WO2021239080A1 - 一种兼具抗凝血和抗钙化性能的生物瓣膜及其制备方法 - Google Patents

一种兼具抗凝血和抗钙化性能的生物瓣膜及其制备方法 Download PDF

Info

Publication number
WO2021239080A1
WO2021239080A1 PCT/CN2021/096560 CN2021096560W WO2021239080A1 WO 2021239080 A1 WO2021239080 A1 WO 2021239080A1 CN 2021096560 W CN2021096560 W CN 2021096560W WO 2021239080 A1 WO2021239080 A1 WO 2021239080A1
Authority
WO
WIPO (PCT)
Prior art keywords
biological valve
valve
biological
cross
preparing
Prior art date
Application number
PCT/CN2021/096560
Other languages
English (en)
French (fr)
Inventor
王云兵
李高参
杨立
Original Assignee
杭州启明医疗器械股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 杭州启明医疗器械股份有限公司 filed Critical 杭州启明医疗器械股份有限公司
Publication of WO2021239080A1 publication Critical patent/WO2021239080A1/zh

Links

Classifications

    • 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
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/24—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
    • 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
    • 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
    • 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
    • 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
    • A61L33/0005—Use of materials characterised by their function or physical properties
    • A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
    • 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
    • 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
    • A61L33/0076—Chemical modification of the substrate
    • 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
    • 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

Definitions

  • the invention belongs to the technical field of preparation of medical materials and medical devices, and specifically relates to a biological valve with both anti-coagulation and anti-calcification properties and a preparation method thereof.
  • Heart valve disease is a kind of cardiovascular disease, and it is one of the important reasons for the high prevalence and mortality of cardiovascular disease.
  • Traditional valve replacement surgery needs to be performed through thoracotomy.
  • thoracotomy requires extracorporeal circulation, the risk of surgery is high, and the patient's recovery time is long.
  • this type of surgery cannot be tolerated.
  • transcatheter interventional heart valve replacement technology has brought dawn to patients.
  • Interventional heart valve replacement surgery does not require thoracotomy, the operation risk is low, and the recovery time is short. It provides a new treatment plan for elderly patients and patients who are not suitable for thoracotomy.
  • Biological heart valve refers to a class of biomedical materials used to replace diseased heart valves in humans. Based on the characteristics and advantages of biological valve materials, the current biological valve has become the first choice for interventional valves.
  • the pulmonary valve Compared with the aortic valve, the pulmonary valve has the characteristics of slow pulmonary blood flow and generally lower age of the patient range, so it puts forward higher requirements for the anti-thrombotic and anti-calcification properties of the interventional pulmonary valve.
  • the existing interventional biological valves generally use glutaraldehyde cross-linked biological valve materials.
  • the coagulation and calcification of the glutaraldehyde cross-linked pulmonary valve in the body has become a very important factor in clinical valve failure. Therefore, the anticoagulation and anticalcification treatment of the existing biological valve materials can effectively prolong the service life of the interventional pulmonary valve, which is of great significance to the clinical use of the interventional pulmonary valve and the improvement of the quality of life of patients.
  • the current anticoagulation strategy for glutaraldehyde cross-linked valves is mainly to modify heparin.
  • the present invention provides a biological valve with both anti-coagulation and anti-calcification properties, especially a pulmonary valve and a preparation method thereof, aiming to solve the coagulation and calcification problems of the existing interventional biological valve. While ensuring the mechanical properties of the biological valve material, the anti-coagulation and anti-calcification effects of the valve material are improved, and the service life of the valve is prolonged.
  • a method for preparing a biological valve with both anticoagulant and anticalcification properties The biological valve is cross-linked with glutaraldehyde, and functional molecules containing amine groups are used before and/or after the cross-linking treatment.
  • the biological valve undergoes at least one functional modification treatment, so that the functional molecules are fixed on the biological heart valve by chemical grafting to obtain a biological valve with both anti-coagulation and anti-calcification functions.
  • the functional molecules containing amine groups undergo an amidation reaction with the carboxyl groups on the biological valve, and the functional molecules are grafted on the biological valve through chemical bonds.
  • the biological valve is introduced into the biological valve by introducing functional molecules with anticoagulant effect to achieve the biological valve Anticoagulant.
  • the biological valve is cross-linked with glutaraldehyde, and functional molecules containing an amine group are used to perform functional modification processing on the biological valve after the cross-linking treatment.
  • glutaraldehyde is used to cross-link the biological valve, and then the functional molecules containing amine groups are modified.
  • the steps are simple and the processing is convenient, and the functional molecules containing amine groups block the remaining aldehyde groups to improve The anti-calcification performance of the biological valve, and the functional molecules with anti-coagulation effect synergistically improve the anti-calcification performance of the biological valve.
  • the biological valve is functionally modified once with functional molecules containing amine groups, and then the biological valve is cross-linked with glutaraldehyde, and after the cross-linking treatment, functional molecules containing amine groups are used to The biological valve undergoes secondary functional modification processing.
  • the functional molecule containing the amine group reacts with the carboxyl group on the biological valve, and the functional molecule with anticoagulant effect is introduced into the biological valve through a chemical bond, and then the biological valve is cross-linked with glutaraldehyde After the cross-linking treatment, functional molecules containing amine groups are used to cap the residual aldehyde groups to improve the anti-calcification performance of the biological valve, and the functional molecules with anti-coagulation effect synergistically improve the anti-calcification performance of the biological valve .
  • two different functional molecules containing amine groups can be introduced to synergistically improve the anticoagulant performance of the biological valve.
  • the specific process of the functional modification treatment is: placing the biological valve in a solution of the functional molecule and the condensing agent, and reacting at 4 to 37° C. for 1 to 7 days.
  • the mass concentration of the functional molecules in the mixed solution is 0.1-30%; the mass concentration of the condensing agent is 0.1-20%.
  • the mass concentration (mass percentage concentration) of the functional molecule is preferably 0.5-20%, for example, it can be 0.5%, 8%, 15%, 20%, etc.
  • the mass concentration (mass percentage concentration) of the appropriate amount of the condensing agent is preferably 0.1-20%, for example, it can be 0.1%, 1%, 5%, 10%, 15%, etc.
  • the functional molecule is an anticoagulation functional component containing an amine group, including anticoagulation natural molecules, anticoagulation drugs, and anticoagulation polymers.
  • functional molecules include heparin, chitosan-like heparin, hirudin, protamine, dabigatran, bivalridine, taurine, 2-cyclohexylaminoethanesulfonic acid, aminopropanesulfonic acid , Tris ethanesulfonic acid, polylysine-heparin, ethylenediamine grafted polyglycidyl methacrylate-polyacrylamido-2-methylpropanesulfonic acid, ethylenediamine grafted polyglycidyl methacrylate Ester-poly(p-styrenesulfonic acid), ethylenediamine grafted polyglycidyl methacrylate-poly-2-methacryloxyethanesulfonic acid, ethylenediamine grafted polyglycidyl methacrylate-poly3 -Methacryloxy-2-hydroxypropyl sulfonic acid, ethylenediamine grafted polyglycidyl
  • the condensing agent is dicyclohexylcarbodiimide, N-hydroxysuccinimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or 1-hydroxybenzotrimide Azole and so on.
  • the volume concentration of glutaraldehyde is 0.1-10%, and the pH value is 7-8.
  • the volume concentration of the glutaraldehyde aqueous solution is preferably 0.1-10%, for example, it can be 0.1%, 1%, 5%, 10%, etc.
  • the pH of the glutaraldehyde aqueous solution is preferably 7-8, for example, it can be 7. 7.4, 8 etc.
  • crosslinking reaction temperature is 4 to 37°C
  • reaction time is 1 to 7 days.
  • the glutaraldehyde cross-linking or functional modification treatment it also includes cleaning and pretreatment of the biological valve; the cleaning pretreatment process is: the cleaning process may include: collecting fresh porcine or bovine pericardial tissue, and Store at 4°C under low temperature and humidity. Use gentle friction and fluid pressure to clean the pericardial tissue with deionized water (distilled water) under oscillating conditions to remove adherent non-pericardial and non-collagen tissues.
  • the cleaning of the present invention achieves effective decellularization of pericardial tissue through osmotic shock, and preferably the cleaning continues until there is no visible adherent non-pericardial or non-collagen tissue.
  • the step of cleaning the animal pericardium includes: washing the fresh animal pericardium with deionized water at 3 to 5° C. and 80 to 120 RPM for 1.5 to 3 hours.
  • deionized water for example, it can be washed with deionized water at 4°C and 100RPM oscillating speed for 2 hours, and then the cleaned fresh animal (pig or cow) pericardium can be cross-linked or functionalized.
  • the biological valve is a pulmonary valve, aortic valve, venous valve, mitral valve or tricuspid valve replacement and repair material.
  • the biological valve is subjected to a primary functional modification treatment with hirudin, and then the biological valve is cross-linked with glutaraldehyde, and after the cross-linking treatment, the biological valve is subjected to a secondary functional modification treatment with aminoheparin.
  • taurine is used to perform a functional modification treatment on the biological valve
  • glutaraldehyde is used to crosslink the biological valve
  • chitosan heparin is used to perform a secondary functional modification treatment on the biological valve.
  • heparin is used to perform a functional modification treatment on the biological valve, and then glutaraldehyde is used to cross-link the biological valve.
  • glutaraldehyde is used to cross-link the biological valve.
  • ethylenediamine is used to graft polyglycidyl methacrylate-poly3-methylmethacrylate.
  • Acryloyloxy-2-hydroxypropyl sulfonic acid performs secondary functional modification treatment on the biological valve.
  • the biological valve is subjected to a functional modification treatment with bivalrudine once, then the biological valve is cross-linked with glutaraldehyde, and the biological valve is subjected to a secondary functional modification treatment with aminoheparin after the cross-linking treatment.
  • polylysine-heparin is used for primary functional modification of the biological valve
  • glutaraldehyde is used for cross-linking of the biological valve
  • dabigatran is used for secondary functional modification of the biological valve after the cross-linking. deal with.
  • the biological valve prepared by the above method has both anti-coagulation and anti-calcification properties.
  • the present invention creatively fixes the anticoagulant functional molecules by chemical grafting before and after the biofilm tissue glutaraldehyde is crosslinked and fixed.
  • the biological heart valve On the biological heart valve, the biological heart valve has excellent anticoagulant ability.
  • the functional modification treatment will also block the calcification sites of the carboxyl and aldehyde groups of the glutaraldehyde valve, and further improve the anti-calcification ability of the valve, so that the prepared biological valve material, especially the pulmonary valve, has long-term anticoagulation and Anti-calcification performance, thereby further improving the durability of the pulmonary valve, to meet the clinical needs of the pulmonary valve.
  • the biological valve is placed in a mixed solution of functional molecules and condensing agent, and then grafted at 4 to 37°C for 1 to 7 days to ensure that as many anticoagulant functional molecules are grafted on the biological valve as possible. Then, through the cross-linking treatment of glutaraldehyde, the stable cross-linking of most of the collagen tissue on the biological valve can be realized, the structural stability of the entire pericardial tissue can be improved, and the immunogenicity can be reduced or eliminated.
  • the present invention provides a biological valve with both anti-coagulation and anti-calcification properties and a preparation method thereof.
  • the biological valve prepared by the present invention not only has good mechanical properties, but is also shown in tests such as blood coagulation tests and animal experiments. Outstanding anticoagulant and anticalcification effects.
  • This valve material is not only suitable for pulmonary valves, but also as replacement and repair materials for aortic valves, venous valves, mitral valves, tricuspid valves, etc.
  • Figure 1 is a mechanical test result of the biological valve prepared in Example 1 of the application.
  • FIG 2 shows the results of platelet adhesion experiments between the glutaraldehyde valve (left) and the biological valve prepared in Example 1 of the application (right);
  • Figure 3 shows the results of in vivo calcification quantitative analysis of the glutaraldehyde valve (left) and the biological valve prepared in Example 1 of the present application (right).
  • the anti-calcification biological heart valve prepared in this embodiment has a tensile fracture stress of 34N under a uniaxial tensile test (1*5cm sample size).
  • the biological valve prepared in this implementation has significantly improved anticoagulant performance compared with the traditional glutaraldehyde cross-linked valve.
  • the tensile fracture stress of the anti-calcification biological heart valve prepared in this implementation is greater than 30N under a uniaxial tensile test (1*5cm sample size).
  • the biological valve prepared in this implementation has significantly improved anticoagulant performance compared with the traditional glutaraldehyde cross-linked valve.
  • the tensile fracture stress of the anti-calcification biological heart valve prepared in this implementation is greater than 30N under a uniaxial tensile test (1*5cm sample size).
  • the biological valve prepared in this implementation has significantly improved anticoagulant performance compared with the traditional glutaraldehyde cross-linked valve.
  • the tensile fracture stress of the anti-calcification biological heart valve prepared in this implementation is greater than 30N under a uniaxial tensile test (1*5cm sample size).
  • the biological valve prepared in this implementation has significantly improved anticoagulant performance compared with the traditional glutaraldehyde cross-linked valve.
  • the tensile fracture stress of the anti-calcification biological heart valve prepared in this implementation is greater than 30N under a uniaxial tensile test (1*5cm sample size).
  • the biological valve prepared in this implementation has significantly improved anticoagulant performance compared with the traditional glutaraldehyde cross-linked valve.
  • the tensile fracture stress of the anti-calcification biological heart valve prepared in this implementation is greater than 30N under a uniaxial tensile test (1*5cm sample size).
  • the biological valve prepared in this implementation has significantly improved anticoagulant performance compared with the traditional glutaraldehyde cross-linked valve.
  • the biological valve prepared in this application has excellent mechanical properties; according to Figure 2, it can be seen that there is almost no platelet adhesion on the biological valve prepared in this application, and the biological valve after glutaraldehyde treatment However, platelets are obviously adhered, and it can be seen that the biological valve prepared in the present application has excellent anticoagulant performance.
  • Figure 3 shows the results of the anti-calcification performance test. It can be seen from Figure 3 that the amount of calcium attached to the biological valve prepared in this application is only about 22 ⁇ g/mg, while the glutaraldehyde treatment group reaches about 154 ⁇ g/mg, which is far Lower than the glutaraldehyde treatment group, it can be seen that the biological valve prepared in this application has excellent anti-calcification performance.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Dermatology (AREA)
  • Cardiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Botany (AREA)
  • Vascular Medicine (AREA)
  • Surgery (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Zoology (AREA)
  • Materials Engineering (AREA)
  • General Chemical & Material Sciences (AREA)
  • Materials For Medical Uses (AREA)
  • Prostheses (AREA)

Abstract

本发明公开了一种兼具抗凝血和抗钙化性能的生物瓣膜及其制备方法。该方法的具体过程为：采用戊二醛对生物瓣膜进行交联处理，并在交联处理前和/或后采用含有胺基基团的功能分子对生物瓣膜进行至少一次的功能修饰处理，使功能分子通过化学接枝的方式固定在生物心脏瓣膜上得到兼具抗凝血和抗钙化功能的生物瓣膜。本发明制得的生物瓣膜不仅具有良好的机械性能，同时还具有优异的抗凝血和抗钙化效果。

Description

一种兼具抗凝血和抗钙化性能的生物瓣膜及其制备方法 技术领域
本发明属于医学材料及医疗器械制备技术领域，具体涉及一种兼具抗凝血和抗钙化性能的生物瓣膜及其制备方法。
 背景技术
心脏瓣膜病是心血管疾病的一种，是造成心血管疾病患病率高和死亡率高的重要原因之一。传统的瓣膜替换手术需要通过开胸进行，但是因为开胸手术需建立体外循环，手术风险很高，并且患者的恢复时间长，对于一些老年患者以及不宜开胸的患者不能耐受此类手术。近些年，随着微创介入技术的发展，经导管介入心脏瓣膜置换技术给患者带来了曙光。介入心脏瓣膜置换手术无需要开胸，手术风险低，恢复时间短，为老年患者以及不宜开胸的患者提供了新的治疗方案。生物心脏瓣膜是指一类用于替换人体病变心脏瓣膜的生物医学材料。基于生物瓣膜材料的特点和优势，当前生物瓣已成为介入式瓣膜的首选方案。
相比与主动脉瓣膜，肺动脉瓣膜具有肺动脉血流速度慢、应用患者范围年龄普遍偏低的特点，因而对介入肺动脉瓣膜的抗血栓和抗钙化等性能提出了更高的要求。目前，现有的介入生物瓣膜一般采用戊二醛交联的生物瓣膜材料，戊二醛交联的肺动脉瓣膜在体内的凝血和钙化问题已成为造成临床上瓣膜失效非常重要的因素。因此，对现有生物瓣膜材料进行抗凝血和抗钙化处理能有效延长介入肺动脉瓣膜的使用寿命，对介入肺动脉瓣膜的临床使用以及提高患者的生活质量均具有重要的意义。
目前针对戊二醛交联瓣膜抗凝的策略主要是进行肝素修饰，常见的方法主要有以下两种：(1)通过直接浸泡的方式，将戊二醛交联瓣膜浸泡至含有肝素的溶液中实现肝素在瓣膜材料上的修饰；(2)利用静电吸附组装的方式，通过与正电性化合物的静电组装，进而修饰在瓣膜材料表面。由于上述方法均是通过物理吸附等弱的结合力将肝素修饰在瓣膜材料表面，造成肝素在材料表面的保存时间较短，无法实现长期抗凝的目的。
 技术问题
针对现有技术中的上述不足，本发明提供一种兼具抗凝血和抗钙化性能的生物瓣膜、特别是肺动脉瓣膜及其制备方法，旨在解决现有介入生物瓣膜的凝血和钙化问题，在保证生物瓣膜材料机械性能的同时，提高瓣膜材料的抗凝血和抗钙化效果，延长瓣膜使用寿命。
 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：
一种兼具抗凝血和抗钙化性能的生物瓣膜的制备方法，采用戊二醛对生物瓣膜进行交联处理，并在交联处理前和/或后采用含有胺基基团的功能分子对生物瓣膜进行至少一次的功能修饰处理，使功能分子通过化学接枝的方式固定在生物心脏瓣膜上得到兼具抗凝血和抗钙化功能的生物瓣膜。
含有胺基基团的功能分子与生物瓣膜上的羧基发生酰胺化反应，通过化学键将功能分子接枝在生物瓣膜上，在生物瓣膜上通过引入具有抗凝血作用的功能分子，实现生物瓣膜的抗凝血。
可选的，采用戊二醛对生物瓣膜进行交联处理，在交联处理后采用含有胺基基团的功能分子对生物瓣膜进行功能修饰处理。
首先采用戊二醛对生物瓣膜进行交联，然后进行含胺基基团的功能分子的修饰，步骤简单，处理方便，且含胺基基团的功能分子对残余的醛基进行封端，提高生物瓣膜的抗钙化性能，具有抗凝血作用的功能分子协同改善生物瓣膜的抗钙化性能。
可选的，采用含有胺基基团的功能分子对生物瓣膜进行一次功能修饰处理，然后采用戊二醛对生物瓣膜进行交联处理，在交联处理后采用含有胺基基团的功能分子对生物瓣膜进行二次功能修饰处理。
进行一次功能修饰时，通过含有胺基基团的功能分子与生物瓣膜上的羧基反应，在生物瓣膜上通过化学键引入具有抗凝血作用的功能分子，然后采用戊二醛对生物瓣膜进行交联处理，在交联处理后，采用含有胺基基团的功能分子对残余的醛基进行封端，提高生物瓣膜的抗钙化性能，具有抗凝血作用的功能分子协同改善生物瓣膜的抗钙化性能。
通过两次含有胺基基团的功能分子对生物瓣膜进行修饰，可以引入两种不同的含有胺基基团的功能分子，协同改善生物瓣膜的抗凝血性能。
进一步地，功能修饰处理的具体过程为：将生物瓣膜置于功能分子和缩合剂混合的溶液中，于4～37℃反应1～7天。
进一步地，混合溶液中功能分子的质量浓度为0.1～30％；缩合剂的质量浓度为0.1～20％。
进一步地，功能分子的质量浓度(质量百分浓度)优选为0.5～20％，例如可以为0.5％、8％、15％、20％等。
进一步地，缩合剂适量的质量浓度(质量百分浓度)优选为0.1-20％，例如可以为0.1％、1％、5％、10％、15％等。
进一步地，功能分子为含有胺基的抗凝功能分，包括抗凝类天然分子、抗凝药物和抗凝高分子。
进一步地，功能分子包括氨基肝素、壳聚糖类肝素、水蛭素、鱼精蛋白、达比加群、比伐芦定、牛磺酸、2-环己胺基乙磺酸、氨基丙烷磺酸、Tris乙磺酸、聚赖氨酸-肝素、乙二胺接枝聚甲基丙烯酸缩水甘油酯-聚丙烯酰胺基-2-甲基丙磺酸、乙二胺接枝聚甲基丙烯酸缩水甘油酯-聚对苯乙烯磺酸、乙二胺接枝聚甲基丙烯酸缩水甘油酯-聚2-甲基丙烯酰氧基乙磺酸、乙二胺接枝聚甲基丙烯酸缩水甘油酯-聚3-甲基丙烯酰氧基-2-羟丙基磺酸、乙二胺接枝聚甲基丙烯酸缩水甘油酯-聚烯丙基磺酸和乙二胺接枝聚甲基丙烯酸缩水甘油酯-聚3-甲基丙烯酰氧基丙磺酸等中的至少一种。
进一步地、缩合剂为二环己基碳二亚胺、N-羟基丁二酰亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺或1-羟基苯并三唑等。
进一步地，采用戊二醛进行交联处理时，戊二醛的体积浓度为0.1～10％，pH值为7～8。
进一步地，戊二醛水溶液的体积浓度优选为0.1～10％，例如可以为0.1％、1％、5％、10％等，戊二醛水溶液的pH优选为7～8，例如可以为7、7.4、8等。
进一步地，交联反应温度为4～37℃，反应时间为1～7天。
进一步地，在进行戊二醛交联或功能修饰处理之间，还包括对生物瓣膜进行清洗预处理；清洗预处理过程为：清洗过程可以包括：采集新鲜的猪或牛的心包组织，并于4℃低温湿润状态下保存。采用柔和摩擦和流体压力在振荡条件之下用去离子水(蒸馏水)清洗心包组织，去除粘附的非心包和非胶原组织。本发明所述清洗通过渗压休克实现对心包组织有效脱细胞，优选清洗持续到没有可见的粘附的非心包或非胶原组织。具体实施时，优选的，所述将动物心包膜清洗干净的步骤包括：将新鲜的动物心包膜在3～5℃、80～120RPM的转速振荡条件下以去离子水清洗1.5～3h。例如，可以在4℃100RPM转速振荡条件之下去离子水清洗2h，然后将清洗干净的新鲜动物(猪或牛)心包膜进行交联处理或功能化处理。
进一步地，生物瓣膜为肺动脉瓣、主动脉瓣、静脉瓣、二尖瓣或三尖瓣置换及修补材料。
进一步地，采用水蛭素对生物瓣膜进行一次功能修饰处理，然后采用戊二醛对生物瓣膜进行交联处理，在交联处理后采用氨基肝素对生物瓣膜进行二次功能修饰处理。
进一步地，采用牛磺酸对生物瓣膜进行一次功能修饰处理，然后采用戊二醛对生物瓣膜进行交联处理，在交联处理后采用壳聚糖类肝素对生物瓣膜进行二次功能修饰处理。
进一步地，采用肝素对生物瓣膜进行一次功能修饰处理，然后采用戊二醛对生物瓣膜进行交联处理，在交联处理后采用乙二胺接枝聚甲基丙烯酸缩水甘油酯-聚3-甲基丙烯酰氧基-2-羟丙基磺酸对生物瓣膜进行二次功能修饰处理。
进一步地，采用比伐芦定对生物瓣膜进行一次功能修饰处理，然后采用戊二醛对生物瓣膜进行交联处理，在交联处理后采用氨基肝素对生物瓣膜进行二次功能修饰处理。
进一步地，采用聚赖氨酸-肝素对生物瓣膜进行一次功能修饰处理，然后采用戊二醛对生物瓣膜进行交联处理，在交联处理后采用达比加群对生物瓣膜进行二次功能修饰处理。
上述方法制备得到的兼具抗凝血和抗钙化性能的生物瓣膜。
 有益效果
本发明的有益效果为：
1、由于未经处理的生物膜片材料抗凝血和抗钙化能力较差，本发明创造性的在生物膜组织戊二醛交联固定前后，将抗凝血功能分子通过化学接枝的方式固定在生物心脏瓣膜上，从而使生物心脏瓣膜具备优异的抗凝血能力。同时，功能修饰处理还会封闭戊二醛瓣膜的羧基和醛基等瓣膜钙化位点，进一步提高瓣膜的抗钙化能力，使得制备得到的生物瓣膜材料，特别是肺动脉瓣莫具有长效抗凝和抗钙化性能，从而进一步提高肺动脉瓣膜的耐久性，满足肺动脉瓣膜的临床需求。
2、本申请将生物瓣膜置于功能分子和缩合剂的混合溶液中，然后于4～37℃接枝反应1～7天，能够确保生物瓣膜上尽可能多的接枝上抗凝功能分子，然后再通过戊二醛的交联处理，能够实现生物瓣膜上大部分胶原组织的稳定交联，提高整个心包组织的结构稳定性，降低以至于消除免疫原性。
3、本发明提供了一种兼具抗凝血和抗钙化性能的生物瓣膜及其制备方法，采用本发明制得的生物瓣膜不仅具有良好的机械性能，在凝血测试和动物实验等测试中呈现出优异的抗凝血和抗钙化效果。此瓣膜材料除适合用于肺动脉瓣，也可用作主动脉瓣、静脉瓣、二尖瓣、三尖瓣等的置换及修补材料。
 附图说明
图1为本申请实施例1制备得到的生物瓣膜的力学测试结果；
图2为戊二醛瓣膜(左)与本申请实施例1制备得到的生物瓣膜(右)的血小板粘附实验结果；
图3为戊二醛瓣膜(左)与本申请实施例1制备得到的生物瓣膜(右)的体内钙化定量分析结果。
 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
一种兼具抗凝血和抗钙化性能的生物瓣膜的制备方法，具体过程为：
 (1)将猪心包瓣膜用去离子水清洗干净后，于4℃下，在浓度为5％的水蛭素和浓度为1％的缩合剂的水溶液中浸泡2天；
 (2)于4℃下，在浓度为5％的戊二醛溶液中浸泡7天；
 (3)于4℃下，在浓度为3％的氨基肝素水溶液中浸泡2天得到目标生物瓣膜材料。
本实施制备的抗钙化生物心脏瓣膜在单轴拉伸测试之下(1*5cm样品尺寸)拉伸断裂应力为34N。
经血小板粘附实验发现，本实施制备的生物瓣膜与传统的戊二醛交联瓣膜相比，抗凝血性能显著提高。
经动物大鼠皮下植入实验发现，本实施制备的生物瓣膜与传统的戊二醛交联瓣膜相比，抗钙化效果提高600％以上。
实施例2
一种兼具抗凝血和抗钙化性能的生物瓣膜的制备方法，具体过程为：
 (1)将牛心包瓣膜用去离子水清洗干净后，于4℃下，在浓度为3％的牛磺酸和浓度为5％的缩合剂的水溶液中浸泡2天；
 (2)于4℃下，在浓度为5％的戊二醛溶液中浸泡7天；
 (3)于4℃下，在浓度为5％的壳聚糖类肝素水溶液中浸泡2天得到目标生物瓣膜材料。
本实施制备的抗钙化生物心脏瓣膜在单轴拉伸测试之下(1*5cm样品尺寸)拉伸断裂应力大于30N。
经血小板粘附实验发现，本实施制备的生物瓣膜与传统的戊二醛交联瓣膜相比，抗凝血性能显著提高。
经动物大鼠皮下植入实验发现，本实施制备的生物瓣膜与传统的戊二醛交联瓣膜相比，抗钙化效果提高500％以上。
实施例3
一种兼具抗凝血和抗钙化性能的生物瓣膜的制备方法，具体过程为：
 (1)将猪心包瓣膜用去离子水清洗干净后，于4℃下，在浓度为5％的戊二醛溶液中浸泡7天；
 (2)于4℃下，在浓度为20％的Tris乙磺酸和浓度为5％的缩合剂的水溶液中浸泡5天；
 (3)于4℃下，在浓度为3％的乙二胺接枝聚甲基丙烯酸缩水甘油酯-聚丙烯酰胺基-2-甲基丙磺酸水溶液中浸泡5天得到目标生物瓣膜材料。
本实施制备的抗钙化生物心脏瓣膜在单轴拉伸测试之下(1*5cm样品尺寸)拉伸断裂应力大于30N。
经血小板粘附实验发现，本实施制备的生物瓣膜与传统的戊二醛交联瓣膜相比，抗凝血性能显著提高。
经动物大鼠皮下植入实验发现，本实施制备的生物瓣膜与传统的戊二醛交联瓣膜相比，抗钙化效果提高600％以上。
实施例4
一种兼具抗凝血和抗钙化性能的生物瓣膜的制备方法，具体过程为：
 (1)将猪心包瓣膜用去离子水清洗干净后，于37℃下，在浓度为2％的肝素和浓度为5％的缩合剂的水溶液中浸泡3天；
 (2)于4℃下，在浓度为5％的戊二醛溶液中浸泡7天；
 (3)于37℃下，在浓度为50％的乙二胺接枝聚甲基丙烯酸缩水甘油酯-聚3-甲基丙烯酰氧基-2-羟丙基磺酸水溶液中浸泡3天得到目标生物瓣膜材料。
本实施制备的抗钙化生物心脏瓣膜在单轴拉伸测试之下(1*5cm样品尺寸)拉伸断裂应力大于30N。
经血小板粘附实验发现，本实施制备的生物瓣膜与传统的戊二醛交联瓣膜相比，抗凝血性能显著提高。
经动物大鼠皮下植入实验发现，本实施制备的生物瓣膜与传统的戊二醛交联瓣膜相比，抗钙化效果提高400％以上。
实施例5
一种兼具抗凝血和抗钙化性能的生物瓣膜的制备方法，具体过程为：
 (1)将猪心包瓣膜用去离子水清洗干净后，于4℃下，在浓度为5％的比伐芦定和浓度为10％的缩合剂的水溶液中浸泡3天；
 (2)于4℃下，在浓度为5％的戊二醛溶液中浸泡7天；
 (3)于4℃下，在浓度为3％的氨基肝素水溶液中浸泡3天得到目标生物瓣膜材料。
本实施制备的抗钙化生物心脏瓣膜在单轴拉伸测试之下(1*5cm样品尺寸)拉伸断裂应力大于30N。
经血小板粘附实验发现，本实施制备的生物瓣膜与传统的戊二醛交联瓣膜相比，抗凝血性能显著提高。
经动物大鼠皮下植入实验发现，本实施制备的生物瓣膜与传统的戊二醛交联瓣膜相比，抗钙化效果提高400％以上。
实施例6
一种兼具抗凝血和抗钙化性能的生物瓣膜的制备方法，具体过程为：
 (1)将猪心包瓣膜用去离子水清洗干净后，于室温下，在浓度为1％的聚赖氨酸-肝素和浓度为1％的缩合剂的水溶液中浸泡5天；
 (2)于37℃下，在浓度为5％的戊二醛溶液中浸泡7天；
 (3)于室温下，在浓度为2％的达比加群水溶液中浸泡5天得到目标生物瓣膜材料。
本实施制备的抗钙化生物心脏瓣膜在单轴拉伸测试之下(1*5cm样品尺寸)拉伸断裂应力大于30N。
经血小板粘附实验发现，本实施制备的生物瓣膜与传统的戊二醛交联瓣膜相比，抗凝血性能显著提高。
经动物大鼠皮下植入实验发现，本实施制备的生物瓣膜与传统的戊二醛交联瓣膜相比，抗钙化效果提高600％以上。
如图1所示，可以看出本申请制备得到的生物瓣膜具有优异的机械性能；根据图2可知，本申请制备得到的生物瓣膜上几乎没有血小板黏附，而戊二醛处理后的生物瓣膜上则是明显黏附有血小板，可以看出本申请制备得到的生物瓣膜具有优异的抗凝血性能。
图3为抗钙化性能检测结果，由图3可知，本申请制备得到的生物瓣膜上的挂钙量仅为22μg/mg左右，而戊二醛处理组则是达到了154μg/mg左右，远远低于戊二醛处理组，可以看出本申请制备得到的生物瓣膜具有优异的抗钙化性能。

Claims (16)

  1. 一种兼具抗凝血和抗钙化性能的生物瓣膜的制备方法，其特征在于，采用含有胺基基团的功能分子对生物瓣膜进行一次功能修饰处理，然后采用戊二醛对生物瓣膜进行交联处理，在交联处理后采用含有胺基基团的功能分子对生物瓣膜进行二次功能修饰处理。
  2. 根据权利要求1所述的兼具抗凝血和抗钙化性能的生物瓣膜的制备方法，其特征在于，所述功能修饰处理的具体过程为：将生物瓣膜置于功能分子和缩合剂混合的溶液中，于4～37℃反应1～7天。
  3. 根据权利要求2所述的兼具抗凝血和抗钙化性能的生物瓣膜的制备方法，其特征在于，所述混合溶液中功能分子的质量浓度为0.1～30％；缩合剂的质量浓度为0.1～20％。
  4. 根据权利要求2所述的兼具抗凝血和抗钙化性能的生物瓣膜的制备方法，其特征在于，所述功能分子为包含胺基基团的抗凝血分子。
  5. 根据权利要求2所述的兼具抗凝血和抗钙化性能的生物瓣膜的制备方法，其特征在于，所述功能分子包括氨基肝素、壳聚糖类肝素、水蛭素、鱼精蛋白、达比加群、比伐芦定、牛磺酸、2-环己胺基乙磺酸、氨基丙烷磺酸、Tris乙磺酸、聚赖氨酸-肝素、乙二胺接枝聚甲基丙烯酸缩水甘油酯-聚丙烯酰胺基-2-甲基丙磺酸、乙二胺接枝聚甲基丙烯酸缩水甘油酯-聚对苯乙烯磺酸、乙二胺接枝聚甲基丙烯酸缩水甘油酯-聚2-甲基丙烯酰氧基乙磺酸、乙二胺接枝聚甲基丙烯酸缩水甘油酯-聚3-甲基丙烯酰氧基-2-羟丙基磺酸、乙二胺接枝聚甲基丙烯酸缩水甘油酯-聚烯丙基磺酸和乙二胺接枝聚甲基丙烯酸缩水甘油酯-聚3-甲基丙烯酰氧基丙磺酸中的至少一种。
  6. 根据权利要求2所述的兼具抗凝血和抗钙化性能的生物瓣膜的制备方法，其特征在于，所述缩合剂为二环己基碳二亚胺、N-羟基丁二酰亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺或1-羟基苯并三唑。
  7. 根据权利要求1所述的兼具抗凝血和抗钙化性能的生物瓣膜的制备方法，其特征在于，采用戊二醛进行交联处理时，戊二醛的体积浓度为0.1～10％，pH值为7～8。
  8. 根据权利要求7所述的兼具抗凝血和抗钙化性能的生物瓣膜的制备方法，其特征在于，所述交联反应温度为4～37℃，反应时间为1～7天。
  9. 根据权利要求1 所述的兼具抗凝血和抗钙化性能的生物瓣膜的制备方法，其特征在于，在进行戊二醛交联或功能修饰处理之前，还包括对生物瓣膜进行清洗预处理；所述清洗预处理过程为：将生物瓣膜置于3～5℃、80～120rpm的转速振荡条件下以去离子水清洗1.5～3h。
  10. 根据权利要求1 所述的兼具抗凝血和抗钙化性能的生物瓣膜的制备方法，其特征在于，所述生物瓣膜为肺动脉瓣、主动脉瓣、静脉瓣、二尖瓣或三尖瓣置换及修补材料。
  11. 根据权利要求1 所述的兼具抗凝血和抗钙化性能的生物瓣膜的制备方法，其特征在于，采用水蛭素对生物瓣膜进行一次功能修饰处理，然后采用戊二醛对生物瓣膜进行交联处理，在交联处理后采用氨基肝素对生物瓣膜进行二次功能修饰处理。
  12. 根据权利要求1 所述的兼具抗凝血和抗钙化性能的生物瓣膜的制备方法，其特征在于，采用牛磺酸对生物瓣膜进行一次功能修饰处理，然后采用戊二醛对生物瓣膜进行交联处理，在交联处理后采用壳聚糖类肝素对生物瓣膜进行二次功能修饰处理。
  13. 根据权利要求1 所述的兼具抗凝血和抗钙化性能的生物瓣膜的制备方法，其特征在于，采用肝素对生物瓣膜进行一次功能修饰处理，然后采用戊二醛对生物瓣膜进行交联处理，在交联处理后采用乙二胺接枝聚甲基丙烯酸缩水甘油酯-聚3-甲基丙烯酰氧基-2-羟丙基磺酸对生物瓣膜进行二次功能修饰处理。
  14. 根据权利要求1 所述的兼具抗凝血和抗钙化性能的生物瓣膜的制备方法，其特征在于，采用比伐芦定对生物瓣膜进行一次功能修饰处理，然后采用戊二醛对生物瓣膜进行交联处理，在交联处理后采用氨基肝素对生物瓣膜进行二次功能修饰处理。
  15. 根据权利要求1 所述的兼具抗凝血和抗钙化性能的生物瓣膜的制备方法，其特征在于，采用聚赖氨酸-肝素对生物瓣膜进行一次功能修饰处理，然后采用戊二醛对生物瓣膜进行交联处理，在交联处理后采用达比加群对生物瓣膜进行二次功能修饰处理。
  16. 权利要求1～15任一项所述方法制备得到的兼具抗凝血和抗钙化性能的生物瓣膜。
PCT/CN2021/096560 2020-05-28 2021-05-27 一种兼具抗凝血和抗钙化性能的生物瓣膜及其制备方法 WO2021239080A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010466435.0 2020-05-28
CN202010466435.0A CN111569152A (zh) 2020-05-28 2020-05-28 一种兼具抗凝血和抗钙化性能的生物瓣膜及其制备方法

Publications (1)

Publication Number Publication Date
WO2021239080A1 true WO2021239080A1 (zh) 2021-12-02

Family

ID=72127202

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/096560 WO2021239080A1 (zh) 2020-05-28 2021-05-27 一种兼具抗凝血和抗钙化性能的生物瓣膜及其制备方法

Country Status (2)

Country Link
CN (1) CN111569152A (zh)
WO (1) WO2021239080A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114533969A (zh) * 2022-01-18 2022-05-27 深圳市儿童医院 一种促进内皮化阻流膜的制备方法与应用

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111569152A (zh) * 2020-05-28 2020-08-25 四川大学 一种兼具抗凝血和抗钙化性能的生物瓣膜及其制备方法
CN112472871B (zh) * 2020-12-08 2022-05-24 吉林启明皓月生物科技有限公司 一种提高力学及抗凝血性能的生物瓣膜交联方法
CN112641998B (zh) * 2020-12-22 2021-10-15 四川大学 一种长效超疏水抗凝生物瓣膜及其制备方法
CN113082292A (zh) * 2021-03-02 2021-07-09 四川大学华西医院 一种两性离子聚合物修饰的生物瓣膜材料及其制备方法
CN113289064A (zh) * 2021-03-26 2021-08-24 浙江大学 一种双网络水凝胶修饰的生物心脏瓣膜及其制备方法
CN113769169A (zh) * 2021-10-22 2021-12-10 四川大学华西医院 一种抗凝促细胞黏附生物瓣膜材料及其制备方法
WO2023088330A1 (zh) * 2021-11-17 2023-05-25 四川大学 一种生物瓣膜材料及其制备方法和应用
CN114748693B (zh) * 2021-11-17 2022-11-15 四川大学 一种共交联联合双键交联制备生物瓣膜材料的方法及生物瓣膜材料
CN114949347B (zh) * 2022-05-31 2023-05-12 四川大学 一种改性交联生物瓣膜及其制备方法和用途

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988001155A1 (en) * 1986-08-20 1988-02-25 The Children's Medical Center Corporation Biomaterial implant with a net positively charged surface
CN1961971A (zh) * 2005-11-11 2007-05-16 重庆市中山医院 医用牛颈静脉带瓣管道的制备方法
CN101947147A (zh) * 2010-06-23 2011-01-19 乐普（北京）医疗器械股份有限公司 一种生物组织材料的化学处理方法
CN103705980A (zh) * 2007-12-21 2014-04-09 爱德华兹生命科学公司 加帽生物假体组织以减少钙化
KR20160028253A (ko) * 2014-09-03 2016-03-11 서울대학교산학협력단 스페이스 필러를 이용한 이종이식조직의 제조방법
CN109172867A (zh) * 2018-09-19 2019-01-11 杭州启明医疗器械有限公司 一种可快速复水的预装式生物心脏瓣膜及其制备方法
CN111569152A (zh) * 2020-05-28 2020-08-25 四川大学 一种兼具抗凝血和抗钙化性能的生物瓣膜及其制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102475919B (zh) * 2010-11-29 2015-04-29 吴忠仕 一种去细胞生物组织材料肝素涂层的制备方法
CN108785747A (zh) * 2018-07-07 2018-11-13 四川大学 一种提高生物材料抗钙化性能的处理方法及其生物材料

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988001155A1 (en) * 1986-08-20 1988-02-25 The Children's Medical Center Corporation Biomaterial implant with a net positively charged surface
CN1961971A (zh) * 2005-11-11 2007-05-16 重庆市中山医院 医用牛颈静脉带瓣管道的制备方法
CN103705980A (zh) * 2007-12-21 2014-04-09 爱德华兹生命科学公司 加帽生物假体组织以减少钙化
CN101947147A (zh) * 2010-06-23 2011-01-19 乐普（北京）医疗器械股份有限公司 一种生物组织材料的化学处理方法
KR20160028253A (ko) * 2014-09-03 2016-03-11 서울대학교산학협력단 스페이스 필러를 이용한 이종이식조직의 제조방법
CN109172867A (zh) * 2018-09-19 2019-01-11 杭州启明医疗器械有限公司 一种可快速复水的预装式生物心脏瓣膜及其制备方法
CN111569152A (zh) * 2020-05-28 2020-08-25 四川大学 一种兼具抗凝血和抗钙化性能的生物瓣膜及其制备方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114533969A (zh) * 2022-01-18 2022-05-27 深圳市儿童医院 一种促进内皮化阻流膜的制备方法与应用

Also Published As

Publication number Publication date
CN111569152A (zh) 2020-08-25

Similar Documents

Publication Publication Date Title
WO2021239080A1 (zh) 一种兼具抗凝血和抗钙化性能的生物瓣膜及其制备方法
CN111420120A (zh) 一种具有抗凝血和抗钙化功能的生物瓣膜及其制备方法
WO2021213516A1 (zh) 一种抗凝血抗钙化生物材料及其制备方法
CN111467574B (zh) 基于edc/nhs活化和重组人源胶原蛋白修饰的生物瓣膜材料及其制备方法
US20210268151A1 (en) Pre-Loadable Biological Heart Valve Capable of Rapid Rehydration and Preparation Method Thereof
JP2002532134A (ja) 組織の固定方法
WO2022057841A1 (zh) 一种人工生物心脏瓣膜及其制备方法
WO2021212787A1 (zh) 一种人工生物瓣膜及其制备方法
WO2022121912A1 (zh) 一种提高力学及抗凝血性能的生物瓣膜交联方法、生物瓣膜材料及其应用
CN114748697B (zh) 一种双键后交联生物瓣膜材料及其制备和应用
WO2021254346A1 (zh) 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
CN111701077B (zh) 一种具有抗血栓抗钙化功能的瓣膜及其制备方法和应用
Zheng et al. A bioprosthetic heart valve prepared by copolymerization of 2-isocyanatoethyl methacrylate modified pericardium and functional monomer
WO2021254347A1 (zh) 一种具有长效抗血栓性能的瓣膜材料及其制备方法
CN112773936B (zh) 一种改性心包膜及其制备方法、人工心脏瓣膜假体
WO2022083759A1 (zh) 一种抗凝血抗钙化的人工心脏瓣膜材料及其制备方法与应用
WO2022083758A1 (zh) 一种抗凝血的人工心脏瓣膜材料及其制备方法与应用
WO2023088330A1 (zh) 一种生物瓣膜材料及其制备方法和应用
WO2020038293A1 (zh) 一种采用酶交联和茶多酚组合联用处理生物瓣膜的方法
CN111317866B (zh) 一种重组人源ⅲ型胶原蛋白修饰的生物瓣膜材料及其制备方法
CN115920131A (zh) 一种兼具抗凝和抗钙化的生物瓣膜材料、医疗器械及其交联方法和用途
CN115887770A (zh) 一种利用甲基丙烯酸异氰基乙酯交联的生物瓣膜材料、医疗器械及其方法和用途
CN114028617A (zh) 一种生物材料及其制备方法和应用
Murabayashi et al. Biolized Material for Cardiac Prosthesis

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21813833

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21813833

Country of ref document: EP

Kind code of ref document: A1