WO2018058874A1 - 一次成型的凝胶纤维复合支架材料及其制备方法与应用 - Google Patents

一次成型的凝胶纤维复合支架材料及其制备方法与应用 Download PDF

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WO2018058874A1
WO2018058874A1 PCT/CN2017/072608 CN2017072608W WO2018058874A1 WO 2018058874 A1 WO2018058874 A1 WO 2018058874A1 CN 2017072608 W CN2017072608 W CN 2017072608W WO 2018058874 A1 WO2018058874 A1 WO 2018058874A1
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solution
electrospinning
phase separation
preparation
fiber composite
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French (fr)
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韩鑫晓
韩东
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国家纳米科学中心
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/222—Gelatin
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
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    • 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
    • D04H1/4382—Stretched reticular film fibres; Composite fibres; Mixed fibres; Ultrafine fibres; Fibres for artificial leather
    • D04H1/43825—Composite fibres
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    • D06M13/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment
    • D06M13/322—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing nitrogen
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    • D06M13/322—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing nitrogen
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    • D06M15/00—Treating fibres, threads, yarns, fabrics, or fibrous goods made from such materials, with macromolecular compounds; Such treatment combined with mechanical treatment
    • D06M15/01—Treating fibres, threads, yarns, fabrics, or fibrous goods made from such materials, with macromolecular compounds; Such treatment combined with mechanical treatment with natural macromolecular compounds or derivatives thereof
    • D06M15/03—Polysaccharides or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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    • C12N2533/00—Supports or coatings for cell culture, characterised by material
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    • C—CHEMISTRY; METALLURGY
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    • C12N2533/00—Supports or coatings for cell culture, characterised by material
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    • C12N2533/54—Collagen; Gelatin
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    • 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
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    • D06M2101/00—Chemical constitution of the fibres, threads, yarns, fabrics or fibrous goods made from such materials, to be treated
    • D06M2101/02—Natural fibres, other than mineral fibres
    • D06M2101/10—Animal fibres
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    • D06M2101/00—Chemical constitution of the fibres, threads, yarns, fabrics or fibrous goods made from such materials, to be treated
    • D06M2101/02—Natural fibres, other than mineral fibres
    • D06M2101/10—Animal fibres
    • D06M2101/14—Collagen fibres
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    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
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    • D06M2101/00—Chemical constitution of the fibres, threads, yarns, fabrics or fibrous goods made from such materials, to be treated
    • D06M2101/16—Synthetic fibres, other than mineral fibres
    • D06M2101/30—Synthetic polymers consisting of macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • D06M2101/32—Polyesters

Definitions

  • the invention relates to a once-molded gel fiber composite scaffold material and a preparation method and application thereof.
  • the extracellular matrix is a highly hydrated fibrous network gel structure composed of proteins and polysaccharides distributed in the extracellular space.
  • the structure and composition ratio of the extracellular matrix are slightly different in different tissues, but the basic composition is similar.
  • the extracellular matrix consists essentially of collagen/elastin, which forms a gel-like matrix and provides attachment sites for surrounding cells.
  • the extracellular matrix not only participates in the maintenance of the tissue structure, but also affects the basic life activities such as cell survival, function, metabolism, value-added, differentiation, and migration.
  • the object of the present invention is to overcome the shortcomings of the prior art, such as the preparation of more cumbersome products, high price and low yield, and to provide a one-time gel fiber composite scaffold material and a preparation method and application thereof, so as to apply in different biological basic research. .
  • the research of the invention finds that the preparation process of the extracellular matrix material prepared by the prior art is complicated, and the preparation component is relatively simple, and the gel fiber composite material cannot be formed at one time.
  • Common materials usually only consider fiber structure or single component, while natural extracellular matrix products have higher cost, less yield, and less basic application.
  • High-voltage electrospinning technology is a common method for producing micro-nano-grade fiber materials.
  • Type 1 collagen and gelatin are commonly used materials for cell substrate pretreatment, both of which promote cell adhesion spreading.
  • the present invention provides a gel fabric composite scaffold material which is molded at a lower cost and which is prepared based on a high voltage electrospinning technique and a phase separation technique.
  • the one-shot gel fiber composite scaffold material comprises the following steps: preparing the electrospun film by a high-voltage electrostatic method; and then immersing in the phase separation solution to prepare the one-time gel fiber composite scaffold material.
  • the electrospun film is phase separated by the action of a phase separation solution to form a fibrillated gel network structure.
  • the raw material for preparing the electrospinning film comprises polycaprolactone, gelatin, and type I collagen; wherein preferably, the mass ratio of polycaprolactone, gelatin, and type I collagen is 10-20:10-20:5. Further, it is preferably 10:10:5.
  • the solvent for preparing the electrospinning solution is preferably trifluoroethanol.
  • the conditions for preparing the electrospun film include: a voltage of 15-20 kv, an electrospinning distance of 10-20 cm, and an electrospinning time of 10-60 min.
  • the electrospinning needle model is available in 12G type.
  • the phase separation solution is a mixed solution of a water-soluble carbodiimide and N-hydroxysuccinimide, preferably, wherein the molar concentration of the water-soluble carbodiimide and the N-hydroxysuccinimide is 0.05-0.1, respectively. M; further preferably both are 0.05M.
  • the phase separation solution is a mixed solution of a mixed solution of the above water-soluble carbodiimide and N-hydroxysuccinimide and an aqueous solution of sodium hyaluronate.
  • the above-mentioned one-shot gel fiber composite scaffold material the preparation method thereof comprises:
  • polycaprolactone, gelatin and type I collagen are respectively dissolved in trifluoroethanol, and magnetically stirred for 3-6 hours to prepare a mass fraction of 10-20% polycaprolactone solution, 10- 20% gelatin solution, 5-10% type I collagen solution;
  • Electrospinning conditions voltage is 15-20kv, electrospinning distance is 10-20cm, electrospinning needle model is 12G, electrospinning time is 10-60min;
  • Phase separation solution preparation separately prepare 1M water-soluble carbodiimide solution and 1M N-hydroxy succinate Perimide solution; after the two solutions are completely mixed in equal volume, diluted 10 times to prepare a phase separation solution;
  • the electrospun film obtained in the step 2) is immersed in the phase separation solution prepared in the step 3) for at least 20 minutes, and washed with pure water to obtain the gel-fiber composite scaffold material which is formed once.
  • the present invention also encompasses a one-shot gel fiber composite scaffold material produced by the method.
  • the present invention also includes the use of the above-described one-shot gel fiber composite scaffold material for use as a cell culture substrate, a graft material, and the like.
  • the composite scaffold material in the present invention is a kind of imitation extracellular matrix composite material, and can also be modified by adding a variety of natural biological materials to make the composition closer to the extracellular matrix.
  • the invention has the advantages or beneficial effects that the preparation process is simpler, easier to store and transport than other existing extracellular matrix materials, and the cost is lower, which is beneficial to the broad application in basic research.
  • the high-voltage electrospun film prepared by the invention has high biocompatibility, higher modulus of elasticity, good adhesion on the surface of skin and organs, and is more suitable for use in cell culture medium and transplant materials.
  • Figure 1 is an electron micrograph of the surface morphology of the experimental sample of Experimental Example 1.
  • Polycaprolactone having a molecular weight of 80,000, purchased from sigma/vetec;
  • Gelatin purchased from sigma/vetec;
  • Type I collagen purchased from Sichuan Mingrang Biotechnology Co., Ltd.;
  • Trifluoroethanol purchased from Aladdin (Shanghai Jingchun Biochemical Technology Co., Ltd.);
  • High voltage power supply was purchased from Dongwen High Voltage Power Co., Ltd.;
  • Water-soluble carbodiimide purchased from Aladdin (Shanghai Jingchun Biochemical Technology Co., Ltd.); N-hydroxysuccinimide, purchased from Aladdin (Shanghai Jingchun Biochemical Technology Co., Ltd.).
  • Sodium hyaluronate purchased from Aladdin (Shanghai Jingchun Biochemical Technology Co., Ltd.), was prepared by microbial fermentation.
  • a once-formed gel fiber composite scaffold material the preparation method thereof comprises:
  • the electrospinning film was prepared by high-voltage electrospinning using the 10% polycaprolactone solution prepared in the step 1), the 10% gelatin solution, and the 5% type I collagen solution as raw materials.
  • Electrospinning conditions voltage is 15-20kv, electrospinning distance is 10-20cm, electrospinning needle model is 12G, and electrospinning time is 10min, 30min, 60min respectively.
  • Phase separation solution preparation 1 M water-soluble carbodiimide solution and 1 M N-hydroxysuccinimide solution were separately prepared. After the two solutions were thoroughly mixed, they were diluted 10 times to prepare a phase separation solution.
  • the electrospun film obtained in the step 2) is immersed in the phase separation solution prepared in the step 3) for at least 20 minutes, and washed with pure water to obtain the gel-fiber composite scaffold material which is formed once.
  • the one-shot gel fiber composite scaffold material is prepared by a method different from that of Example 1 except that the phase separation solution used in the step 3) is different.
  • phase separation solution of the present embodiment separately preparing 1M water-soluble carbodiimide solution and 1M N-hydroxysuccinimide solution; after the two solutions are completely mixed in equal volume, diluted 10 times to prepare a liquid solution;
  • a sodium hyaluronate aqueous solution having a mass fraction of 1% was prepared as the liquid B.
  • the mixture of the liquid A and the liquid B was mixed in a volume of 1:1 to obtain a phase separation solution, followed by phase separation of the film.
  • the one-shot gel fiber composite scaffold material is prepared in the same manner as in the first embodiment except that the electrospinning solution in the step 1) is separately prepared into a mass fraction of 20% polycaprolactone solution, 20% gelatin solution, and 10% of I. Type collagen solution.
  • the one-shot gel fiber composite scaffold material is prepared in the same manner as in the first embodiment only in the step 3).
  • the phase separation solution is prepared by separately preparing a 1 M water-soluble carbodiimide solution and 1 M N-hydroxysuccinimide. Solution; after the two solutions are completely mixed in equal volume, they are diluted 5 times to prepare a phase separation solution.
  • the surface morphology of the experimental samples was characterized by electron microscopy and measurement: the instrument was a field emission environment scanning electron microscope (brand FEI, Quanta 200FEG); 120KV transmission electron microscope (brand Hitachi, HT7700), the results are shown in Figure 1, where:
  • (A) is a transmission electron microscope image of an electrospun film (before phase separation);
  • (B) is a transmission electron microscope image of the once-formed gel fiber composite scaffold material (after phase separation); it can be seen that a gel-like polymer network is formed on the surface of the high-voltage electrospinning film after phase separation;
  • (C) is an environmental scanning electron microscope image of an electrospun film (before phase separation);
  • the film thickness of the experimental sample was measured by a step meter: the instrument was a contact surface topography measuring instrument (BRUKER, Dektak-XT), and the results are shown in Table 1. It can be seen that the thickness of the same fiber film is greatly reduced after phase separation.
  • the elastic modulus of the experimental sample was measured by a dynamic mechanical property analyzer: the instrument was a dynamic mechanical property analyzer (brand TA, DMA-Q800), quasi-static tensile test, and the results are shown in Fig. 2.
  • Fig. 2 The abscissa Strain represents the percentage change of stress, the ordinate Stress represents the stress magnitude, the solid line “-2" represents the stress-strain curve of the electrospun film (before phase separation); the dotted line “--1” represents the one-shot molding. Stress-strain curve of gel fiber composite scaffold material (after phase separation). It is calculated that the elastic modulus of the fiber film before phase separation is: 148.23 ⁇ 21.68MP; the elastic modulus of the fiber film after phase separation is: 180.55 ⁇ 60.46MPa. It can be seen that the elastic modulus increases remarkably after phase separation of the same fiber film.
  • the invention provides a once-molded gel fiber composite scaffold material and a preparation method and application thereof.
  • the gel fiber composite material can be rapidly prepared by the method of the invention, which is simpler than other existing extracellular matrix materials, is easier to store and transport, and has lower cost, and is beneficial to be widely used in basic research.
  • the gel fiber composite scaffold material of the invention has high biocompatibility, higher elastic modulus, good adhesion on the surface of the skin and organs, and is more suitable for the bottom of the cell culture medium and the transplant material.
  • the invention has broad application prospects and good industrial applicability in the fields of biotechnology and the like.

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Abstract

一种一次成型的凝胶纤维复合支架材料及其制备方法与应用。该复合支架材料的制备方法包括通过高压静电方法制备电纺丝薄膜；然后浸泡于相分离溶液中制得。制得的复合支架材料是一种仿细胞外基质复合材料，还可添加多种天然生物材料进行改造，使之成分上更接近细胞外基质。

Description

一次成型的凝胶纤维复合支架材料及其制备方法与应用
相关申请的交叉引用
本申请要求2016年09月29日提交、申请号为201610866896.0的中国专利申请的优先权，其所公开的内容作为参考全文并入本申请。
技术领域
本发明涉及一种一次成型的凝胶纤维复合支架材料及其制备方法与应用。
背景技术
细胞外基质是分布于细胞外空间，细胞分泌的由蛋白质和多糖构成的高度水合性纤维网络凝胶结构。细胞外基质的结构和成分比例在不同组织中略有差别，但是基本组成相似。细胞外基质基本由胶原/弹性蛋白构成纤维网络，其他非胶原糖蛋白、氨基聚糖和蛋白聚糖形成凝胶样基质并且为周围细胞提供附着位点。细胞外基质不仅参与组织结构的维持，而且对于细胞的存活形态、功能、代谢、增值、分化、迁移等基本生命活动产生影响。
细胞外基质对于细胞各项病理生理活动产生重要影响早已引起生物学领域的重视，也产生了许多细胞外基质材料产品。但是多数产品制备工艺较繁琐，产品价格较高，不能进行广泛基础研究应用。
发明内容
本发明的目的在于克服采用现有技术制备较繁琐产品价格高产量较低等缺点，提供一种一次成型的凝胶纤维复合支架材料及其制备方法与应用，以期在不同生物学基础研究进行应用。
本发明研究发现，采用现有技术制备的放细胞外基质材料中，制备工艺比较复杂，制备成分较单一，不能一次成型形成凝胶纤维复合材料。常见材料通常只考虑纤维结构或单一组分，而天然细胞外基质产品成本较高，产量少，基础应用较少。高压静电纺丝技术是一种工艺成熟的产生微纳米级纤维材料的常用方法。一型胶原蛋白和明胶是常用的用于细胞培养基底预处理的材料，两者均有促进细胞粘附铺展的功能。
基于以上发现，本发明提供了一种成本较低一次成型的凝胶纤维复合支架材料，该材料是基于高压静电纺丝技术和相分离技术制备而成。
本发明技术方案如下：
一次成型的凝胶纤维复合支架材料，其制备方法包括：通过高压静电方法制备电纺丝薄膜；然后浸泡于相分离溶液中制成所述一次成型的凝胶纤维复合支架材料。
电纺丝薄膜通过相分离溶液的作用，发生相分离形成纤维化凝胶网络结构。
所述制备电纺丝薄膜的原料包括聚己内酯、明胶、I型胶原蛋白；其中优选地，聚己内酯、明胶、I型胶原蛋白的质量比为10-20∶10-20∶5-10；进一步优选为10∶10∶5。
制备电纺溶液的溶剂优选为三氟乙醇。
制备电纺丝薄膜的条件包括：电压15-20kv，电纺距离10-20cm，电纺时间10-60min。
电纺针头型号可用12G型。
所述相分离溶液为水溶性碳二亚胺和N-羟基琥珀酰亚胺的混合溶液，优选地，其中水溶性碳二亚胺和N-羟基琥珀酰亚胺的摩尔浓度分别为0.05-0.1M；进一步优选均为0.05M。
或者所述相分离溶液为上述水溶性碳二亚胺和N-羟基琥珀酰亚胺的混合溶液与透明质酸钠水溶液的混合溶液。
具体地，上述一次成型的凝胶纤维复合支架材料，其制备方法包括：
1)电纺溶液配制：将聚己内酯、明胶、I型胶原蛋白分别溶于三氟乙醇中，磁力搅拌3-6小时，制成质量分数10-20％聚己内酯溶液、10-20％明胶溶液、5-10％的I型胶原蛋白溶液；
2)高压静电纺丝：以步骤1)制备的聚己内酯溶液、明胶溶液和I型胶原蛋白溶液为原料，进行高压静电纺丝，制得电纺丝薄膜；
电纺条件：电压为15-20kv，电纺距离为10-20cm，电纺针头型号为12G，电纺时间为10-60min；
3)相分离溶液配制：分别配制1M水溶性碳二亚胺溶液和1M的N-羟基琥 珀酰亚胺溶液；将该两种溶液等体积完全混合后，稀释10倍，制得相分离溶液；
或者进一步将所制得的相分离溶液与质量体积分数为1％的透明质酸钠水溶液按1∶1的体积混合；
4)将步骤2)制得的电纺丝薄膜浸泡于步骤3)制得的相分离溶液中，作用至少20min，用纯水洗净，即得所述一次成型的凝胶纤维复合支架材料。
本发明还包括所述方法制得的一次成型的凝胶纤维复合支架材料。
本发明还包括上述一次成型的凝胶纤维复合支架材料在用作细胞培养基底、移植材料等方面的应用。
本发明中所述复合支架材料是一种仿细胞外基质复合材料，还可添加多种天然生物材料进行改造，使之成分上更接近细胞外基质。
本发明优点或有益效果在于：较其他现有细胞外基质材料制备工艺更简单，更易储存和运输，成本更低，有利于广泛应用于基础研究。
本发明制备的高压静电纺丝薄膜生物相容性高，弹性模量更高，在皮肤、器官表面贴合度好，更适应用于细胞培养基底、移植材料。
附图说明
图1为实验例1实验样品表面形貌电子显微表征图。
图2为实验例1实验样品应力应变曲线图。
具体实施方式
以下实施例用于说明本发明，但不用来限制本发明的范围。实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件，或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可通过正规渠道商购买得到的常规产品。
聚己内酯，分子量为80000，购于sigma/vetec；
明胶，购于sigma/vetec；
I型胶原蛋白，购于四川铭让生物科技有限公司；
三氟乙醇，购于阿拉丁(上海晶纯生化科技股份有限公司)；
高压电源购于东文高压电源有限公司；
水溶性碳二亚胺，购自阿拉丁(上海晶纯生化科技股份有限公司)公司； N-羟基琥珀酰亚胺，购自阿拉丁(上海晶纯生化科技股份有限公司)公司。
透明质酸钠，购自阿拉丁(上海晶纯生化科技股份有限公司)公司，由微生物发酵法制备。
实施例1
一次成型的凝胶纤维复合支架材料，其制备方法包括：
1)电纺溶液配制：将聚己内酯、明胶、I型胶原蛋白分别溶于三氟乙醇中，磁力搅拌3-6小时，制成质量分数10％聚己内酯溶液、10％明胶溶液、5％的I型胶原蛋白溶液。
2)高压静电纺丝：以步骤1)制备的10％聚己内酯溶液、10％明胶溶液和5％的I型胶原蛋白溶液为原料，进行高压静电纺丝，制得电纺丝薄膜。
电纺条件：电压为15-20kv，电纺距离为10-20cm，电纺针头型号为12G，电纺时间分别为10min、30min、60min。
3)相分离溶液配制：分别配制1M水溶性碳二亚胺溶液和1M的N-羟基琥珀酰亚胺溶液。将该两种溶液完全混合后，稀释10倍，制得相分离溶液。
4)将步骤2)制得的电纺丝薄膜浸泡于步骤3)制得的相分离溶液中，作用至少20min，用纯水洗净，即得所述一次成型的凝胶纤维复合支架材料。
实施例2
一次成型的凝胶纤维复合支架材料，其制备方法包括与实施例1的区别仅在于步骤3)所用相分离溶液不同。
本实施例相分离溶液：分别配制1M水溶性碳二亚胺溶液和1M的N-羟基琥珀酰亚胺溶液；将该两种溶液等体积完全混合后，稀释10倍，制得甲液；
配制质量体积分数为1％的透明质酸钠水溶液，作为乙液。将甲液与乙液按1∶1的体积混合后作为相分离溶液，再进行薄膜的相分离。
实施例3
一次成型的凝胶纤维复合支架材料，其制备方法与实施例1的区别仅在于步骤1)中电纺溶液分别配制成质量分数20％聚己内酯溶液、20％明胶溶液、10％的I型胶原蛋白溶液。
实施例4
一次成型的凝胶纤维复合支架材料，其制备方法与实施例1的区别仅在于步骤3)相分离溶液配制包括：分别配制1M水溶性碳二亚胺溶液和1M的N-羟基琥珀酰亚胺溶液；将该两种溶液等体积完全混合后，稀释5倍，制得相分离溶液。
实验例材料表面形貌表征
实验样品：实施例1步骤2)制得的电纺丝薄膜(分相前)及步骤4)制得的一次成型的凝胶纤维复合支架材料(分相后)。
实验样品表面形貌表征通过电子显微镜和测得：仪器为场发射环境扫描电子显微镜(品牌FEI，Quanta 200FEG)；120KV透射电子显微镜(品牌日立，HT7700)，结果见图1，其中：
(A)为电纺丝薄膜(分相前)透射电子显微镜图像；
(B)为一次成型的凝胶纤维复合支架材料(分相后)透射电子显微镜图像；可见高压静电纺丝薄膜分相后表面产生了凝胶状高分子网络；
(C)为电纺丝薄膜(分相前)环境扫描电子显微镜图像；
(D)为一次成型的凝胶纤维复合支架材料(分相后)环境扫描电子显微镜图像；可见高压静电纺丝分相后表面变得不光滑的凝胶状物质。
实验样品膜厚度通过台阶仪测得：仪器为接触式表面形貌测量仪(品牌BRUKER，Dektak-XT)，结果见表1，可见同一纤维薄膜分相后厚度大大减小。
表1
Figure PCTCN2017072608-appb-000001
实验样品弹性模量通过动态机械性能分析仪测得：仪器为动态机械性能分析仪(品牌TA，DMA-Q800)，准静态拉伸测试，结果详见图2。
图2横坐标Strain表示应力变化百分比，纵坐标Stress表示应力大小，实线“-2”表示电纺丝薄膜(分相前)应力应变曲线；虚线“--1”表示一次成型的 凝胶纤维复合支架材料(分相后)应力应变曲线。经计算，分相前纤维薄膜弹性模量为：148.23±21.68MP；分相后纤维薄膜弹性模量为：180.55±60.46MPa。可见，同一纤维薄膜分相后，弹性模量显著增加。
虽然，上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
工业实用性
本发明提供了一种一次成型的凝胶纤维复合支架材料及其制备方法与应用。采用本发明方法可快速制备凝胶纤维复合材料，较其他现有细胞外基质材料制备工艺更简单，更易储存和运输，成本更低，有利于广泛应用于基础研究。本发明凝胶纤维复合支架材料生物相容性高，弹性模量更高，在皮肤、器官表面贴合度好，更适应用于细胞培养基底、移植材料。本发明在生物技术等领域具有广阔的应用前景及良好的工业实用性。

Claims (9)

  1. 一种一次成型的凝胶纤维复合支架材料的制备方法，其特征在于，包括通过高压静电方法制备电纺丝薄膜；然后浸泡于相分离溶液中制得；所述制备电纺丝薄膜的原料包括聚己内酯、明胶、I型胶原蛋白。
  2. 根据权利要求1所述的制备方法，其特征在于，所述制备电纺丝薄膜的原料聚己内酯、明胶、I型胶原蛋白的质量比为10-20∶10-20∶5-10；优选为10∶10∶5。
  3. 根据权利要求1或2所述的制备方法，其特征在于，制备电纺溶液的溶剂为三氟乙醇。
  4. 根据权利要求1或2所述的制备方法，其特征在于，制备电纺丝薄膜的条件包括：电压15-20kv，电纺距离10-20cm，电纺时间10-60min。
  5. 根据权利要求1或2所述的制备方法，其特征在于，所述相分离溶液为水溶性碳二亚胺和N-羟基琥珀酰亚胺的混合溶液；优选地，其中水溶性碳二亚胺和N-羟基琥珀酰亚胺的摩尔浓度分别为0.05-0.1M；进一步优选均为0.05M。
  6. 根据权利要求5所述的制备方法，其特征在于，所述相分离溶液中还含有透明质酸钠。
  7. 根据权利要求1-6任一项所述的制备方法，其特征在于，包括：
    1)电纺溶液配制：将聚己内酯、明胶、I型胶原蛋白分别溶于三氟乙醇中，磁力搅拌3-6小时，制成质量分数10-20％聚己内酯溶液、10-15％明胶溶液、5-10％的I型胶原蛋白溶液；
    2)高压静电纺丝：以步骤1)制备的聚己内酯溶液、明胶溶液和I型胶原蛋白溶液为原料，进行高压静电纺丝，制得电纺丝薄膜；
    电纺条件：电压为15-20kv，电纺距离为10-20cm，电纺针头型号为12G，电纺时间为10-60min；
    3)相分离溶液配制：分别配制1M水溶性碳二亚胺溶液和1M的N-羟基琥珀酰亚胺溶液；将该两种溶液等体积完全混合后，稀释10倍，制得相分离溶液；
    或者进一步将所制得的相分离溶液与质量体积分数为1％的透明质酸钠水溶液按1∶1的体积混合；
    4)将步骤2)制得的电纺丝薄膜浸泡于步骤3)制得的相分离溶液中，作用 至少20min，用纯水洗净，即得。
  8. 权利要求1-7任一项所述方法制备的一次成型的凝胶纤维复合支架材料。
  9. 权利要求8所述一次成型的凝胶纤维复合支架材料在用作细胞培养基底、移植材料方面的应用。
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