WO2021254346A1 - 一种具有协同抗凝及抗钙化功能的瓣膜材料及其制备方法 - Google Patents

一种具有协同抗凝及抗钙化功能的瓣膜材料及其制备方法 Download PDF

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WO2021254346A1
WO2021254346A1 PCT/CN2021/100181 CN2021100181W WO2021254346A1 WO 2021254346 A1 WO2021254346 A1 WO 2021254346A1 CN 2021100181 W CN2021100181 W CN 2021100181W WO 2021254346 A1 WO2021254346 A1 WO 2021254346A1
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Prior art keywords
valve material
valve
anticalcification
preparing
functions according
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PCT/CN2021/100181
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English (en)
French (fr)
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王云兵
杨立
罗日方
李林华
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吉林启明皓月生物科技有限公司
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Priority to EP21826690.6A priority Critical patent/EP4137169A4/en
Priority to US18/000,374 priority patent/US20230218803A1/en
Publication of WO2021254346A1 publication Critical patent/WO2021254346A1/zh

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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
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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
    • 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
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    • 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
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    • 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
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    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
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Definitions

  • the invention belongs to the technical field of biomedical materials and medical device modification, and specifically relates to a valve material with synergistic anticoagulation and anticalcification functions and a preparation method thereof.
  • the valve material prepared according to the method can be used for aortic valve, Valve materials required for pulmonary valve, venous valve, mitral valve and tricuspid valve replacement.
  • Transcatheter interventional valve therapy is becoming the mainstream direction in valve replacement surgery.
  • the current relative development of technologies includes aortic valve, pulmonary valve, mitral valve, tricuspid valve and venous valve replacement.
  • the current mainstream valve materials used for interventional valve surgery are heterogeneous biological valve materials, which are mainly derived from porcine pericardium, bovine pericardium, small intestinal submucosa and fish bladder.
  • By chemically cross-linking animal-derived valve materials the mechanical strength and service life of the materials can be improved.
  • most of the more mature commercial cross-linking methods are cross-linking methods based on glutaraldehyde. Materials cross-linked with glutaraldehyde have also been widely used in the market.
  • Interventional valve replacement surgery has relatively special requirements for biological valve materials, which mainly include mechanical properties, heat shrinkage temperature, fluid mechanical properties, anti-calcification, and anti-coagulation requirements.
  • biological valve materials which mainly include mechanical properties, heat shrinkage temperature, fluid mechanical properties, anti-calcification, and anti-coagulation requirements.
  • the anti-calcification performance is almost a function that all valve materials must have, and it is also an effective guarantee for improving the service life of the valve.
  • the requirements for the antithrombotic performance of valve materials are also particularly prominent.
  • glutaraldehyde cross-linked valves have many shortcomings, such as calcification and cytotoxicity caused by aldehyde residues and the risk of thrombosis, it is still the mainstream method adopted by commercial biological valves.
  • the simultaneous development of many new cross-linking methods is expected to become an alternative to glutaraldehyde.
  • new cross-linked valves are still far from commercialization. Therefore, in response to the urgent need to improve the anti-calcification and anti-thrombotic properties of valve materials in clinical applications of pulmonary valve and venous valve, the development of pulmonary artery/venous valve materials with excellent anti-coagulation and anti-calcification properties has great clinical applications and Market value.
  • the present invention provides a valve material with synergistic anticoagulation and anticalcification functions and a preparation method thereof.
  • the problem of easy calcification and thrombosis caused by the valve material prepared by this method can be used as the valve material required for aortic valve, pulmonary valve, venous valve, mitral valve and tricuspid valve replacement.
  • a method for preparing a valve material with synergistic anticoagulation and anticalcification functions includes the following steps:
  • step (2) Immerse the valve material processed in step (1) in an amine-based compound sealing solution for processing;
  • step (3) Put the valve material processed in step (2) into a reaction solution containing an anticoagulant and a cross-linking agent for processing;
  • step (3) The valve material processed in step (3) is cleaned to obtain it.
  • a method for preparing a valve material with synergistic anticoagulation and anticalcification functions includes the following steps:
  • step (2) Immerse the valve material treated in step (1) in an amine-based compound sealing solution for 0.5-6 hours, and then block the remaining aldehyde groups after glutaraldehyde cross-linking;
  • step (3) Put the valve material processed in step (2) into the reaction solution containing anticoagulant and cross-linking agent, and cross-link it at 4°C-37°C for 6-24 hours;
  • valve material processed in step (3) is cleaned and prepared, and then the valve material is stored in a mixed solvent of glutaraldehyde or isopropanol/glycerol.
  • animal-derived biological valve material includes one of porcine pericardium, bovine pericardium, and small intestinal submucosa.
  • the concentration of glutaraldehyde in step (1) is 0.3%-3%.
  • the crosslinking treatment time of glutaraldehyde in step (1) is 24-96h, and the crosslinking pH value is 6-9.
  • step (1) the concentration of glutaraldehyde is 0.3%-3%, the crosslinking treatment time is 24-96h, and the crosslinking pH value is 6-9.
  • step (1) the concentration of glutaraldehyde is 1%, the cross-linking treatment time is 72 hours, and the cross-linking pH value is 7.
  • the glutaraldehyde cross-linking method in step (1) includes one-step cross-linking, multi-step cross-linking and concentration gradient cross-linking, and the solvent used for cross-linking is water, PBS or other salt ion buffer.
  • the amino compound in step (2) carries at least 3 primary amino groups.
  • the amine compound in step (2) includes one of polyethyleneimine, chitosan, carboxymethyl chitosan, polylysine, polyarginine, and hexamethylene diamine.
  • concentration of the compound blocking solution is 0.1-100 mg/mL.
  • step (2) the concentration of the amino compound blocking solution is 0.1-100 mg/mL.
  • step (2) the concentration of the amine-based compound in the blocking solution is 10 mg/mL.
  • step (2) the treated valve material is immersed in an amine-based compound sealing solution for 0.5-6 hours.
  • the anticoagulant compound in step (3) includes heparin, heparan sulfate, bivalerutin and hirudin.
  • the crosslinking agent includes 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride)/N-hydroxysuccinimide, 1-cyclohexyl- One of 2-morpholinoethylcarbodiimide p-toluenesulfonate and N,N'-dicyclohexylcarbodiimide.
  • the solvent in the reaction solution in step (3) includes water, morpholine ethanesulfonic acid sodium salt solution and PBS buffer.
  • step (3) the concentration of the anticoagulant in the reaction solution is 0.2 mg/mL-20 mg/mL, and the molar ratio of the anticoagulant to the cross-linking agent is 0.2-5:0.2-2.
  • step (3) the concentration of the crosslinking agent in the reaction solution is 0.1-5 mg/mL.
  • step (3) the concentration of the anticoagulant in the reaction solution is 5 mg/mL, and the molar ratio of the anticoagulant to the crosslinking agent is 0.3:2.
  • valve material with synergistic anticoagulation and anticalcification functions is prepared by the above method.
  • the glutaraldehyde cross-linked valve material is a material with oriented fibers and a pore structure.
  • the fibers contain aldehyde groups, carboxyl groups and other groups.
  • the present invention realizes valve resistance by infusing polyamine-based compounds and then fixing anticoagulant compounds.
  • the amplification effect of coagulation provides better antithrombotic activity for the complex blood flow environment of pulmonary artery/venous valve materials; the introduction of polyamine-based compounds, through the Schiff base between the amino group on the polyamine-based compound and the aldehyde group on the valve material
  • the reaction directly blocks the residual aldehyde groups to prevent calcium ions from adhering to the residual aldehyde groups to form calcium salt crystals, improve the anti-calcification ability of the valve material, thereby increasing the service life of the valve; at the same time, the carboxyl group on the anticoagulant can be combined with the introduced amine group
  • the amide bond is formed through dehydration and condensation to achieve covalent fixation, thereby improving the anticoagulation effect of the valve.
  • Figure 1 is a diagram of thrombus deposition on the surface of glutaraldehyde cross-linked membrane
  • Figure 2 is a diagram of thrombus deposition on the surface of the modified valve material
  • the left picture is a calcification picture of the glutaraldehyde cross-linked valve material after subcutaneous implantation 3 months
  • the right picture is a calcification picture of the modified valve material 3 months after subcutaneous implantation.
  • a valve material with synergistic anticoagulation and anticalcification functions, and its preparation method includes the following steps:
  • step (2) Immerse the valve material treated in step (1) in a sealing solution (pH 7.4) containing polyethyleneimine (10mg/mL), treat it at room temperature for 0.5h, and seal the remaining glutaraldehyde after cross-linking The aldehyde group;
  • a valve material with synergistic anticoagulation and anticalcification functions, and its preparation method includes the following steps:
  • step (2) Immerse the valve material treated in step (1) in a blocking solution (pH 7.4) containing polylysine (5mg/mL), treat it at room temperature for 6 hours, and seal the remaining glutaraldehyde after cross-linking The aldehyde group;
  • a valve material with synergistic anticoagulation and anticalcification functions, and its preparation method includes the following steps:
  • valve material is immersed in a sealing solution (pH 7.4) containing hexamethylene diamine (4 mg/mL), and treated at room temperature for 3 hours to block the remaining aldehyde groups after glutaraldehyde cross-linking group;
  • a valve material with synergistic anticoagulation and anticalcification functions, and its preparation method includes the following steps:
  • valve material Immerse the valve material in a sealing solution (pH 5) containing chitosan (10 mg/mL), treat it at room temperature for 6 hours, and block the remaining aldehyde groups after glutaraldehyde cross-linking;
  • a valve material with synergistic anticoagulation and anticalcification functions, and its preparation method includes the following steps:
  • step (2) Immerse the valve material treated in step (1) in a sealing solution (pH 7.4) containing polyarginine (5mg/mL), treat it at room temperature for 4 hours, and seal the glutaraldehyde after cross-linking.
  • a sealing solution pH 7.4 containing polyarginine (5mg/mL)
  • polyarginine 5mg/mL
  • Example 1 Take the valve prepared in Example 1 as an example, observe the surface of the valve material after glutaraldehyde cross-linking, and then observe the blood clot deposition on the surface of the valve after the modified rabbit half body blood circulation test for 2 hours. The specific results are shown in Figure 1. And Figure 2; the valve material cross-linked with glutaraldehyde and the modified valve material in Example 1 were implanted subcutaneously for 3 months respectively, and the calcification of the valve material was observed, see Figure 3 for details.
  • FIG. 1 shows that in the traditional unmodified glutaraldehyde cross-linking process, a large number of thrombi are deposited on the valve material, and a large number of red blood cells and a large number of fiber networks are interlaced.
  • Figure 2 shows that after the anticoagulation modification described in the method in Example 1, the surface of the valve material is still smooth and there is no obvious thrombus deposition, which confirms the excellent blood compatibility and anticoagulation function of the modified valve material.

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Abstract

本发明提供了一种具有协同抗凝及抗钙化功能的瓣膜材料及其制备方法，其制备方法包括以下步骤：对动物源生物瓣膜材料进行戊二醛交联处理；将处理后的瓣膜材料浸入含有胺基化合物的封闭液中处理0.5-6h，进而封闭戊二醛交联后残留的醛基基团；然后瓣膜材料放入含有抗凝剂和交联剂的反应液中，于4℃-37℃条件下交联处理6-24h；最后对瓣膜材料进行清洗，制得，将瓣膜材料保存于戊二醛或异丙醇/丙三醇的混合溶剂中。该方法可有效解决现有方法制得的瓣膜材料存在的由于醛基残留引发的易钙化和形成血栓的问题，按照本方法制得的瓣膜材料可用作于主动脉瓣、肺动脉瓣、静脉瓣、二尖瓣及三尖瓣置换术所需的瓣膜材料。

Description

一种具有协同抗凝及抗钙化功能的瓣膜材料及其制备方法 技术领域
本发明属于生物医用材料及医疗器械改性技术领域，具体涉及一种具有协同抗凝及抗钙化功能的瓣膜材料及其制备方法，按照本方法制得的瓣膜材料可用作于主动脉瓣、肺动脉瓣、静脉瓣、二尖瓣及三尖瓣置换术所需的瓣膜材料。
 背景技术
经导管介入瓣膜治疗手段正成为瓣膜置换术中的主流方向，目前与之相对发展的技术则包括主动脉瓣、肺动脉瓣、二尖瓣、三尖瓣及静脉瓣置换术等。目前主流用于介入瓣膜术的瓣膜材料为异种生物瓣膜材料，主要是来源于猪心包、牛心包、小肠粘膜下层及鱼鳔等。通过对动物来源的瓣膜材料进行化学交联，可以提升材料的力学强度和使用寿命，目前较为成熟的商业化交联手段多数是基于戊二醛的交联方法，而猪心包和牛心包膜经戊二醛交联后的材料也已经广泛投入市场使用。
介入瓣膜置换术，对于生物瓣膜材料有着较为特殊的需求，主要包括力学性能、热收缩温度、流体力学性能、抗钙化、抗凝血需求等。从瓣膜材料本身角度，抗钙化性能几乎是所有瓣膜材料必须具备的功能，也是提升瓣膜服役寿命的有效保障。其中对于静脉瓣和肺动脉瓣而言，由于其血流环境较为复杂，且流通血液为流速较慢且易凝的静脉血，因此，对瓣膜材料的抗血栓性能要求也格外突出。尽管戊二醛交联瓣膜存在诸多不足，如醛基残留引发的钙化和细胞毒性及致血栓风险，它依旧是目前商业生物瓣膜采取的主流方式。诸多新型交联方法的同步发展有望成为替代戊二醛的方案，然而目前受限于瓣膜灭菌、灭毒工艺及保存工艺上的挑战，新型交联瓣膜离商业化还有一定的距离。因此，针对肺动脉瓣和静脉瓣在临床应用中需要提高瓣膜材料抗钙化和抗血栓性能的迫切需求，开发具有优良抗凝血和抗钙化性能的肺动脉/静脉瓣膜材料，具有极大的临床应用和市场价值。
 技术问题
针对现有技术中存在的上述问题，本发明提供一种具有协同抗凝及抗钙化功能的瓣膜材料及其制备方法，该方法可有效解决现有方法制得的瓣膜材料存在的由于醛基残留引发的易钙化和形成血栓的问题，按照本方法制得的瓣膜材料可用作于主动脉瓣、肺动脉瓣、静脉瓣、二尖瓣及三尖瓣置换术所需的瓣膜材料。
 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：
一种具有协同抗凝及抗钙化功能的瓣膜材料的制备方法，包括以下步骤：
（1）对动物源生物瓣膜材料进行戊二醛交联处理；
（2）将步骤（1）中处理后的瓣膜材料浸入胺基化合物封闭液中处理；
（3）将步骤（2）中处理后的瓣膜材料放入含有抗凝剂和交联剂的反应液中进行处理；
（4）对步骤（3）中处理后的瓣膜材料进行清洗，制得。
一种具有协同抗凝及抗钙化功能的瓣膜材料的制备方法，包括以下步骤：
（1）对动物源生物瓣膜材料进行戊二醛交联处理，使得瓣膜材料可以长久抗腐败；
（2）将步骤（1）中处理后的瓣膜材料浸入胺基化合物封闭液中处理0.5-6h，进而封闭戊二醛交联后残留的醛基基团；
（3）将步骤（2）中处理后的瓣膜材料放入含有抗凝剂和交联剂的反应液中，于4℃-37℃条件下交联处理6-24h；
（4）对步骤（3）中处理后的瓣膜材料进行清洗，制得，然后将瓣膜材料保存于戊二醛或异丙醇/丙三醇的混合溶剂中。
进一步地，所述动物源生物瓣膜材料包括猪心包膜、牛心包膜、小肠粘膜下层中一种。
进一步地，步骤（1）中戊二醛的浓度为0.3%-3%。
进一步地，步骤（1）中戊二醛的交联处理时间为24-96h，交联pH值6-9。
进一步地，步骤（1）中戊二醛的浓度为0.3%-3%，交联处理时间为24-96h，交联pH值6-9。
进一步地，步骤（1）中戊二醛的浓度为1%，交联处理时间为72h，交联pH值7。
进一步地，步骤（1）中戊二醛交联方式包括一步交联、多步交联和浓度梯度交联，交联用的溶剂为水、PBS或其他盐离子缓冲液。
进一步地，步骤（2）中的胺基化合物上携带有至少3个伯氨基基团。
进一步地，步骤（2）中的胺基化合物包括聚乙烯亚胺、壳聚糖、羧甲基壳聚糖、多聚赖氨酸、多聚精氨酸和己二胺中的一种，胺基化合物封闭液的浓度为0.1-100 mg/mL。
进一步地，步骤（2）中胺基化合物封闭液的浓度为0.1-100 mg/mL。
进一步地，步骤（2）中胺基化合物在封闭液中的浓度为10 mg/mL。
进一步地，步骤（2）中，处理后的瓣膜材料浸入胺基化合物封闭液中处理0.5-6h。
进一步地，步骤（3）中抗凝化合物包括肝素、硫酸乙酰肝素、比伐芦丁和水蛭素。
进一步地，步骤（3）中交联剂包括1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐）/N-羟基琥珀酰亚胺、1-环已基-2-吗啉乙基碳二亚胺对甲苯磺酸盐和N,N'-二环己基碳二亚胺中的一种。
进一步地，步骤（3）中反应液中的溶剂包括水、吗啉乙磺酸钠盐溶液和PBS缓冲液。
进一步地，步骤（3）反应液中抗凝剂的浓度为0.2mg/mL-20mg/mL，抗凝剂与交联剂的摩尔比为0.2-5:0.2-2。
进一步地，步骤（3）反应液中交联剂的浓度为0.1~5 mg/mL。
进一步地，步骤（3）反应液中抗凝剂的浓度为5mg/mL，抗凝剂与交联剂的摩尔比为0.3：2。
通过上述的方法制备得到具有协同抗凝及抗钙化功能的瓣膜材料。
 有益效果
本发明产生的有益效果为：
在瓣膜中通过两步放大效应，制备了具有协同抗钙化及抗凝功能的瓣膜材料用作于肺动脉/静脉瓣膜。戊二醛交联的瓣膜材料是纤维取向排布且具有孔隙结构的材料，其纤维上含有醛基、羧基等基团，本发明通过灌注多胺基化合物再固定抗凝化合物的方式实现瓣膜抗凝的放大效应，为肺动脉/静脉瓣膜材料的复杂血流环境提供较好的抗血栓活性；引入多胺基化合物，通过多胺基化合物上的氨基与瓣膜材料上的醛基间的席夫碱反应直接封闭残留醛基，避免钙离子附着在残留的醛基上形成钙盐结晶，提高瓣膜材料的抗钙化能力，进而提高瓣膜的使用寿命；同时抗凝剂上的羧基可以与引入的胺基通过脱水缩合形成酰胺键，实现共价固定，进而提高瓣膜的抗凝效果。
 附图说明
图1为戊二醛交联膜表面血栓沉积图；
图2为改性瓣膜材料表面血栓沉积图；
图3中左图为皮下植入3个月后，戊二醛交联瓣膜材料钙化图，右图为皮下植入3个月后改性瓣膜材料钙化图。
 本发明的实施方式
下面结合附图对本发明的具体实施方式做详细的说明。
实施例1
一种具有协同抗凝及抗钙化功能的瓣膜材料，其制备方法包含以下步骤：
（1）将去脂后的猪心包材料切割成合适大小，绷板后浸入到浓度为1%，pH值为7的戊二醛溶液中，24小时换液处理，持续处理72小时；
（2）将步骤（1）中处理后的瓣膜材料浸入到具有含有聚乙烯亚胺（10mg/mL）的封闭液中（pH7.4），常温处理0.5h，封闭戊二醛交联后残留的醛基基团；
（3）将上述步骤得到的戊二醛瓣膜转移到MES缓冲液中，添加肝素（5mg/mL）和N,N'-二环己基碳二亚胺（0.5mg/mL），在pH5.5条件下，于4℃交联处理24h；
（4）将上述反应液处理后得到的瓣膜材料进行清洗后，得到目标瓣膜材料。
实施例2
一种具有协同抗凝及抗钙化功能的瓣膜材料，其制备方法包含以下步骤：
（1）将去脂后的猪心包材料切割成合适大小，绷板后浸入到浓度为0.5%，pH值为8.5的戊二醛溶液中处理24小时，随后转移到1%的戊二醛溶液中处理48小时；
（2）将步骤（1）中处理后的瓣膜材料浸入到具有含有多聚赖氨酸（5mg/mL）的封闭液中（pH7.4），常温处理6h，封闭戊二醛交联后残留的醛基基团；
（3）将上述步骤得到的戊二醛瓣膜转移到PBS缓冲液中，添加比伐芦丁（1mg/mL）和1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐（0.3mg/mL），在pH6条件下，于25℃交联处理4h；
（4）将上述反应液处理后得到的瓣膜材料进行清洗后，得到目标瓣膜材料。
实施例3
一种具有协同抗凝及抗钙化功能的瓣膜材料，其制备方法包含以下步骤：
（1）将去脂后的牛心包材料切割成合适大小，绷板后浸入到浓度为1%，pH值为6.5的戊二醛溶液中处理24小时，随后转移到0.5%的戊二醛溶液中处理48小时；
（2）将步骤（1）处理后瓣膜材料浸入到具有含有己二胺（4mg/mL）的封闭液中（pH7.4），常温处理3h，封闭戊二醛交联后残留的醛基基团；
（3）将上述步骤得到的戊二醛瓣膜转移到PBS缓冲液中，添加水蛭素（2mg/mL）和1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐）（0.4mg/mL），在pH5条件下，于37℃交联处理2h；
（4）将上述反应液处理后得到的瓣膜材料进行清洗后，得到目标瓣膜材料。
实施例4
一种具有协同抗凝及抗钙化功能的瓣膜材料，其制备方法包含以下步骤：
（1）将小肠粘膜下层剥离后切割成合适大小，绷板后浸入到浓度为1%，pH值为8的戊二醛溶液中处理72小时；
（2）将瓣膜材料浸入到具有含有壳聚糖（10mg/mL）的封闭液中（pH5），常温处理6h，封闭戊二醛交联后残留的醛基基团；
（3）将上述步骤得到的戊二醛瓣膜转移到PBS缓冲液中，添加硫酸乙酰肝素（3mg/mL）和1-环已基-2-吗啉乙基碳二亚胺对甲苯磺酸盐（0.8mg/mL），在pH6.5条件下，于20℃交联处理8h；
（4）将上述反应液处理后得到的瓣膜材料进行清洗后，得到目标瓣膜材料。
实施例5
一种具有协同抗凝及抗钙化功能的瓣膜材料，其制备方法包含以下步骤：
（1）将猪心包材料去脂后切割成合适大小，绷板后浸入到1%的戊二醛溶液中处理72小时；
（2）将步骤（1）中处理后的瓣膜材料浸入到具有含有多聚精氨酸（5mg/mL）的封闭液中（pH7.4），常温处理4h，封闭戊二醛交联后残留的醛基基团；
（3）将上述步骤得到的戊二醛瓣膜转移到吗啉乙磺酸钠盐缓冲液中，添加肝素（6mg/mL）和1-环已基-2-吗啉乙基碳二亚胺对甲苯磺酸盐（1mg/mL），在pH5.5条件下，于10℃交联处理20h；
（4）将上述反应液处理后得到的瓣膜材料进行清洗后，得到目标瓣膜材料。 试验例
以实施例1中制得的瓣膜为例，观察戊二醛交联后瓣膜材料表面，然后观察改性处理后兔半体血液循环试验2小时后，瓣膜表面血栓沉积情况，具体结果见图1和图2；将实施例1中戊二醛交联后的瓣膜材料和改性后的瓣膜材料分别皮下植入3个月，观察瓣膜材料钙化情况，具体见图3。
通过图1可以看出，未经改性的传统戊二醛交联工艺，其瓣膜材料上沉积了大量血栓，红细胞和大量纤维网络交错。而图2则显示，经实施例1方法中描述的抗凝改性后，瓣膜材料表面依旧光洁，无明显的血栓沉积，证实了改性瓣膜材料优异的血液相容性和抗凝血功能。
通过图3的皮下植入实验看出，3个月后，经茜素红染色，戊二醛交联膜（左）上有明显的钙化斑点沉积，而经改性的瓣膜材料（右）依旧十分的光洁，无明显的钙化斑点，证实了材料的抗钙化性能。

Claims (16)

  1. 一种具有协同抗凝及抗钙化功能的瓣膜材料的制备方法，其特征在于，包括以下步骤：
    （1）对动物源生物瓣膜材料进行戊二醛交联处理；
    （2）将步骤（1）中处理后的瓣膜材料浸入胺基化合物封闭液中处理；
    （3）将步骤（2）中处理后的瓣膜材料放入含有抗凝剂和交联剂的反应液中进行处理；
    （4）对步骤（3）中处理后的瓣膜材料进行清洗，制得。
  2. 如权利要求1所述的具有协同抗凝及抗钙化功能的瓣膜材料的制备方法，其特征在于，步骤（2）中的胺基化合物上携带有至少三个伯氨基基团。
  3. 如权利要求1所述的具有协同抗凝及抗钙化功能的瓣膜材料的制备方法，其特征在于，步骤（2）中的胺基化合物为聚乙烯亚胺、壳聚糖、羧甲基壳聚糖、多聚赖氨酸、多聚精氨酸、己二胺中的至少一种。
  4. 如权利要求1所述的具有协同抗凝及抗钙化功能的瓣膜材料的制备方法，其特征在于，步骤（3）中抗凝剂为肝素、硫酸乙酰肝素、比伐芦丁、水蛭素中的至少一种。
  5. 如权利要求1所述的具有协同抗凝及抗钙化功能的瓣膜材料的制备方法，其特征在于，步骤（3）中交联剂为1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐、N-羟基琥珀酰亚胺、1-环已基-2-吗啉乙基碳二亚胺对甲苯磺酸盐、N,N'-二环己基碳二亚胺中的至少一种。
  6. 如权利要求1所述的具有协同抗凝及抗钙化功能的瓣膜材料的制备方法，其特征在于，步骤（2）中胺基化合物封闭液的浓度为0.1-100 mg/mL。
  7. 如权利要求1所述的具有协同抗凝及抗钙化功能的瓣膜材料的制备方法，其特征在于，步骤（2）中，处理后的瓣膜材料浸入胺基化合物封闭液中处理0.5-6h。
  8. 如权利要求1所述的具有协同抗凝及抗钙化功能的瓣膜材料的制备方法，其特征在于，将步骤（2）中处理后的瓣膜材料放入含有抗凝剂和交联剂的反应液中，于4℃-37℃条件下交联处理6-24h。
  9. 如权利要求1所述的具有协同抗凝及抗钙化功能的瓣膜材料的制备方法，其特征在于，步骤（3）反应液中抗凝剂的浓度为0.2mg/mL-20mg/mL。
  10. 如权利要求1所述的具有协同抗凝及抗钙化功能的瓣膜材料的制备方法，其特征在于，步骤（3）反应液中交联剂的浓度为0.1~5 mg/mL。
  11. 如权利要求1所述的具有协同抗凝及抗钙化功能的瓣膜材料的制备方法，其特征在于，步骤（3）中抗凝剂与交联剂的摩尔比为0.2-5:0.2-2。
  12. 如权利要求1所述的具有协同抗凝及抗钙化功能的瓣膜材料的制备方法，其特征在于，步骤（3）中反应液中的溶剂包括水、吗啉乙磺酸钠盐溶液和PBS缓冲液。
  13. 如权利要求1所述的具有协同抗凝及抗钙化功能的瓣膜材料的制备方法，其特征在于，步骤（1）中戊二醛的浓度为0.3%-3%。
  14. 如权利要求1所述的具有协同抗凝及抗钙化功能的瓣膜材料的制备方法，其特征在于，步骤（1）中戊二醛的交联处理时间为24-96h，交联pH值6-9。
  15. 如权利要求1所述的具有协同抗凝及抗钙化功能的瓣膜材料的制备方法，其特征在于，所述动物源生物瓣膜材料包括猪心包膜、牛心包膜、小肠粘膜下层中一种。
  16. 通过权利要求1-15中任一项所述的方法制备得到具有协同抗凝及抗钙化功能的瓣膜材料。
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