CN113117139B - Application of hydrogenated styrene thermoplastic elastomer in preparation of artificial heart valve - Google Patents

Abstract

The invention discloses an application of hydrogenated styrene thermoplastic elastomer in preparing a prosthetic heart valve. The thermoplastic elastomer is a block polymer synthesized by living anionic polymerization, wherein the solid phase or dispersed phase is polystyrene, and the rubber phase is hydrogenated conjugated diene polymer or hydrogenated conjugated diene and styrene random copolymer. The hydrogenated styrene elastomer used in the invention has excellent biological stability, anticoagulation performance, calcification resistance and mechanical strength, and can be used for preparing a heart valve prosthesis with more durable performance than a biological valve.

Description

Translated fromChinese

一种加氢苯乙烯类热塑性弹性体在制备人工心脏瓣膜中的应用A kind of hydrogenated styrene thermoplastic elastomer in the preparation of artificial heart valveapplication

技术领域technical field

本发明属于生物医学材料技术领域，具体涉及一种加氢苯乙烯类热塑性弹性体在制备人工心脏瓣膜中的应用。The invention belongs to the technical field of biomedical materials, and in particular relates to the application of a hydrogenated styrene thermoplastic elastomer in the preparation of artificial heart valves.

背景技术Background technique

心脏瓣膜指心房与心室之间或心室与动脉间的瓣膜，包括位于左心室和左心房之间的二尖瓣、位于右心室和右心房之间的三尖瓣、位于左心室出口的主动脉瓣以及位于右心室出口的肺动脉瓣。当心脏瓣膜出现结构或功能改变时，血液无法顺利排出，或者排出去的血液逆流回来,而使心脏负荷加重，由此引发的一系列病症，我们称之为瓣膜性心脏病。形成瓣膜性心脏病的病因很多，主要有风湿性和退行性两种。风湿性瓣膜性心脏病因风湿热常常反复发作，导致心脏瓣膜变形，引起瓣膜的狭窄或关闭不全；风湿性瓣膜性心脏病常于20-40岁发病，多累及二尖瓣，其次是主动脉瓣，也可同时累及二尖瓣、主动脉瓣和三尖瓣，累及肺动脉瓣的很少见。退行性瓣膜性心脏病多起因在于老龄人口(一般六十岁以上)的瓣膜钙化,表现为瓣膜增厚变硬、变形钙盐沉积等,导致瓣膜狭窄或关闭不全；多数患者首先累及主动脉瓣，也可于二尖瓣发生退行性关闭不全或狭窄。Heart valve refers to the valve between the atrium and ventricle or between the ventricle and the artery, including the mitral valve between the left ventricle and left atrium, the tricuspid valve between the right ventricle and right atrium, and the aortic valve at the outlet of the left ventricle and the pulmonary valve at the outlet of the right ventricle. When the structure or function of the heart valve changes, the blood cannot be discharged smoothly, or the discharged blood flows back backwards, which increases the load on the heart. A series of diseases caused by this are called valvular heart disease. There are many causes of valvular heart disease, mainly rheumatic and degenerative. Rheumatic valvular heart disease often occurs repeatedly due to rheumatic fever, resulting in deformation of the heart valve, causing stenosis or insufficiency of the valve; rheumatic valvular heart disease usually occurs at the age of 20-40, mostly involving the mitral valve, followed by the aortic valve , can also involve the mitral valve, aortic valve and tricuspid valve at the same time, and rarely involve the pulmonary valve. Degenerative valvular heart disease is mostly caused by valvular calcification in the elderly population (generally over 60 years old), manifested as valve thickening and hardening, deformation and calcium salt deposition, etc., leading to valvular stenosis or insufficiency; most patients first involve the aortic valve , Degenerative regurgitation or stenosis can also occur in the mitral valve.

对于瓣膜结构严重钙化或受损的病人，人工瓣膜置换术是最为有效的治疗手段。早期人工瓣膜置换需要外科开胸手术，而人工瓣膜产品主要有两大类：机械瓣和生物瓣。机械瓣的材质一般为钛、石墨基质和热解碳等人工材料，虽然耐久性好，但病人需终生服用抗凝血药物。生物瓣通常取牛或马的心包或猪瓣膜，经人工加工制作而成，其特点是更接近人体生理瓣膜的特性；虽然生物瓣抗凝血性好而病人无需长期服用抗凝血药物，但由于老化和逐渐磨损耐久性只有5-10年。近年来，经导管置入心瓣手术因手术伤害小而成为心瓣置换技术的主流[Ann Cardiothorac Surg(2017)6(5):493–7]。由于机械瓣无法经导管置入，此类介入治疗手段只能采用可以折叠的生物瓣。生物瓣除了耐久性差，其原材料-动物心包膜因动物来源材料的个体性差异难以保证原材料的一致性，而且成本很高，难以实现大规模生产；此外，生物瓣甚至可能携带动物源疾病而引起病人死亡。For patients with severely calcified or damaged valve structures, prosthetic valve replacement is the most effective treatment. Early artificial valve replacement required surgical open chest surgery, and there are two main types of artificial valve products: mechanical valves and biological valves. Mechanical valves are generally made of artificial materials such as titanium, graphite matrix, and pyrolytic carbon. Although they have good durability, patients need to take anticoagulant drugs for life. Biological valves are usually artificially processed from bovine or horse pericardium or pig valves, which are closer to the characteristics of human physiological valves; although biological valves have good anticoagulant properties and patients do not need to take anticoagulant drugs for a long time, due to Aging and gradual wear durability is only 5-10 years. In recent years, transcatheter heart valve surgery has become the mainstream of heart valve replacement technology because of less surgical injury [Ann Cardiothorac Surg(2017)6(5):493–7]. Since mechanical valves cannot be placed through the catheter, this type of interventional treatment can only use foldable biological valves. In addition to the poor durability of biological valves, the raw material - animal pericardium is difficult to ensure the consistency of raw materials due to individual differences in animal-derived materials, and the cost is high, making it difficult to achieve large-scale production; in addition, biological valves may even carry animal-derived diseases. cause the death of the patient.

因而临床上亟需性能更加优异的人工瓣膜材料，不但兼具机械瓣的耐久性和生物瓣的生物相容性，还可像生物瓣那样通过微创手术介入治疗，还能解决生物瓣的高成本、原料质量难控制等不足。Therefore, there is an urgent need for artificial valve materials with better performance in clinical practice, which not only have the durability of mechanical valves and the biocompatibility of biological valves, but also can be treated through minimally invasive surgery like biological valves, and can also solve the high Insufficiencies such as cost and raw material quality are difficult to control.

聚合物材料用以制作人工心脏瓣膜具有几个明显的优势：1)聚合物材料可以大规模生产，性能和质量可以得到稳定控制，进而大大降低成本；2)聚合物材料的机械力学性能宽泛，可以通过分子结构和化学组成的设计以达到心瓣产品所需的性能(包括柔软可折叠的特性，以符合经导管置入等微创手术的要求)；3)聚合物材料可以通过不同的加工方式得到不同尺寸和形状的心脏瓣膜，而生物瓣除了裁剪缝制外基本上不能再加工以改变厚度和形状；4)聚合物材料一般不携带动物源疾病。聚合物材料的生物相容性、耐久性和耐疲劳性是其用于心瓣产品的主要挑战。The use of polymer materials to make artificial heart valves has several obvious advantages: 1) polymer materials can be produced on a large scale, and their performance and quality can be stably controlled, thereby greatly reducing costs; 2) polymer materials have a wide range of mechanical properties, The performance required for heart valve products can be achieved through the design of molecular structure and chemical composition (including soft and foldable characteristics to meet the requirements of minimally invasive surgery such as transcatheter insertion); 3) polymer materials can be processed through different Heart valves of different sizes and shapes can be obtained by means of different methods, while biological valves can basically not be reprocessed to change thickness and shape except for cutting and sewing; 4) polymer materials generally do not carry animal-derived diseases. The biocompatibility, durability and fatigue resistance of polymer materials are the main challenges for their use in heart valve products.

聚合物材料用以开发人工心瓣已有几十年的开发历史，但尚未有成功的临床应用[Biomaterials 36(2015)6-25]。用于制作人工心瓣的聚合物材料包括硅胶，发泡聚四氟乙烯，聚氨酯，SIBS(苯乙烯-异丁烯-苯乙烯三嵌段聚合物)，乙丙橡胶以及聚乙烯醇水凝胶。硅胶和发泡聚四氟乙烯的机械力学性能达不到心瓣使用要求，而聚氨酯材料因水解稳定性差而达不到耐久性要求。SIBS(苯乙烯-异丁烯-苯乙烯三嵌段聚合物)是一种生物相容性和生物稳定性都很优异的一种弹性材料，但由于其热塑性的特点而容易在长期作用力下发生蠕变变形。用聚酯纤维增强的SIBS材料制作的心瓣，在羊动物模型实验中，因聚合物蠕变导致内部包埋的聚酯纤维暴露而导致钙化和凝血现象。热交联的SIBS材料(XSIBS)具有抗蠕变性能，用该材料制作的心瓣具有改进的血液动力学和抗凝血性能，但目前任处于实验室开发阶段，尚未进入临床应用。乙丙橡胶和聚乙烯醇水凝胶均未见临床实验报道，遑论产品注册以及商业化。Polymer materials have been developed for decades in the development of artificial heart valves, but have not yet had successful clinical applications [Biomaterials 36(2015) 6-25]. Polymer materials used to make artificial heart valves include silicone, expanded polytetrafluoroethylene, polyurethane, SIBS (styrene-isobutylene-styrene triblock polymer), ethylene-propylene rubber, and polyvinyl alcohol hydrogel. The mechanical properties of silica gel and expanded polytetrafluoroethylene cannot meet the requirements of heart valves, and polyurethane materials cannot meet the durability requirements due to poor hydrolytic stability. SIBS (styrene-isobutylene-styrene triblock polymer) is an elastic material with excellent biocompatibility and biostability, but it is prone to creep under long-term force due to its thermoplastic characteristics. Change shape. Heart valves made of polyester fiber-reinforced SIBS materials, in sheep animal model experiments, caused calcification and coagulation due to exposure of embedded polyester fibers due to polymer creep. Heat-crosslinked SIBS material (XSIBS) has anti-creep properties, and heart valves made of this material have improved hemodynamic and anticoagulant properties, but it is currently in the stage of laboratory development and has not yet entered clinical application. Neither ethylene propylene rubber nor polyvinyl alcohol hydrogel has been reported on clinical trials, let alone product registration and commercialization.

加氢苯乙烯类嵌段聚合物(HSBC)是一种通过阴离子聚合合成然后进行选择性催化加氢得到的嵌段聚合物材料，具有热塑性弹性体的特性(即既可以像热塑性塑料一样易于加工，又具有热固性橡胶一样的弹性)。HSBC中有聚苯乙烯这样的硬段聚合物，还有加氢的聚丁二烯或聚异戊二烯这样的软段；硬段是分散相，处于聚合物的两端，而软段是连续相，处于聚合物的中间，这样分散的硬段在连续的软段中形成了物理交联使得材料具有橡胶弹性，同时材料可以熔融或溶液加工而具有热塑性塑料的可加工性。商用的HSBC聚合物主要有SEBS和SEPS两大类，其中SEBS使用丁二烯单体，而SEPS使用异戊二烯单体。HSBC的橡胶相可以通过引入苯乙烯与共轭二烯单体无规共聚，得到含有苯乙烯单体单元的橡胶相；HSBC的橡胶相通过无规共聚引入苯乙烯单体单元后，可以大大提高弹性体的机械力学性能(如拉伸模量、耐磨性以及抗撕裂性能)，接近聚氨酯弹性体的性能，从而扩展其应用范围[美国专利US 7169848]。Hydrogenated styrene block polymer (HSBC) is a block polymer material synthesized by anionic polymerization followed by selective catalytic hydrogenation, which has the characteristics of thermoplastic elastomer (that is, it can be processed as easily as thermoplastic , and has the same elasticity as thermosetting rubber). In HSBC, there are hard segment polymers such as polystyrene, and soft segments such as hydrogenated polybutadiene or polyisoprene; the hard segments are dispersed phases, located at both ends of the polymer, and the soft segments are The continuous phase is in the middle of the polymer, so that the dispersed hard segments form physical crosslinks in the continuous soft segments to make the material rubbery, and the material can be melt or solution processed to have thermoplastic processability. Commercial HSBC polymers mainly include SEBS and SEPS, among which SEBS uses butadiene monomer, while SEPS uses isoprene monomer. The rubber phase of HSBC can be randomly copolymerized by introducing styrene and conjugated diene monomer to obtain a rubber phase containing styrene monomer units; the rubber phase of HSBC can greatly improve the elasticity after introducing styrene monomer units through random copolymerization The mechanical and mechanical properties of the body (such as tensile modulus, wear resistance and tear resistance), are close to the properties of polyurethane elastomers, thereby expanding its application range [US Patent US 7169848].

HSBC材料是理想的医用材料，以其具有以下优点：不含塑化剂和过敏原，很低量的可浸出物和可滤出物，不水解也不降解，不引起人体刺激反应，便于加工成型，适合各种消毒手段(环氧乙烷、伽马射线、电子束、紫外线、高温)等[https://kraton.com/products/pdf/Medical％20Brochure.pdf]。HSBC材料可以通过所有相关医学标准测试，如ISO10993生物相容性测试和美国药典USP 6级认证。目前HSBC材料的生物医学应用仅限于风险较低的医疗器械(一类和二类)或耗材。在医用领域，HSBC一般和其他组分(如聚烯烃、聚氨酯、工程塑料、矿物油等)共混，然后加工成医用制品(如输液管、输液袋、注射器、密封件、医用连接件、药物瓶塞和瓶盖、医用包6装、伤口绷带、皮肤贴片、手术用帘布、医用服等)。这些应用虽然也有涉及人体植入，但限于30天之内，尚未有长期植入人体的应用。HSBC material is an ideal medical material, which has the following advantages: no plasticizers and allergens, very low amount of leachables and leachables, no hydrolysis or degradation, no irritation to the human body, and easy processing Molded, suitable for various disinfection methods (ethylene oxide, gamma rays, electron beams, ultraviolet rays, high temperature), etc. [https://kraton.com/products/pdf/Medical%20Brochure.pdf]. HSBC materials can pass all relevant medical standard tests, such as ISO10993 biocompatibility test and USPClass 6 certification. Biomedical applications of HSBC materials are currently limited to lower-risk medical devices (Class I and II) or consumables. In the medical field, HSBC is generally blended with other components (such as polyolefin, polyurethane, engineering plastics, mineral oil, etc.), and then processed into medical products (such as infusion tubes, infusion bags, syringes, seals, medical connectors, pharmaceuticals, etc. Bottle stoppers and caps, medical packs of 6, wound bandages, skin patches, surgical drapes, medical gowns, etc.). Although these applications also involve human implantation, they are limited to within 30 days, and there is no long-term implantation application in the human body.

HSBC和SIBS都是不水解的碳氢化合物，不含具有生物毒性的小分子可浸出物和可滤出物，因此均具有很好的生物相容性。两者实质上的唯一差别在于在分子结构上橡胶相的单体组成。SIBS的橡胶相是聚异丁烯，而HSBC的橡胶相是乙烯和1-丁烯的共聚物或乙烯和丙烯的共聚物。SIBS的生物稳定性被归结于聚异丁烯分子结构，没有易于攫取的氢原子产生降解反应，因此具有完全的生物惰性[美国专利US 6102939]。然而事实上，SIBS材料在紫外线、伽马射线、电子束等照射下易于发生降解(因此一般适合用环氧乙烷消毒)，而HSBC在这些射线下更为稳定。这表明HSBC可能在人体内具有更好的稳定性，至少可以和SIBS一样可以用于长期人体植入。事实上，HSBC由于更优异的机械力学性能而应该具有更宽泛的应用范围。Both HSBC and SIBS are non-hydrolyzable hydrocarbons and do not contain biotoxic small molecule leachables and leachables, so both have good biocompatibility. The only substantial difference between the two lies in the monomer composition of the rubber phase in the molecular structure. The rubber phase of SIBS is polyisobutylene, while that of HSBC is a copolymer of ethylene and 1-butene or a copolymer of ethylene and propylene. The biological stability of SIBS is attributed to the molecular structure of polyisobutylene, and there is no degradation reaction of hydrogen atoms that are easy to grab, so it is completely biologically inert [US Patent US 6102939]. However, in fact, SIBS materials are prone to degradation under irradiation of ultraviolet rays, gamma rays, electron beams, etc. (so they are generally suitable for disinfection with ethylene oxide), while HSBC is more stable under these rays. This suggests that HSBC may have better stability in humans, at least as useful for long-term human implantation as SIBS. In fact, HSBC should have a wider range of applications due to its superior mechanical properties.

综上所述，目前人工心脏瓣膜产品需要新的高分子弹性材料以克服现有产品的不足，而HSBC产品作为一种优异的生物材料尚未用于长期植入人体的医疗器械(包括人工心脏瓣膜)。In summary, the current artificial heart valve products need new polymer elastic materials to overcome the shortcomings of existing products, and HSBC products, as an excellent biomaterial, have not yet been used in medical devices (including artificial heart valves) implanted in the human body for a long time. ).

发明内容Contents of the invention

针对现有技术中的上述不足，本发明提供一种加氢苯乙烯类热塑性弹性体在制备人工心脏瓣膜中的应用，可以用于制作新型人工心脏瓣膜以克服机械瓣和生物瓣的不足。In view of the above-mentioned shortcomings in the prior art, the present invention provides an application of hydrogenated styrene thermoplastic elastomer in the preparation of artificial heart valves, which can be used to manufacture new artificial heart valves to overcome the shortcomings of mechanical valves and biological valves.

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：In order to achieve the above object, the technical solution adopted by the present invention to solve the technical problems is:

一种加氢苯乙烯类热塑性弹性体在制备人工心脏瓣膜中的应用。该热塑性弹性体是一种用阴离子聚合合成并通过选择性催化加氢后形成的嵌段聚合物；该嵌段聚合物的分散相或者固相是乙烯基芳香烃聚合物，而且所述嵌段聚合物的连续相或橡胶相是加氢后的聚共轭二烯或加氢后的共轭二烯和乙烯基芳香烃无规共聚物。The application of a hydrogenated styrene thermoplastic elastomer in the preparation of artificial heart valves. The thermoplastic elastomer is a block polymer synthesized by anionic polymerization and formed by selective catalytic hydrogenation; the dispersed phase or solid phase of the block polymer is a vinyl aromatic hydrocarbon polymer, and the block The continuous or rubber phase of the polymer is hydrogenated polyconjugated diene or hydrogenated random copolymer of conjugated diene and vinyl aromatic hydrocarbon.

进一步地，加氢型苯乙烯类热塑性弹性体为一种通过活性阴离子聚合合成并进行选择性催化加氢的嵌段聚合物。Furthermore, the hydrogenated styrene thermoplastic elastomer is a block polymer synthesized by living anion polymerization and subjected to selective catalytic hydrogenation.

进一步地，嵌段聚合物的分散相或者固相为乙烯基芳香烃聚合物；所述嵌段聚合物的连续相或橡胶相是加氢后的聚共轭二烯或加氢后的共轭二烯和乙烯基芳香烃无规共聚物。Further, the dispersed phase or solid phase of the block polymer is vinyl aromatic hydrocarbon polymer; the continuous phase or rubber phase of the block polymer is hydrogenated polyconjugated diene or hydrogenated conjugated diene Random copolymer of diene and vinyl aromatic hydrocarbons.

进一步地，乙烯基芳香烃为苯乙烯、4-乙烯基苯并环丁烯、α-甲基苯乙烯、4-甲基苯乙烯、乙烯基萘、1,1-二苯乙烯和二乙烯基苯中的至少一种。Further, vinyl aromatic hydrocarbons are styrene, 4-vinylbenzocyclobutene, α-methylstyrene, 4-methylstyrene, vinylnaphthalene, 1,1-diphenylethylene and divinyl at least one of benzene.

进一步地，乙烯基芳香烃为苯乙烯。Further, the vinyl aromatic hydrocarbon is styrene.

进一步地，共轭二烯为异戊二烯、1,3-丁二烯、1,3-戊二烯、4-甲基戊二烯和2-甲基戊二烯中的至少一种。Further, the conjugated diene is at least one of isoprene, 1,3-butadiene, 1,3-pentadiene, 4-methylpentadiene and 2-methylpentadiene.

进一步地，共轭二烯异戊二烯和1,3-丁二烯中的至少一种。Further, at least one of the conjugated diene isoprene and 1,3-butadiene.

进一步地，人工心脏瓣膜为主动脉瓣、肺动脉瓣、二尖瓣或三尖瓣。Further, the artificial heart valve is an aortic valve, a pulmonary valve, a mitral valve or a tricuspid valve.

进一步地，人工心脏瓣膜的厚度为0.02～0.40mm。Further, the thickness of the artificial heart valve is 0.02-0.40 mm.

进一步地，人工心脏瓣膜的厚度为0.08～0.15mm。Further, the thickness of the artificial heart valve is 0.08-0.15mm.

进一步地，人工心脏瓣膜可以经开胸手术或者小切口微创置换手术植入。Furthermore, artificial heart valves can be implanted through open chest surgery or minimally invasive replacement surgery with small incisions.

本发明的有益效果为：The beneficial effects of the present invention are:

本发明使用的加氢苯乙烯类热塑性弹性体(HSBC)具备优异的生物稳定性、抗凝血性能、抗钙化性能和机械强度，由此，经由该材料制备得到的人工心脏瓣膜可以克服其他人工心脏瓣(如机械瓣和生物瓣)的不足。The hydrogenated styrene thermoplastic elastomer (HSBC) used in the present invention has excellent biological stability, anticoagulation performance, anticalcification performance and mechanical strength, thus, the artificial heart valve prepared by this material can overcome other artificial heart valves. Insufficiency of heart valves (such as mechanical and biological valves).

本发明使用的聚合物材料可以大规模生产，性能和质量可以得到稳定控制，进而大大降低心脏瓣膜产品的成本。本发明使用的聚合物材料的机械力学性能宽泛，可以通过分子结构和化学组成的设计以达到心瓣产品所需的性能(包括柔软可折叠的特性，可以通过经导管置入等微创手术置入)。本发明使用的聚合物材料可以通过不同的加工方式得到不同尺寸和形状的心脏瓣膜，而生物瓣除了裁剪缝制外基本上不能再加工并改变厚度和形状。而且，本发明使用的聚合物材料不携带动物源疾病。The polymer material used in the invention can be produced on a large scale, and its performance and quality can be stably controlled, thereby greatly reducing the cost of heart valve products. The mechanical properties of the polymer material used in the present invention are wide, and the performance required by the heart valve product (including soft and foldable characteristics can be achieved through the design of molecular structure and chemical composition, and can be placed through minimally invasive surgery such as transcatheter insertion) enter). The polymer material used in the present invention can obtain heart valves of different sizes and shapes through different processing methods, while the biological valve basically cannot be reprocessed and its thickness and shape can be changed except for cutting and sewing. Furthermore, the polymeric materials used in the present invention do not carry diseases of animal origin.

附图说明Description of drawings

图1为本申请的高分子弹性材料以及生物瓣膜材料的血小板黏附检测结果图；Fig. 1 is the platelet adhesion detection result diagram of the polymer elastic material and biological valve material of the present application;

图2为本申请的高分子弹性材料以及生物瓣膜材料的全血黏附检测结果图；Fig. 2 is the graph of whole blood adhesion detection results of the polymer elastic material and biological valve material of the present application;

图3为本申请的高分子弹性材料以及生物瓣膜材料的凝血四项检测结果图；其中，A为PT检测结果图；B为APTT检测结果图；C为TT检测结果图；D为FIB检测结果图；Fig. 3 is the graph of four coagulation test results of the polymer elastic material and biological valve material of the present application; wherein, A is a graph of PT test results; B is a graph of APTT test results; C is a graph of TT test results; D is a graph of FIB test results picture;

图4为本申请的高分子弹性材料以及生物瓣膜材料的抗钙化性能检测结果图；Fig. 4 is the detection result chart of the anti-calcification performance of the polymer elastic material and biological valve material of the present application;

图5为本申请的高分子弹性材料以及生物瓣膜材料缝合强度模拟测试结果。Fig. 5 is the simulation test results of the suture strength of the polymer elastic material and biological valve material of the present application.

具体实施方式Detailed ways

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，但应该明确，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。The specific embodiments of the present invention are described below so that those skilled in the art can understand the present invention, but it should be clear that the present invention is not limited to the scope of the specific embodiments. For those of ordinary skill in the art, as long as various changes are within the spirit and scope of the present invention defined and determined by the appended claims, these changes are obvious, and all inventions and creations utilizing the concept of the present invention are protected. List.

实施例1Example 1

一种加氢型苯乙烯类弹性体(样品号为HW009)，其苯乙烯含量为42％，其分子结构如下：A hydrogenation type styrenic elastomer (sample number is HW009), its styrene content is 42%, and its molecular structure is as follows:

然后将其置于厚度为0.1mm的模具内，于240℃模压30min即可制备得到该高分子瓣膜。Then it was placed in a mold with a thickness of 0.1mm, and molded at 240° C. for 30 minutes to prepare the polymer valve.

实施例2Example 2

一种加氢型苯乙烯类弹性体(样品号为HW010)，其苯乙烯含量为58％，其分子结构如下：A hydrogenation type styrene elastomer (sample number is HW010), its styrene content is 58%, and its molecular structure is as follows:

然后将其置于厚度为0.1mm的模具内，于240℃模压30min即可制备得到该高分子瓣膜。Then it was placed in a mold with a thickness of 0.1mm, and molded at 240° C. for 30 minutes to prepare the polymer valve.

实施例3：生物稳定性的体外加速测试Example 3: In Vitro Accelerated Test of Biostability

生物稳定性的一种加速体外测试是把样品置于沸腾的浓硝酸(65％)中，因为硝酸不仅是强酸还是强氧化剂【美国专利US 6102939】。为实验安全考虑，本实例的测试温度为室温，样品和浓硝酸通过涂敷有特氟龙的转子和磁力搅拌器进行混合6小时(若非另由说明)。An accelerated in vitro test of biostability is to place the sample in boiling concentrated nitric acid (65%), because nitric acid is not only a strong acid but also a strong oxidant [US Patent US 6102939]. For the sake of experimental safety, the test temperature of this example is room temperature, and the sample and concentrated nitric acid are mixed for 6 hours by a Teflon-coated rotor and a magnetic stirrer (unless otherwise specified).

对本发明实施例2制备得到的弹性材料与其他弹性材料和生物瓣膜一同进行生物稳定性检测，其检测结果见表1。The elastic material prepared in Example 2 of the present invention was tested for biological stability together with other elastic materials and biological valves, and the test results are shown in Table 1.

由表1的检测结果可知，生物瓣膜材料(猪心包)在浓硝酸中会蜷缩、变色、在表面形成不少微小凹陷处同时强度大大降低；聚醚聚氨酯约35分钟即被浓硝酸完全销蚀；聚碳聚氨酯虽然没有被销蚀但完全失去了弹性，表明分子结构尤其是软段发生严重结构改变；其他弹性体(包括SIBS、聚烯烃弹性体、聚烯烃嵌段聚合物、本实施例2样品、SEPS)显然要稳定得多，虽然SEPS有发黄现象，但所有样品都没有发生形态的改变，而且基本保持了橡胶弹性(除了SEPS样品，橡胶弹性基本不变或下降仅10％)。基于该测试的生物稳定性，虽然聚碳聚氨酯明显优于聚醚聚氨酯，但这两个聚氨酯样品远远不及其他基于碳氢聚合物的弹性材料(包括SEBS、SEPS、基于聚乙烯的共聚物弹性体、基于聚乙烯的聚烯烃嵌段弹性体、基于聚异丁烯的SIBS、以及本发明的热交联弹性材料)。这表明根据本发明制备得到的弹性材料具有比生物瓣膜材料和聚氨酯材料更为优异的生物稳定性。From the test results in Table 1, it can be seen that the biological valve material (pig pericardium) will curl up and change color in concentrated nitric acid, and form many tiny depressions on the surface while the strength is greatly reduced; polyether polyurethane is completely eroded by concentrated nitric acid in about 35 minutes; Although the polycarbonate polyurethane has not been eroded, it has completely lost its elasticity, indicating that the molecular structure, especially the soft segment, has undergone serious structural changes; other elastomers (including SIBS, polyolefin elastomer, polyolefin block polymer, the sample of thisembodiment 2, SEPS) is obviously much more stable, although SEPS has a yellowing phenomenon, all samples do not change in shape, and basically keep the rubber elasticity (except the SEPS sample, the rubber elasticity is basically unchanged or only drops by 10%). Based on the biostability of this test, although polycarbonate polyurethane is significantly better than polyether polyurethane, these two polyurethane samples are far inferior to other hydrocarbon polymer-based elastic materials (including SEBS, SEPS, polyethylene-based copolymer elastic polymers, polyethylene-based polyolefin block elastomers, polyisobutylene-based SIBS, and thermally crosslinked elastic materials of the present invention). This shows that the elastic material prepared according to the present invention has better biological stability than biological valve materials and polyurethane materials.

表1生物稳定性体外加速测试结果Table 1 Biostability in vitro accelerated test results

实施例4血液相容性检测Embodiment 4 blood compatibility detection

以生物瓣膜材料为对照，对三种高分子材料(HW010，HW014和HZ009)进行血液相容性各项检测。HW010是实施例2中使用的高分子材料，这种高分子材料一种HSBC；HW014是一种聚烯烃弹性体；HZ009是一种可交联SIBS(XSIBS)材料。Taking the biological valve material as a control, the blood compatibility tests were carried out on the three polymer materials (HW010, HW014 and HZ009). HW010 is the polymer material used in Example 2, which is a kind of HSBC; HW014 is a kind of polyolefin elastomer; HZ009 is a kind of cross-linkable SIBS (XSIBS) material.

图1为血小板黏附实验结果，图2为全血黏附实验结果，图3为凝血四项测试结果。这些测试结果表明，这些高分子材料与生物瓣膜材料的血液相容性无明显差异，因此这些材料用于心脏瓣膜将和生物瓣膜一样不会引起凝血问题。。Figure 1 shows the results of the platelet adhesion test, Figure 2 shows the results of the whole blood adhesion test, and Figure 3 shows the results of the four blood coagulation tests. These test results show that there is no significant difference in blood compatibility between these polymer materials and biological valve materials, so these materials used in heart valves will not cause blood clotting problems like biological valves. .

实施例5抗钙化性能检测Embodiment 5 Anti-calcification performance detection

以生物瓣膜材料为对照，将三种高分子材料(HW010，HW014和HZ009)植入大鼠体内90天进行钙化实验。HW010是实施例2中使用的高分子材料，这种高分子材料一种HSBC；HW014是一种聚烯烃弹性体；HZ009是一种可交联SIBS(XSIBS)材料。图4钙化实验结果，表明这些高分子材料(HW010，HW014和HZ009)钙化情况明显低于生物瓣膜材料,因此用这些材料制作的人工心脏瓣膜可以克服生物瓣膜容易发生钙化的问题。Using biological valve material as a control, three polymer materials (HW010, HW014 and HZ009) were implanted into rats for 90 days to conduct calcification experiments. HW010 is the polymer material used in Example 2, which is a kind of HSBC; HW014 is a kind of polyolefin elastomer; HZ009 is a kind of cross-linkable SIBS (XSIBS) material. The results of calcification experiments in Figure 4 show that the calcification of these polymer materials (HW010, HW014 and HZ009) is significantly lower than that of biological valve materials, so artificial heart valves made of these materials can overcome the problem of calcification of biological valves.

实施例6缝合强度测试Embodiment 6 suture strength test

以生物瓣膜材料为对照，将三种高分子材料(HW010，HW014和HZ009)通过热压方法制备成约0.15毫米厚度的薄膜，然后模拟实验测试其缝合强度。HW010是实施例2中使用的高分子材料，这种高分子材料一种HSBC；HW014是一种聚烯烃弹性体；HZ009是一种可交联SIBS(XSIBS)材料。图5为缝合强度结果，表明高分子材料HW010和HW014的缝合强度接近生物瓣膜材料，而HZ009的缝合强度明显偏低。这表明，本发明的高分子材料具有必要的缝合强度，可以和生物瓣膜材料一样缝制成合格的人工心脏瓣膜产品。Taking the biological valve material as a control, three polymer materials (HW010, HW014 and HZ009) were prepared into thin films with a thickness of about 0.15 mm by hot pressing, and then the suture strength was tested by simulation experiments. HW010 is the polymer material used in Example 2, which is a kind of HSBC; HW014 is a kind of polyolefin elastomer; HZ009 is a kind of cross-linkable SIBS (XSIBS) material. Figure 5 shows the results of suture strength, which shows that the suture strength of polymer materials HW010 and HW014 is close to that of biological valve materials, while the suture strength of HZ009 is obviously lower. This shows that the polymer material of the present invention has the necessary suturing strength, and can be sewn into a qualified artificial heart valve product like the biological valve material.

Claims (7)

Translated fromChinese

1.一种加氢苯乙烯类热塑性弹性体在制备人工心脏瓣膜中的应用，其特征在于，所述加氢型苯乙烯类热塑性弹性体为一种通过活性阴离子聚合合成并进行选择性催化加氢的嵌段聚合物；1. The application of a hydrogenated styrene-based thermoplastic elastomer in the preparation of an artificial heart valve, characterized in that, the hydrogenated styrene-based thermoplastic elastomer is synthesized by living anion polymerization and selectively catalyzed Hydrogen block polymers;所述嵌段聚合物的分散相或者固相为乙烯基芳香烃聚合物；所述嵌段聚合物的连续相或橡胶相是加氢后的共轭二烯和乙烯基芳香烃无规共聚物；The dispersed phase or solid phase of the block polymer is vinyl aromatic hydrocarbon polymer; the continuous phase or rubber phase of the block polymer is hydrogenated random copolymer of conjugated diene and vinyl aromatic hydrocarbon ;所述共轭二烯为异戊二烯、1,3-丁二烯、1,3-戊二烯、4-甲基戊二烯和2-甲基戊二烯中的至少一种。The conjugated diene is at least one of isoprene, 1,3-butadiene, 1,3-pentadiene, 4-methylpentadiene and 2-methylpentadiene.2.根据权利要求1所述的应用，其特征在于，所述乙烯基芳香烃为苯乙烯、4-乙烯基苯并环丁烯、α-甲基苯乙烯、4-甲基苯乙烯、乙烯基萘、1,1-二苯乙烯和二乙烯基苯中的至少一种。2. The application according to claim 1, wherein the vinyl aromatic hydrocarbon is styrene, 4-vinylbenzocyclobutene, α-methylstyrene, 4-methylstyrene, ethylene at least one of diphenylnaphthalene, 1,1-stilbene and divinylbenzene.3.根据权利要求2所述的应用，其特征在于，所述乙烯基芳香烃为苯乙烯。3. The application according to claim 2, characterized in that the vinyl aromatic hydrocarbon is styrene.4.根据权利要求1所述的应用，其特征在于，所述共轭二烯为异戊二烯和1,3-丁二烯中的至少一种。4. The application according to claim 1, characterized in that the conjugated diene is at least one of isoprene and 1,3-butadiene.5.根据权利要求1~4任一项所述的应用，其特征在于，所述人工心脏瓣膜为主动脉瓣、肺动脉瓣、二尖瓣或三尖瓣。5. The application according to any one of claims 1 to 4, wherein the artificial heart valve is an aortic valve, a pulmonary valve, a mitral valve or a tricuspid valve.6.根据权利要求5所述的应用，其特征在于，所述人工心脏瓣膜的厚度为0.05~0.40mm。6. The application according to claim 5, wherein the artificial heart valve has a thickness of 0.05-0.40mm.7.根据权利要求6所述的应用，其特征在于，所述人工心脏瓣膜可以经开胸手术或者小切口微创置换手术植入。7. The application according to claim 6, characterized in that, the artificial heart valve can be implanted through thoracotomy or minimally invasive replacement surgery through small incisions.

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