operations are:
  • TPU electrospinning solution 15cm
  • the flow rate is 13.33 ⁇ L/min
  • the tubular TPU electrospun membrane is obtained after electrospinning for a certain period of time; then the above-mentioned sintered tubular PTFE membrane is sleeved outside the TPU electrospun membrane, and a heat shrinkable tube is added to the outermost layer.
  • Figure 2 shows the microscopic morphology of electrospinning precursor films with different PTFE:PEO ratios.
  • PEO is used as a bonding component, so that PTFE particles can be bonded together to form continuous fibers under electrostatic spraying.
  • the PEO content in the spinning solution is low, continuous fibers cannot be formed.
  • the PTFF:PEO ratio was 99:1, the fiber breakage was significant (Fig. 2a); when the PEO content gradually increased and the PTFF:PEO ratio was 98:2, the fiber breakage point decreased (Fig. 2b).
  • the solid content was constant, when the ratio of PTFF to PEO was increased to 97:3, continuous fibers without breakage were formed (Fig. 2c).
  • the PTFE/PEO precursor film prepared by electrospinning is very fluffy, has poor mechanical properties, and contains PEO. It needs to be sintered and PEO removed to obtain a PTFE film with a certain mechanical strength. Therefore, it is necessary to find a suitable sintering temperature by DSC and TG tests on the samples.
  • the melting point of PTFE particles is at 335.5 °C; from the TG curve in Figure 3(b), it can be seen that PTFE particles begin to decompose at 480 °C; pure PEO powder begins to decompose at 210 °C , decomposed completely at 400 °C; the TG curve of the PTFE/PEO precursor film showed two-step mass loss, corresponding to the decomposition of PEO and PTFE, respectively, and the thermal decomposition temperature of the PEO component was consistent with the thermal decomposition temperature of pure PEO powder. Therefore, the sintering temperature can be selected from 335.5°C to 480°C. In this temperature range, PEO is thermally decomposed, and PTFE can be melted to fill the voids left by the decomposition of PEO, thereby connecting into a complete PTFE fiber.
  • the covered part of the stent-graft for endovascular isolation should also have good mechanical properties.
  • PEO only acts as a connecting component of PTFE particles, and has no effect on bearing tensile force. Therefore, PEO needs to be removed, so that the PTFE particles are melted to fill the voids existing in PEO, and finally a complete, continuous and Certainly strong PTFE fiber membrane. Therefore, after determining the sintering temperature range according to DSC and TG tests, the effects of sintering temperature and sintering time on the mechanical properties of PTFE films were further explored. Different sintering temperatures were set: 360°C, 380°C, 400°C; and different sintering times: 5min, 10min, 15min.
  • Fig. 5(a) is the stress histogram of the material prepared under different sintering time and different sintering temperature
  • Fig. 5(b) is the strain histogram of the material prepared under different sintering time and different sintering temperature. It can be seen from the figure that when the sintering temperature is 360°C, the stress strain of the PTFE membrane is smaller than that when the sintering temperature is 380°C, and the sintering time is shorter (5min) or longer (15min). It is smaller than 10min.
  • the sintering temperature is low or the sintering time is short, resulting in incomplete melting of PTFE, which cannot enter the nano-cavity generated by the decomposition of PEO components, so the fiber is incomplete and its mechanical properties are poor; and the sintering time is too long. It will lead to fiber shrinkage, resulting in poor mechanical properties.
  • the sintering temperature is 380°C, the stress and strain of the PTFE film are better; when the sintering temperature increases to 400°C, the stress and strain of the PTFE film are significantly reduced. As a result, the mechanical properties are reduced. Therefore, in general, when the sintering temperature is 380 °C and the sintering time is 10 min, it has the best tensile mechanical properties.
  • Water permeability is an important indicator of the stent-graft for endoluminal isolation. It reflects the resistance of the tube wall to blood after the stent is implanted in the body. It is necessary to prepare a stent-graft with good permeability. Since the water permeability of the film is closely related to its thickness, the greater the thickness, the higher the degree of coverage of the pores, and the less the amount of water permeation. In the present invention, PTFE tubular covered stents with different thicknesses are prepared, and the water osmotic pressure and the overall water flux are respectively tested with a self-built water permeability device. The results are shown in Table 1.
  • the water osmotic pressure is about 0.012 MPa, which is slightly less than but close to the human blood pressure 0.016 MPa; and at 0.016 MPa, the 1, 2, and The overall water flux per unit time in 3, 4, 5, 7, and 10min is between 0.02-0.03mL ⁇ cm -2 ⁇ min -1 , which are far less than the standard 100mL ⁇ cm -2 ⁇ min -1 , so After the stent-graft is actually implanted into the human body, a large amount of blood leakage will not occur under normal blood pressure, and at the same time, a small amount of blood can infiltrate to ensure the growth of the intima and the supply of nutrients to the adventitia; the thickness is increased to 0.14mm When the water osmotic pressure increased to 0.023MPa, which was higher than the blood pressure of the human body, the infiltration did not occur, and the overall water flux at each time point was 0 at 0.016
  • the hemolysis of the material can be judged by measuring the degree of red blood cell destruction during the in vitro contact of the material with blood. If the blood compatibility of the material is poor, it is very likely to rupture the red blood cells, resulting in hemolysis. Hemolysis test is an important index to evaluate the blood compatibility of biological materials. According to the standard ISO 10993-4, a material with a hemolysis rate of ⁇ 5% is considered to meet the requirements of a biomedical material.
  • the hemolysis rate of the PTFE tubular covered stent was 2.84%, which was less than 5%, indicating that the material was safe and would not cause hemolysis.
  • Biomaterials should have good cytocompatibility, that is, the adaptability between the material and the cell adhesion and growth.
  • the good cytocompatibility of the material can promote the adhesion and endothelialization of vascular endothelial cells on the surface of the material, and form a vascular endothelial layer structure in a short time.
  • HUVECs cells are selected to be planted on the surface of the material, and the growth of endothelial cells is observed.
  • Figure 6 is the MTT chart of cell proliferation on different materials. It can be seen from the figure that with the increase of culture time, the number of cells on the tubular covered stent and blank control showed an increasing trend, and the tubular covered stent showed an increasing trend. The cells grew faster; on the 7th day, the number of cells on the covered stent was more than that of the blank control, which proved that it had good cytocompatibility.
  • the cell growth on the material was qualitatively characterized by confocal laser and scanning electron microscopy, as shown in Figure 7. It can be seen that on the 1st day of cell seeding, the cells were more evenly distributed on the glass slide (Fig. 7d), while on the tubular covered stent (Fig. 7a), more cells adhered to the part near the metal stent than on the film. , which can also prove that the TPU adhesive used in the present invention is cytocompatible. On day 3, similar to the results of the MTT test, cell proliferation was more evident, and more cells adhered to the covered portion of the tubular stent-graft. On the 7th day (Fig. 7c, f), a large number of cells adhered to the surface of each material, showing a sheet-like adhesion phenomenon, indicating that endothelialization began to occur.
  • Figure 8 is the SEM image of the growth of HUVECs cells on the tubular covered stent and glass slide. It can be seen from the figure that on the first day ( Figure 7a, d), the number of cells attached to the surface of each material is not much, and it can be seen from the scanning electron microscope image with a magnification of 2000 that the cells have not spread at this time. open. With the increase of culture time, by the third day (Fig. 7b,e), the number of cells on the surface of each material increased, and many cells started to form cell clumps, fused together, and gradually formed cell monoliths The layer adheres to the fiber mesh and glass slide. After 7 days of culture (Fig.
  • HUVECs cells had spread all over the fiber mesh and cell slides, and a cell monolayer could be seen very significantly covering the surface of the material.
  • PTFE:PEO electrospinning solution is prepared by stirring PTFE dispersion emulsion and PEO aqueous solution, and then the PTFE film obtained after electrospinning, vacuum drying and sintering can ensure that the PEO component in it is basically removed, Has good mechanical properties. Then, the directly prepared tubular PTFE membrane is bonded and heat-shrinked to obtain a tubular membrane stent, which has good water permeability, a hemolysis rate of less than 5%, and good blood compatibility. In vitro cell experiments showed that the PTFE tubular covered stent supports the cell adhesion and proliferation of HUVECs without cytotoxicity. The PTFE tubular covered stent has potential application value in the field of vascular covered stent.

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Abstract

一种聚四氟乙烯(PTFE)管状覆膜支架的制备方法，包括：S1.以金属芯轴外套编织管作为接收装置，通过静电纺丝的方法制备PTFE/PEO(聚氧化乙烯)管状纤维膜；S2.将PTFE/PEO管状纤维膜干燥后，于360℃-400℃下烧结5-15min；S3.提供一金属支架，在其表面刷涂聚氨酯(TPU)粘合剂，然后将管状PTFE纤维膜套在金属支架上，放入水中以除去N，N–二甲基甲酰胺(DMF)并使TPU固化；再取出金属支架，干燥，在管状PTFE纤维膜外套上热收缩管，升温，使管状PTFE纤维膜收缩以与金属支架结合更紧密，从而得到PTFE管状覆膜支架。该PTFE管状覆膜支架具有良好的力学性能、水渗透性和血液相容性，溶血率低于5％，能够支持人脐静脉内皮细胞(HUVECs)细胞黏附与增殖，没有细胞毒性。

Description

PTFE管状覆膜支架及其制备方法 技术领域
本发明涉及血管覆膜支架技术领域，具体涉及一种PTFE管状覆膜支架及其制备方法。
背景技术
因外伤、感染、手术、免疫性疾病、高血压、动脉粥样硬化等原因而导致的假性动脉瘤等动脉扩张性疾病严重威胁着人类的健康。如不及时进行治疗，逐渐变薄的血管壁或缺少肌层及弹力层的瘤壁极易破裂，死亡率高达78％-95％。该类疾病的传统疗法是开放性手术，具有风险大、创伤大、操作复杂等不利因素。随着材料科学、工程技术以及外科技术的进步，新型的覆膜支架腔内隔绝术被发明出来。该技术是利用覆膜支架将载瘤动脉和假性动脉瘤瘤腔完全隔绝，血流流经覆膜支架而无法进入瘤腔内。覆膜支架腔内隔绝术疗法具有创伤小、恢复快及并发症少等优点，目前被广泛应用于动脉瘤等疾病的治疗。腔内隔绝术用覆膜支架是金属支架和覆膜的结合体，既保留了金属支架的功能，又具有覆膜材料的特性，目前覆膜部分大多采用涤纶机织物，ePTFE，聚氨酯等，这些材料制备的覆膜在血液相容性、结构稳定性等方面存在缺陷，易造成血栓或内膜增生等问题。
静电纺丝技术是一种简便而通用的工艺，可以制备直径范围从几纳米到几微米的纤维，具有高的比表面积和孔隙率，易于模仿细胞外基质的组成和结构，有利于细胞生长增殖。然而，利用静电纺丝技术制备血管支架覆膜的研究甚少。
发明内容
本发明要解决的技术问题是提供一种静电纺丝法制备PTFE管状覆膜支架，该覆膜支架具有良好的力学性能和水渗透性，溶血率低于5％，血液相容性较好，能够支持HUVECs细胞黏附与增殖，没有细胞毒性，为之后应用于腔内隔绝术提供了参考。
为解决上述技术问题，本发明提供了如下的技术方案：
本发明第一方面提供了一种PTFE管状覆膜支架的制备方法，包括以下步骤：
S1.以金属芯轴外套编织管作为接收装置，通过静电纺丝的方法制备PTFE/PEO管状纤维膜；
S2.将所述PTFE/PEO管状纤维膜干燥后，于360℃-400℃下烧结；
S3.提供一金属支架，在所述金属支架的表面刷涂TPU粘合剂，然后将烧结后的管状PTFE纤维膜套在金属支架上，放入水中以除去粘合剂中的DMF并使TPU固化；接着取出金属支架，干燥，并在管状PTFE纤维膜外套上热收缩管，对收缩管进行升温，使管状PTFE纤维膜收缩以与金属支架结合更紧密，从而得到所述PTFE管状覆膜支架；
或以金属支架作为接收装置，通过静电纺丝的方法在金属支架上接收得到管状TPU电纺膜；然后将烧结后的管状PTFE纤维膜套在TPU电纺膜外，再于管状PTFE纤维膜外套上热收缩管，对热收缩管升温使TPU电纺膜熔融，使管状PTFE纤维膜与金属支架相黏结，从而得到所述PTFE管状覆膜支架。
在PTFE/PEO管状纤维膜中，PEO只是充当弱粘合剂来连接PTFE颗粒，而对承受拉力并无作用，因此需除去PEO。本发明中，对PTFE/PEO管状纤维膜进行烧结，其目的是除去纤维膜中的PEO，同时使得PTFE颗粒熔融后填补 PEO所存在的空隙，最终得到完整连续且具备一定强力的PTFE纤维膜。
进一步地，步骤S1中，所采用的纺丝液为PTFE/PEO的静电纺丝液，所述纺丝液中PTFE与PEO的质量比为99:1-97:3，优选为97:3。
进一步地，步骤S1中，所述静电纺丝的参数为：电压为12-20kV，注射速度为6-15μL/min，接收距离为15-22cm，接收装置的转速为200-600r/min，相对湿度为(35±5)-(45±5)％，温度为(18±3)-(25±3)℃。
进一步地，步骤S2中，所述烧结的温度为360-400℃，优选为380℃，烧结时间为5-15min，优选为10min。
进一步地，步骤S3中，所述金属支架为镍钛合金支架。
进一步地，步骤S3中，所述TPU粘合剂是由TPU粉末溶于DMF中得到的，其浓度为18％-25％，优选为20wt％。
进一步地，步骤S3中，对收缩管进行升温的温度为140-160℃，优选为150℃。
本发明第二方面提供了第一方面所述的方法制备的PTFE管状覆膜支架。
进一步地，所述PTFE管状覆膜支架的厚度为0.08-0.14mm，优选为0.1mm。
本发明第三方面提供了第二方面所述的PTFE管状覆膜支架作为血管支架的应用。
与现有技术相比，本发明的有益效果在于：
本发明的PTFE管状覆膜支架，具有良好的力学性能和水渗透性，溶血率低于5％，血液相容性较好。体外细胞实验表明，PTFE管状覆膜支架能够支持HUVECs细胞黏附与增殖，没有细胞毒性。该PTFE管状覆膜支架在组织工程领域具有潜在的应用价值。
附图说明
图1是PTFE管状覆膜支架的制备流程图；
图2是PTFE/PEO前体膜的形貌图：(a):PTFF:PEO＝99:1；(b):PTFF:PEO＝98:2；(c)PTFF:PEO＝97:3；
图3为热分析图：(a):PTFE颗粒的DSC曲线；(b):PTFE颗粒，PEO粉末，PTFE/PEO前体膜和380℃烧结后覆膜的TG曲线；
图4是烧结前PTFE/PEO前体膜和380℃烧结后PTFE膜的红外光谱图；
图5是不同烧结温度和不同烧结时间下PTFE膜的(a):应力；(b):应变；
图6是各组材料上培养1,3,7天HUVECs增殖MTT图；
图7是各组材料上培养1,3,7天HUVECs激光共聚焦图；
图8是各组材料上培养1,3,7天HUVECs的SEM图。
具体实施方式
下面结合附图和具体实施例对本发明作进一步说明，以使本领域的技术人员可以更好地理解本发明并能予以实施，但所举实施例不作为对本发明的限定。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。本文所使用的术语“及/或”包括一个或多个相关的所列项目的任意的和所有的组合。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法，所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
以下实施例中，所使用的试验材料如下：
聚四氟乙烯分散乳液(PTFE，含固量60％，苏州科同生物医药科技有限公司)，聚氧化乙烯(PEO，M w＝5,000,000Da，苏州格瑞特医药技术有限公司)， 弹性聚氨酯(TPU，德国巴斯夫)，N，N–二甲基甲酰胺(DMF，苏州科同生物医药科技有限公司)，戊二醛(C 5H 8O 2，上海国药化学试剂有限公司)，胎牛血清(FBS，美国Gibco公司)，磷酸盐缓冲溶液(PBS，美国Coring公司)，二甲基亚砜(DMSO，美国Sigma公司)，胰蛋白酶(EDTA，美国Gibco公司)，二乙酸荧光素(FDA，美国Sigma公司)，双抗(青链霉素，美国Gibco公司)，人脐静脉内皮细胞(HUVECs)，噻唑蓝(MTT，上海如吉生物科技发展有限公司)，DMEM培养基(美国Corning公司)，75％乙醇消毒液(安徽安特食品股份有限公司)。
实施例1
1.PTFE/PEO前体膜的制备
用Adventurer型电子天平(常州奥豪斯仪器有限公司)称取适量PEO粉末加入去离子水中用84-1型磁力搅拌器(上海梅颖浦仪器仪表制造有限公司)搅拌至完全溶解，得到4wt％PEO水溶液。称取PTFE分散乳液，以及PEO水溶液和去离子水混合，不断搅拌至均匀，得到不同比例PTFE/PEO的静电纺丝液。将纺丝液导入5mL的注射器内，将包裹有不锈钢编织套管的芯轴(直径为4mm)作为接收装置进行静电纺丝(JDS02型静电纺丝机，长沙纳仪仪器科技有限公司)，设置静电纺丝参数为：电压为15kV，注射速度为8μL/min，接收距离为20cm，接收装置转速为400r/min，相对湿度为(40±5)％，温度为(23±3)℃。
2.PTFE覆膜的制备
静电纺丝结束后，将覆盖有PTFE/PEO纤维膜的不锈钢编织套管试样放入真空烘箱(DZF-6020B，天津工兴实验室仪器有限公司)中，于60℃下真空干燥10h，去除纤维膜中水分。干燥结束后再将试样立即转移到箱式炉(MF-1200C，安徽贝意克设备技术有限公司)中，在不同烧结温度，不同烧结时间下进行烧结，以探究不同烧结条件对覆膜制备的影响。烧结结束后，将覆膜从不锈钢编织套管上取下，即为管状PTFE覆膜。
3.覆膜支架的制备
采用TPU溶液涂刷法制备覆膜支架，具体操作为：
首先用电子天平称取适量TPU粉末加入到DMF中搅拌至完全溶解，得到20wt％TPU溶液，即TPU粘合剂。后如图1所示将TPU粘合剂刷涂在金属支架外，再把管状PTFE覆膜套在TPU粘合剂外，放入去离子水中，以除去粘合剂中的DMF并使TPU固化，再放入WGLL-125BE型电热恒温鼓风干燥箱(天津市泰斯特仪器有限公司)中干燥10min。从烘箱中取出后，把PTFE覆膜套在芯轴上，并在PTFE覆膜外套上热收缩管，将热风枪(DH-HG2-2000，德力西电气有限公司)调至150℃对收缩管进行升温，使PTFE覆膜与金属支架收缩更紧密，得到PTFE覆膜支架。
实施例2
实施例2与实施例1的区别在于：采用TPU电纺法制备覆膜支架，具体操作为：
称取适量TPU粉末溶于DMF搅拌至完全溶解，得到30wt％TPU静电纺丝液，设置静电纺丝参数为：电压为16-17kV，以包裹有金属支架的芯轴作为接收装置，接收距离为15cm，流速为13.33μL/min，电纺一定的时间后得到管状TPU电纺膜；然后将上述烧结后的管状PTFE覆膜套在TPU电纺膜外，再在最外层加上热收缩管，将热风枪温度调高对热收缩管升温使TPU电纺膜熔融，从而将PTFE膜与金属支架相黏结，且收缩管在高温作用下使两者结合更紧密，得到PTFE覆膜支架。
测试与表征
1.形貌分析
图2是不同PTFE:PEO比例的静电纺前体膜的微观形貌，在纺丝液中，PEO 作为粘结成分，使PTFE颗粒在静电喷射下能够粘结在一起形成连续纤维。从图2中可以看出，当纺丝液中PEO含量较少时，不能形成连续的纤维。当PTFF:PEO为99:1时，纤维断裂情况显著(图2a)；当PEO含量逐渐增加，PTFF:PEO为98:2时，纤维断裂点减少(图2b)；在保持纺丝液总含固量不变的情况下，PTFF与PEO比例上升到97:3时，形成连续无断裂的纤维(图2c)。
2.热分析
静电纺制备出的PTFE/PEO前体膜很蓬松，力学性能较差，且含有PEO，需要将其进行烧结并除去PEO才能获得具有一定力学强度的PTFE覆膜。因此需要通过对样品进行DSC和TG测试找到合适的烧结温度。
从图3(a)的DSC曲线中可以看出，PTFE颗粒的熔点在335.5℃；图3(b)的TG曲线中可以看出PTFE颗粒在480℃开始分解；纯PEO粉末在210℃开始分解，到400℃分解完全；PTFE/PEO前体膜的TG曲线显示两步质量损失，分别对应于PEO和PTFE的分解，其中PEO组分热分解温度与纯PEO粉末热分解温度一致。因此烧结温度可选择在335.5℃-480℃，在此温度区间，PEO发生热分解，且PTFE可熔融后填补PEO分解后留下的空隙，从而连接成完整的PTFE纤维。
3.傅立叶变换红外光谱(FTIR)分析
通过傅立叶变换红外光谱证明烧结后从聚四氟乙烯膜中基本去除了水和PEO，结果如图4所示。从图中可以看出，烧结前的前体膜有明显的PEO特征峰：在962cm -1和1105cm -1处出现谱带，这归因于PEO的不对称CO伸缩振动，1350cm -1和1467cm -1处出现的谱带对应于PEO的CH 2振动，2880cm -1处出现的谱带对应于PEO的CH伸展。在烧结后的膜中无PEO特征峰，而前体膜和烧结后的膜都能在1201cm -1和1145cm -1处观察到最大峰值，这对应于聚四氟乙烯中的CF 2的不对称拉伸和对称拉伸，这表明已去除前体膜中的PEO，至少 不能通过FTIR测量检测到。
4.力学性能分析
腔内隔绝术用覆膜支架的覆膜部分还应具有较好的力学性能。在PTFE/PEO前体膜中，PEO只是充当PTFE颗粒的连接成分，而对承受拉力并无作用，因此需除去PEO，使得PTFE颗粒熔融后填补PEO所存在的空隙，最终得到完整、连续且具备一定强力的PTFE纤维膜。所以根据DSC和TG测试确定烧结温度范围后，进一步探究烧结温度和烧结时间对PTFE覆膜力学性能的影响。设置了不同烧结温度：360℃，380℃，400℃；以及不同烧结时间：5min，10min，15min。
图5(a)为不同烧结时间和不同烧结温度下制得的材料的应力柱状图，图5(b)为不同烧结时间和不同烧结温度下制得的材料的应变柱状图。从图中可以看出，烧结温度为360℃时PTFE膜的应力应变都比烧结温度380℃时的小，且烧结时间较短(5min)或较长(15min)，膜的应力应变相对烧结时间为10min的更小，原因是烧结温度较低或烧结时间短导致PTFE熔融不完全，不能进入PEO组分分解后产生的纳米空腔，因此纤维不完整，其力学性能差；而烧结时间过长则会导致纤维收缩，从而力学性能较差。烧结温度为380℃时，PTFE膜的应力和应变都较优；当烧结温度升高到400℃，PTFE覆膜的应力和应变又显著降低，原因是烧结温度过高，导致纤维严重收缩断裂，从而力学性能下降。因此综合而言，烧结温度为380℃，烧结时间为10min时具有最优的拉伸力学性能。
5.水渗透性分析
水渗透性是腔内隔绝术用覆膜支架的重要表征指标，反应了支架植入体内后，管壁对血液的抗渗透性，需要制备出具有良好渗透性的覆膜支架。由于覆膜的水渗透性和其厚度有密切的关系，厚度越大，孔隙被覆盖的程度越高，水 渗透量就会越少。本发明中制备了不同厚度的PTFE管状覆膜支架，用自行搭建的水渗透性装置分别测试了水渗透压和整体水通量，结果如表1所示。
从表1中可以看出，当厚度为0.1mm左右时，水渗透压约为0.012MPa，略小于但接近人体血压0.016MPa；且在0.016MPa下，流过有效长度血管壁的1、2、3、4、5、7、10min内单位时间的整体水通量为0.02-0.03mL·cm -2·min -1之间，均远小于标准规定的100mL·cm -2·min -1，因此该覆膜支架在实际植入到人体后在正常的血压下不至于出现大量漏血的情况，同时又能有少量的血渗入保证内膜的生长和外膜营养的供应；厚度增加到0.14mm左右时，水渗透压提高到0.023MPa，高于人体血压，因此不会发生渗透，且在0.016MPa下各时间点的整体水通量均为0，不利于内膜生长。因此，当厚度为0.1mm左右时，其水渗透性是符合要求的。
表1 不同厚度PTFE管状覆膜支架的渗透压及整体水渗透量
Figure PCTCN2021118144-appb-000001
7.溶血实验分析
通过测定材料在与血液体外接触过程中，红细胞破坏程度来判断材料的溶血情况。若材料的血液相容性差，极有可能使红细胞破裂，从而发生溶血。溶血实验是评价生物材料血液相容性的重要指标。根据标准ISO 10993-4，材料的溶血率<5％则被认为是符合生物医用材料的要求。
如表2所示，PTFE管状覆膜支架的溶血率为2.84％，小于5％，说明该材料是安全的，不会引起溶血。
表2 PTFE覆膜和管状覆膜支架的溶血试验结果
材料 吸光度 溶血率
PTFE管状覆膜支架 0.048±0.002 2.84％
阴性对照 0.026±0.003 0.00％
阳性对照 0.776±0.007 100％
6.细胞毒性分析
生物材料应具有良好的细胞相容性，即材料与细胞的贴附及生长之间的适应性。材料的细胞相容性好可以促进材料表面血管内皮细胞黏附内皮化，在短时间内形成血管内皮层结构。本发明选用HUVECs细胞种植在材料表面，观察其内皮细胞生长情况。
图6为不同材料上细胞的增殖MTT图，从图中可以看出，随着培养时间的增加，在管状覆膜支架，空白对照样上的细胞数都呈现增加的趋势，且管状覆膜支架上细胞增长速度较快；在第7天时，覆膜支架上的细胞数多于空白对照样，证明其具有良好的细胞相容性。
通过激光共聚焦和扫描电子显微镜对材料上的细胞增长进行定性表征，如图7所示。可以看出在细胞接种第1天，细胞在玻片(图7d)上较均匀分布，而在管状覆膜支架(图7a)上，靠近金属支架部分细胞粘附的相较覆膜上更多，这也能证明本发明所用的TPU粘合剂是具有细胞相容性的。到第3天，与MTT测试结果类似，能够更明显看到细胞增殖，而且管状覆膜支架上在覆膜部分也黏附了较多细胞。到第7天(图7c,f)，各材料表面都黏附了大量细胞，呈现出片状黏连现象，说明开始出现内皮化。
图8为HUVECs细胞在管状覆膜支架以及玻片上生长情况的SEM图像。从图中可以看出，在第1天(图7a,d)，各材料表面细胞黏附的数量均不多，通过放大倍数为2000的扫描电子显微镜图片可以看到，此时细胞还并未铺展开。随着培养时间的增加，到第3天(图7b,e)，在各材料表面上的细胞数都有所 增加，并且开始有许多细胞形成细胞团块，融合在一起，并逐渐形成细胞单层黏附在纤维网和玻片上。经过7天的培养(图7c,f)，HUVECs细胞已经铺满在整个纤维网和细胞玻片上，并且可以非常显著地看到有细胞单层覆盖在材料表面。这些结果证明管状覆膜支架对HUVECs细胞没有毒性，能够支持内皮细胞的黏附与增殖。
综上，本发明通过PTFE分散乳液和PEO水溶液搅拌制备得到PTFE:PEO静电纺丝液，之后经过静电纺丝、真空干燥、烧结后得到的PTFE覆膜能保证其中的PEO组分被基本去除，具有良好的力学性能。再将直接制备得到的管状PTFE覆膜经过粘结和热收缩加固后得到管状覆膜支架，经测试证实其具有良好的水渗透性，且溶血率低于5％，血液相容性较好。体外细胞实验表明，PTFE管状覆膜支架支持HUVECs细胞黏附与增殖，没有细胞毒性。该PTFE管状覆膜支架在血管覆膜支架领域具有潜在的应用价值。
以上所述实施例仅是为充分说明本发明而所举的较佳的实施例，本发明的保护范围不限于此。本技术领域的技术人员在本发明基础上所作的等同替代或变换，均在本发明的保护范围之内。本发明的保护范围以权利要求书为准。

Claims (10)

  1. 一种PTFE管状覆膜支架的制备方法，其特征在于，包括以下步骤：
    S1.以金属芯轴外套编织管作为接收装置，通过静电纺丝的方法制备PTFE/PEO管状纤维膜；
    S2.将所述PTFE/PEO管状纤维膜干燥后，于360℃-400℃下烧结5-15min；
    S3.提供一金属支架，在所述金属支架的表面刷涂TPU粘合剂，然后将烧结后的管状PTFE纤维膜套在金属支架上，放入水中以除去粘合剂中的DMF并使TPU固化；接着取出金属支架，干燥，并在管状PTFE纤维膜外套上热收缩管，对收缩管进行升温，使管状PTFE纤维膜收缩以与金属支架结合更紧密，从而得到所述PTFE管状覆膜支架；
    或以金属支架作为接收装置，通过静电纺丝的方法在金属支架上接收得到管状TPU电纺膜；然后将烧结后的管状PTFE纤维膜套在TPU电纺膜外，再于管状PTFE纤维膜外套上热收缩管，对热收缩管升温使TPU电纺膜熔融，使管状PTFE纤维膜与金属支架相黏结，从而得到所述PTFE管状覆膜支架。
  2. 根据权利要求1所述的一种PTFE管状覆膜支架的制备方法，其特征在于，步骤S1中，所采用的纺丝液为PTFE/PEO的静电纺丝液，所述纺丝液中PTFE与PEO的质量比为99:1-97:3。
  3. 根据权利要求1所述的一种PTFE管状覆膜支架的制备方法，其特征在于，步骤S1中，所述静电纺丝的参数为：电压为12-20kV，注射速度为6-15μL/min，接收距离为15-22cm，接收装置的转速为200-600r/min，相对湿度为(35±5)-(45±5)％，温度为(18±3)-(25±3)℃。
  4. 根据权利要求1所述的一种PTFE管状覆膜支架的制备方法，其特征在于，步骤S2中，所述烧结的温度为380℃，烧结时间为10min。
  5. 根据权利要求1所述的一种PTFE管状覆膜支架的制备方法，其特征在于，步骤S3中，所述金属支架为镍钛合金支架。
  6. 根据权利要求1所述的一种PTFE管状覆膜支架的制备方法，其特征在于，步骤S3中，所述TPU粘合剂是由TPU粉末溶于DMF中得到的，其浓度为18％-25％。
  7. 根据权利要求1所述的一种PTFE管状覆膜支架的制备方法，其特征在于，步骤S3中，对收缩管进行升温的温度为140℃-160℃。
  8. 根据权利要求1-7任一项所述的方法制备的PTFE管状覆膜支架。
  9. 根据权利要求8所述的PTFE管状覆膜支架，其特征在于，所述PTFE管状覆膜支架的厚度为0.08-0.14mm。
  10. 权利要求9所述的PTFE管状覆膜支架作为血管支架的应用。
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