WO2022135454A1 - 一种长效超疏水抗凝生物瓣膜及其制备方法 - Google Patents

一种长效超疏水抗凝生物瓣膜及其制备方法 Download PDF

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WO2022135454A1
WO2022135454A1 PCT/CN2021/140378 CN2021140378W WO2022135454A1 WO 2022135454 A1 WO2022135454 A1 WO 2022135454A1 CN 2021140378 W CN2021140378 W CN 2021140378W WO 2022135454 A1 WO2022135454 A1 WO 2022135454A1
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superhydrophobic
acting
long
biological valve
preparing
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PCT/CN2021/140378
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English (en)
French (fr)
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杨立
王云兵
罗日方
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吉林启明皓月生物科技有限公司
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Priority to EP21909450.5A priority Critical patent/EP4249009A1/en
Publication of WO2022135454A1 publication Critical patent/WO2022135454A1/zh
Priority to US18/211,274 priority patent/US20230330299A1/en

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    • 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
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A61L27/3625—Vascular tissue, e.g. heart valves
    • 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
    • A61L27/28—Materials for coating prostheses
    • 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
    • A61L27/28—Materials for coating prostheses
    • A61L27/30—Inorganic materials
    • A61L27/306—Other specific inorganic materials not covered by A61L27/303 - A61L27/32
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    • 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
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • 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
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
    • A61L27/3687—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
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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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/34—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from hydroxy compounds or their metallic derivatives
    • C08G65/38—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from hydroxy compounds or their metallic derivatives derived from phenols
    • C08G65/44—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from hydroxy compounds or their metallic derivatives derived from phenols by oxidation of phenols
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/18—Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
    • 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
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/04—Coatings containing a composite material such as inorganic/organic, i.e. material comprising different phases
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/20—Materials or treatment for tissue regeneration for reconstruction of the heart, e.g. heart valves
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/40—Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking

Definitions

  • the invention belongs to the technical field of valve material preparation, in particular to a long-acting superhydrophobic anticoagulation biological valve and a preparation method thereof.
  • the superhydrophobic surface of the bionic lotus leaf structure has been widely studied due to its high water contact angle (>150°) and low rolling angle, and is mainly used in the fields of self-cleaning, moisture resistance, water-oil separation, corrosion resistance, and antifouling.
  • the superhydrophobic surface has a lower platelet adhesion ability compared with the superhydrophilic surface, indicating that the superhydrophobic surface has more excellent antithrombotic properties.
  • the current superhydrophobic surfaces are mainly prepared on the surface of metals, polymers and inorganic materials, and there are few studies on the preparation of superhydrophobic coatings on the surface of biological valve materials. Therefore, the preparation of superhydrophobic coatings with high water contact angle and low adhesion on the surface of biological valve materials Superhydrophobic coatings are crucial to resist thrombosis after valve implantation.
  • the present invention provides a long-acting super-hydrophobic anticoagulation biological valve and a preparation method thereof, which can prepare a layer of high-water-resistant biological valve material on the surface of the biological valve material without changing the mechanical properties of the valve body.
  • a preparation method of a long-acting superhydrophobic anticoagulation biological valve comprising the following steps:
  • step (2) placing the biological valve material treated in step (1) in an acid solution containing polyphenol compounds and metal ions, adding an oxidant to react, and embedding the biological valve material on the surface of the biological valve material by polymerizing polyphenol compounds and metal ions. , and nanoparticles containing double bond groups;
  • step (3) reacting the biological valve material treated in step (2) with a hydrophobic substance, and grafting the hydrophobic substance on the surface of the nanoparticle to form a hydrophobic coating.
  • the glutaraldehyde treatment in step (1) is specifically: soaking the biological valve material in the glutaraldehyde solution for 48-96 hours.
  • step (2) the concentration of the oxidant is 20 ⁇ M ⁇ 1mM, and the reaction conditions are 10 ⁇ 40°C for 20 ⁇ 120min.
  • the molar mass ratio of the polyphenol compound and the metal ion is 1:0.01 ⁇ 1.
  • polyphenolic compounds are tannic acid, gallic acid, salvianolic acid B, epigallocatechin gallate, epicatechin gallate, epicatechin, epigallocatechin, phthalate At least one of phenol, pyrogallol, and flavonoids.
  • the metal ion is at least one of copper ion, silver ion and iron ion.
  • the pH value of the acid solution is 4-6.
  • the acid solution is acetic acid-acetate buffer, 2-(N-morpholine) ethanesulfonic acid buffer, glycine-hydrochloric acid buffer, phthalic acid-hydrochloric acid buffer, potassium hydrogen phthalate- Sodium hydroxide buffer, disodium hydrogen phosphate-citric acid buffer or citric acid-sodium hydroxide-hydrochloric acid buffer.
  • the oxidant is a water-soluble oxidant, specifically at least one of hydrogen peroxide, ammonium persulfate, copper chloride, ferric chloride, concentrated nitric acid, sodium periodate, potassium permanganate and potassium dichromate .
  • step (3) is:
  • step (2) The product obtained in step (2) is immersed in a hydrophobic substance with a concentration of 50 ⁇ M to 1 mM for 10 to 30 minutes, and a hydrophobic coating can be formed on the surface of the nanoparticles by the method of click chemistry.
  • hydrophobic substance is perfluoropentadecane, perfluorododecanoic acid, 1H,1H,2H,2H-perfluorododecanethiol, perfluorobutylethylene, octadecanoyl chloride or stearic acid .
  • the biological valve material is aortic valve, pulmonary valve, venous valve, mitral valve or tricuspid valve.
  • the source of biological valve material is porcine pericardium, bovine pericardium and the like.
  • the present invention also provides a long-acting superhydrophobic anticoagulant biological valve, comprising a biological valve material, and nanoparticles containing double bond groups which are polymerized by polyphenol compounds and metal ions embedded on the surface of the biological valve material. and grafting hydrophobic substances on the surface of the nanoparticles to form a hydrophobic coating.
  • the long-acting superhydrophobic anticoagulant biological valve can be prepared by any of the above-mentioned preparation methods.
  • the present invention utilizes the residual amino groups and aldehyde groups on the surface of the biological valve material, and can introduce polyphenol compounds through the reactivity of polyphenol-related functional groups.
  • the nanoparticles obtained by the oxidation of polyphenol compounds and metals in the presence of strong oxidants The product is rich in double bond groups, and a hydrophobic fluoride modified with functional groups can be subsequently introduced by click chemistry to prepare a biological valve material with long-lasting superhydrophobic anticoagulation properties.
  • the method of the invention has simple and controllable preparation process, mild conditions, stable super-hydrophobic performance of the coating, and can effectively resist platelet adhesion and thrombus formation on the valve surface.
  • the present invention is inspired by the mild self-polymerization reaction conditions of polyphenols and the reaction mechanism of metal ions, double bonds and sulfhydryl groups, without affecting the body performance of the biological valve material, through a simple and stable operation process.
  • the superhydrophobic coating with long-lasting high water contact angle and low rolling angle achieves long-lasting anticoagulation requirements by resisting the adsorption of plasma proteins.
  • Fig. 1 is the electron microscope image of the surface of the superhydrophobic fluoride coating of the biological valve prepared in Example 2;
  • Fig. 2 is the contact angle result of the coating of Fig. 1;
  • Fig. 3 is the in vitro platelet adhesion result of traditional glutaraldehyde valve
  • FIG. 4 is an in vitro platelet adhesion result of the superhydrophobic modified valve material prepared in Example 2 of the present invention.
  • a preparation method of a long-acting superhydrophobic anticoagulation biological valve comprising the following steps:
  • a preparation method of a long-acting superhydrophobic anticoagulation biological valve comprising the following steps:
  • step (2) Immerse the porcine pericardial valve material treated in step (1) in a buffer solution containing epigallocatechin gallate and Ag + ions in a molar mass ratio of 1:0.05, and the buffer solution is glycine-hydrochloric acid
  • the pH of the buffer solution is 4, and then a concentrated nitric acid oxidant with a concentration of 80 ⁇ M is added to the solution, and the reaction is carried out at 25 ° C for 60 minutes, so that epigallocatechin gallate undergoes oxidative polymerization and is chelated with Ag + ions.
  • Ag + -containing polyphenol nanoparticles are generated on the surface of the valve material;
  • a preparation method of a long-acting superhydrophobic anticoagulation biological valve comprising the following steps:
  • a preparation method of a long-acting superhydrophobic anticoagulation biological valve comprising the following steps:
  • FIG. 1 The electron microscope image of the hydrophobic coating of the biological valve material prepared in Example 2 is shown in FIG. 1 , and the contact angle detection result thereof is shown in FIG. 2 .
  • the hydrophobic coating prepared in the present application is uniformly distributed on the surface of the valve material, and has a long-lasting high water contact angle and low rolling angle.
  • the biological valve material prepared in the present application has an excellent anticoagulant effect.

Abstract

一种长效超疏水抗凝生物瓣膜及其制备方法，该制备方法包括以下步骤：(1)采用戊二醛处理生物瓣膜材料；(2)将经步骤(1)处理后的生物瓣膜材料置于含有多酚化合物和金属离子的酸液中，加入氧化剂进行反应；(3)将经步骤(2)处理后的生物瓣膜材料与疏水性物质进行反应。该方法在不影响瓣膜本体性能的同时，通过简单、稳定的操作工艺即在生物瓣膜表面制备具有长效的高水接触角和低滚动角的超疏水涂层，通过阻抗血浆蛋白的吸附实现长效抗凝血需求。

Description

一种长效超疏水抗凝生物瓣膜及其制备方法 技术领域
本发明属于瓣膜材料制备技术领域，具体涉及一种长效超疏水抗凝生物瓣膜及其制备方法。
 背景技术
随着我国社会人口结构步入老龄化阶段，严重瓣膜狭窄、反流等患者较前明显增多，75岁以上人群总发病率较高，一旦患者出现症状而尚未接受治疗， 2到3年内死亡率接近50%。微创介入瓣膜术因其手术创伤小、风险较低、效果佳，正成为被越来越多患者所接受的一项重要治疗措施，而随着微创介入技术的深入发展，目前也遇到许多相应的问题。其中在介入治疗中生物瓣膜的植入会导致血栓形成，瓣膜表面的血栓脱落将加大术后卒中的风险；而且瓣膜表面血栓形成将给瓣膜的耐久性带来严重的影响。所以生物瓣膜材料本身具有优良的长效抗凝血作用对瓣膜的耐久性和患者生命安全则至关重要。
仿生荷叶结构的超疏水表面因具有高的水接触角（>150°）和低滚动角而被广泛研究，主要应用于自清洁、防潮、水-油分离、抗腐蚀和抗污等领域。普通的生物材料表面一旦与血液或者体液接触，就会有大量的蛋白或细胞就会粘附在材料表面，这会材料的性能带来严重的影响；而超亲水表面和超疏水表面则都具有良好的抗污（阻抗蛋白、细胞和微生物的非特异性粘附）效果。有研究报道，与超亲水表面相比，超疏水表面具有更低的血小板粘附能力，表明超疏水表面具有更优异的抗血栓性能。目前的超疏水表面主要制备在金属、聚合物和无机材料表面，在生物瓣膜材料表面制备超疏水涂层研究较少，因此，在生物瓣膜材料表面制备具有高水接触角和低粘附力的超疏水涂层来阻抗瓣膜植入体内后的血栓形成至关重要。
 技术问题
针对现有技术中的上述不足，本发明提供一种长效超疏水抗凝生物瓣膜及其制备方法，可以在不改变瓣膜本体的机械性能下，在生物瓣膜材料的表面制备一层具有高水接触角和低滚动角的超疏水涂层，从而提高生物瓣膜在植入体内后的抗血栓性能。
 技术解决方案
为实现上述目的，本发明解决其技术问题所采用的技术方案是：
一种长效超疏水抗凝生物瓣膜的制备方法，包括以下步骤：
（1）采用戊二醛处理生物瓣膜材料；
（2）将经步骤（1）处理后的生物瓣膜材料置于含有多酚化合物和金属离子的酸液中，加入氧化剂进行反应，在生物瓣膜材料表面嵌入由多酚化合物和金属离子聚合而成，且含有双键基团的纳米颗粒；
（3）将经步骤（2）处理后的生物瓣膜材料与疏水性物质进行反应，在纳米颗粒表面接枝疏水性物质形成疏水涂层。
进一步的，步骤（1）中戊二醛处理具体为：将生物瓣膜材料浸泡于戊二醛溶液中48~96h。
进一步地，步骤（2）中，所述氧化剂的浓度为20µM~1mM，反应条件为10~40℃反应20~120min。
进一步地，多酚化合物和金属离子的摩尔质量比为1:0.01~1。
进一步地，多酚化合物为单宁酸、没食子酸、丹酚酸B、表没食子儿茶素没食子酸酯、表儿茶素没食子酸酯、表儿茶素、表没食子儿茶素、邻苯二酚、邻苯三酚和黄酮类中的至少一种。
进一步地，金属离子为铜离子、银离子和铁离子中的至少一种。
进一步地，酸液pH值为4~6。
进一步地，酸液为乙酸-乙酸盐缓冲液、2-（N-吗啡啉）乙磺酸缓冲液、甘氨酸-盐酸缓冲液、邻苯二甲酸-盐酸缓冲液、邻苯二甲酸氢钾-氢氧化钠缓冲液、磷酸氢二钠-柠檬酸缓冲液或柠檬酸-氢氧化钠-盐酸缓冲液。
进一步地，氧化剂为水溶性氧化剂，具体为过氧化氢、过硫酸铵、氯化铜、三氯化铁、浓硝酸、高碘酸钠、高锰酸钾和重铬酸钾中的至少一种。
进一步地，步骤（3）的具体过程为：
将经步骤（2）所得产物置于浓度为50µM~1mM的疏水性物质中浸泡10~30min，通过点击化学的方法即可在纳米颗粒表面形成疏水涂层。
进一步地，疏水性物质为全氟十五烷、全氟十二烷酸、1H,1H,2H,2H-全氟十二烷硫醇、全氟丁基乙烯、十八烷酰氯或硬脂酸。
进一步地，生物瓣膜材料为主动脉瓣、肺动脉瓣、静脉瓣、二尖瓣或三尖瓣。
进一步地，生物瓣膜材料来源为猪心包、牛心包等。
本发明还提供了一种长效超疏水抗凝生物瓣膜，包括生物瓣膜材料、在所述生物瓣膜材料的表面嵌入由多酚化合物和金属离子聚合而成，且含有双键基团的纳米颗粒以及在所述纳米颗粒表面接枝疏水性物质形成疏水涂层。
所述长效超疏水抗凝生物瓣膜可采用上述任一制备方法制得。
 有益效果
本发明的有益效果为：
1、本发明利用生物瓣膜材料表面残留的氨基、醛基基团，通过多酚相关官能团的反应性，可以引入多酚化合物，此外多酚化合物和金属在强氧化剂存在条件下氧化得到的纳米颗粒产物富含双键基团，可以通过点击化学后续引入带有官能团修饰的疏水性氟化物，制备具有长效超疏水抗凝性能的生物瓣膜材料。本发明方法制备工艺简单、可控，条件温和，涂层超疏水性能稳定，可以有效阻抗瓣膜表面血小板粘附和血栓形成。
2、本发明根据多酚温和的自聚合反应条件和金属离子、双键与巯基反应机理启发，在不影响生物瓣膜材料本体性能的同时，通过简单、稳定的操作工艺即在生物瓣膜材料表面制备具有长效的高水接触角和低滚动角的超疏水涂层，通过阻抗血浆蛋白的吸附实现长效抗凝血需求。
 附图说明
图1 为实施例2制备得到的生物瓣膜超疏水氟化物涂层表面电镜图；
图2为图1涂层的接触角结果；
图3为传统戊二醛瓣膜的体外血小板粘附结果；
图4为本发明实施例2制备得到的超疏水改性瓣膜材料的体外血小板粘附结果。
 本发明的实施方式
下面对本发明的具体实施方式进行描述，以便于本技术领域的技术人员理解本发明，但应该清楚，本发明不限于具体实施方式的范围，对本技术领域的普通技术人员来讲，只要各种变化在所附的权利要求限定和确定的本发明的精神和范围内，这些变化是显而易见的，一切利用本发明构思的发明创造均在保护之列。
实施例1 
一种长效超疏水抗凝生物瓣膜的制备方法，包括以下步骤：
（1）对戊二醛交联后的猪心包瓣膜材料进行处理；
（2）将经步骤（1）处理后的猪心包瓣膜材料浸没在含有摩尔质量比例为1:0.1的单宁酸和Cu 2+离子的缓冲液中，缓冲液为乙酸-乙酸钠，其pH为4，然后在溶液中加入浓度为20µM的高碘酸钠氧化剂，于25℃反应40min，使单宁酸发生氧化聚合反应同时与Cu 2+离子螯合，在生物瓣膜材料表面生成含Cu 2+的多酚纳米颗粒；
（3）将表面含有Cu 2+的多酚纳米颗粒猪心包瓣膜材料置于摩尔浓度为0.8mM的1H,1H,2H,2H-全氟十二烷硫醇中浸泡20min，然后通过化学接枝的方法在瓣膜材料表面生成一层均匀的氟化物涂层，从而制备得到表面具有超疏水性能涂层的生物瓣膜材料。
实施例2
一种长效超疏水抗凝生物瓣膜的制备方法，包括以下步骤：
（1）对戊二醛交联后的猪心包瓣膜材料进行处理；
（2）将经步骤（1）处理后的猪心包瓣膜材料浸没在含有摩尔质量比例为1:0.05的表没食子儿茶素没食子酸酯和Ag +离子的缓冲液中，缓冲液为甘氨酸-盐酸缓冲液，其pH为4，然后在溶液中加入浓度为80µM的浓硝酸氧化剂，于25℃反应60min，使表没食子儿茶素没食子酸酯发生氧化聚合反应同时与Ag +离子螯合，在生物瓣膜材料表面生成含Ag +的多酚纳米颗粒；
（3）将表面含有Ag +的多酚纳米颗粒猪心包瓣膜材料置于摩尔浓度为0.5mM的全氟十二烷酸中浸泡25min，然后通过化学接枝的方法在瓣膜材料表面生成一层均匀致密的氟化物涂层，从而制备得到表面具有超疏水性能涂层的生物瓣膜材料。
实施例3
一种长效超疏水抗凝生物瓣膜的制备方法，包括以下步骤：
（1）对戊二醛交联后的牛心包瓣膜材料进行处理；
（2）将经步骤（1）处理后的猪心包瓣膜材料浸没在含有摩尔质量比例为1:0.2的表儿茶素和Ag +离子的缓冲液中，缓冲液为磷酸氢二钠-柠檬酸缓冲液，其pH为4，然后在溶液中加入浓度为0.05mM的高锰酸钾氧化剂，于20℃反应40min，使表儿茶素发生氧化聚合反应同时与Ag +离子螯合，在生物瓣膜材料表面生成含Ag +的多酚纳米颗粒；
（3）将表面含有Ag +的多酚纳米颗粒牛心包瓣膜材料置于摩尔浓度为0.2mM的十八烷酰氯中浸泡10min，然后通过化学接枝的方法在瓣膜材料表面生成一层均匀致密的疏水涂层，从而制备得到表面具有超疏水性能涂层的生物瓣膜材料。
实施例4
一种长效超疏水抗凝生物瓣膜的制备方法，包括以下步骤：
（1）对戊二醛交联后的牛心包瓣膜材料进行处理；
（2）将经步骤（1）处理后的猪心包瓣膜材料浸没在含有摩尔质量比例为1:0.05的邻苯三酚和Fe 3+离子的混合溶液中，缓冲液为柠檬酸-氢氧化钠-盐酸缓冲液，其pH为4，然后在溶液中加入浓度为0.01mM的过硫酸铵氧化剂，于20℃反应60min，使邻苯三酚发生氧化聚合反应同时与Fe 3+离子螯合，在生物瓣膜材料表面生成含Fe 3+的多酚纳米颗粒；
（3）将表面含有Fe 3+的多酚纳米颗粒牛心包瓣膜材料置于摩尔浓度为0.05mM的硬脂酸中浸泡30min，然后通过化学接枝的方法在瓣膜材料表面生成一层均匀致密的疏水涂层，从而制备得到表面具有超疏水性能涂层的生物瓣膜材料。
实验例
1、实施例2制备得到的生物瓣膜材料疏水涂层的电镜图如图1所示，其接触角检测结果如图2所示。
如图1和图2所示，本申请制备得到的疏水涂层在瓣膜材料表面均匀分布，且具有长效的高水接触角和低滚动角。
2、以戊二醛瓣膜为对照组，实施例2制备得到的生物瓣膜材料为实验组，进行体外血小板粘附实验，分别检测其抗凝血性能，其结果见图3和图4。
如图3和图4所示，与戊二醛瓣膜相比，本申请制备得到的生物瓣膜材料具有优异的抗凝血效果。

Claims (14)

  1. 一种长效超疏水抗凝生物瓣膜的制备方法，其特征在于，包括以下步骤：
    （1）采用戊二醛处理生物瓣膜材料；
    （2）将经步骤（1）处理后的生物瓣膜材料置于含有多酚化合物和金属离子的酸液中，加入氧化剂进行反应；
    （3）将经步骤（2）处理后的生物瓣膜材料与疏水性物质进行反应。
  2. 根据权利要求1所述的长效超疏水抗凝生物瓣膜的制备方法，其特征在于，步骤（1）中戊二醛处理具体为：将生物瓣膜材料浸泡于戊二醛溶液中48~96h。
  3. 根据权利要求1所述的长效超疏水抗凝生物瓣膜的制备方法，其特征在于，步骤（2）中，所述氧化剂的浓度为20µM~1mM，反应条件为10~40℃反应20~120min。
  4. 根据权利要求1所述的长效超疏水抗凝生物瓣膜的制备方法，其特征在于，所述多酚化合物和金属离子的摩尔质量比为1:0.01~1。
  5. 根据权利要求4所述的长效超疏水抗凝生物瓣膜的制备方法，其特征在于，所述多酚化合物为单宁酸、没食子酸、丹酚酸B、表没食子儿茶素没食子酸酯、表儿茶素没食子酸酯、表儿茶素、表没食子儿茶素、邻苯二酚、邻苯三酚和黄酮类中的至少一种。
  6. 根据权利要求4所述的长效超疏水抗凝生物瓣膜的制备方法，其特征在于，所述金属离子为铜离子、银离子和铁离子中的至少一种。
  7. 根据权利要求1所述的长效超疏水抗凝生物瓣膜的制备方法，其特征在于，所述酸液pH为4~6。
  8. 根据权利要求1所述的长效超疏水抗凝生物瓣膜的制备方法，其特征在于，所述酸液为乙酸-乙酸盐缓冲液、2-（N-吗啡啉）乙磺酸缓冲液、甘氨酸-盐酸缓冲液、邻苯二甲酸-盐酸缓冲液、邻苯二甲酸氢钾-氢氧化钠缓冲液、磷酸氢二钠-柠檬酸缓冲液或柠檬酸-氢氧化钠-盐酸缓冲液。
  9. 根据权利要求1所述的长效超疏水抗凝生物瓣膜的制备方法，其特征在于，所述氧化剂为水溶性氧化剂，具体为过氧化氢、过硫酸铵、氯化铜、三氯化铁、浓硝酸、高碘酸钠、高锰酸钾和重铬酸钾中的至少一种。
  10. 根据权利要求1所述的长效超疏水抗凝生物瓣膜的制备方法，其特征在于，步骤（3）的具体过程为：
    将经步骤（2）处理后的生物瓣膜材料置于浓度为50µM~1mM的疏水性物质中浸泡10~30min。
  11. 根据权利要求10所述的长效超疏水抗凝生物瓣膜的制备方法，其特征在于，所述疏水性物质为全氟十五烷、全氟十二烷酸、1H,1H,2H,2H-全氟十二烷硫醇、全氟丁基乙烯、十八烷酰氯或硬脂酸。
  12. 根据权利要求1所述的长效超疏水抗凝生物瓣膜的制备方法，其特征在于，所述生物瓣膜材料为主动脉瓣、肺动脉瓣、静脉瓣、二尖瓣或三尖瓣。
  13. 根据权利要求12所述的长效超疏水抗凝生物瓣膜的制备方法，其特征在于，所述生物瓣膜材料来源为猪心包或牛心包。
  14. 一种长效超疏水抗凝生物瓣膜，其特征在于，包括生物瓣膜材料、在所述生物瓣膜材料的表面嵌入由多酚化合物和金属离子聚合而成，且含有双键基团的纳米颗粒以及在所述纳米颗粒表面接枝疏水性物质形成疏水涂层。
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