CN112220970B - 一种抗凝血的人工心脏瓣膜材料及其制备方法与应用 - Google Patents
一种抗凝血的人工心脏瓣膜材料及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种抗凝血的人工心脏瓣膜材料及其制备方法与应用，属于生物医学材料技术领域。所述抗凝血的人工心脏瓣膜材料，包括生物心脏瓣膜材料、与所述生物心脏瓣膜材料化学结合的氟化物超润滑抗凝涂层、保持在所述氟化物超润滑抗凝涂层中的润滑剂，通过在生物心脏瓣膜材料表面构建氟化物超润滑抗凝涂层，能够显著减小血小板黏附以及全血黏附，大幅提高材料的抗凝血性能，有效克服了生物瓣膜的血栓原性。所述瓣膜材料制备方法制备方法简单，只需要简单地溶液浸泡或气相沉积，对动物心包膜生物瓣膜材料的损伤较小，额外引入或残留的化学试剂少，有利于保持材料良好的生物相容性。
Description
技术领域
本发明属于生物医学材料技术领域，具体涉及一种抗凝血的人工心脏瓣膜材料及其制备方法与应用。
技术背景
人工瓣膜是血管植入物，因此需要具有良好的血液相容性。对于介入生物心脏瓣膜，心脏内血液流速快，生物瓣膜的血液相容性相对较好，因此形成血栓的概率小，介入生物瓣膜一般无需长期服用抗凝药。尽管传统上生物瓣膜被认为是抗凝的一个很好选择，但近年来的数据分析显示，与人工生物瓣膜相关的血栓形成发生率较高，尤其是随着经导管主动脉瓣置换术的出现，生物瓣膜血栓形成是导致急性或慢性生物瓣膜变性的主要原因。
最近，关于生物瓣膜置换术后的患者的亚临床小叶血栓形成的报道进一步加剧了这一争论。传统上，超声心动图诊断瓣膜血栓形成，但随着电子计算机断层扫描(CT)的广泛应用，越来越多的病例出现在人们的视野。利用四维容积CT研究发现，在一个生物瓣膜临床试验中40％的患者和在两个注册中心接受瓣膜置换治疗13％的患者中发现瓣叶运动减少与瓣叶血栓形成一致(Cardiol Res,2018.9(6):p.335-342；Curr Treat OptionsCardiovasc Med,2018.20(5):p.42；Heart,2017.103(24):p.1934-1941.)。
综上所述，生物瓣膜的血栓原性仍然是需要解决的问题。瓣膜的凝血问题，是除去钙化、免疫排斥反应之外，导致生物瓣膜失效的重要因素。然而，目前尚没有一种能够很好地克服生物瓣膜的血栓原性的人工心脏瓣膜材料问世。
发明内容
本发明针对上述问题，开发了一种抗凝血的人工心脏瓣膜材料，通过在生物心脏瓣膜材料表面构建氟化物超润滑抗凝涂层，来显著减小血小板黏附以及全血黏附，大幅提高材料的抗凝血性能。
本发明包含以下技术方案：
一种抗凝血的人工心脏瓣膜材料，包括生物心脏瓣膜材料、与所述生物心脏瓣膜材料化学结合的氟化物超润滑抗凝涂层、保持在所述氟化物超润滑抗凝涂层中的润滑剂。
作为可选方式，在上述人工心脏瓣膜材料中，所述生物心脏瓣膜材料可以是现有技术中常用的生物瓣膜材料，可以选自心包膜、瓣膜、肠膜、脑膜、肺膜、血管、皮肤或韧带，优选为猪或牛心包膜。
作为可选方式，在上述人工心脏瓣膜材料中，所述氟化物超润滑抗凝涂层是通过化学气相沉积或液相沉积将三氯硅烷氟化物与生物心脏瓣膜材料进行化学结合而成。三氯硅烷氟化物由于具有良好的羟基反应活性，容易与生物心脏瓣膜材料进行化学结合。进一步的，所述三氯硅烷氟化物具体为：三氯(1H,1H,2H,2H-全氟辛基)硅烷(CAS号：78560-45-9)。
作为可选方式，在上述人工心脏瓣膜材料中，所述氟化物超润滑抗凝涂层是通过将双键氟化物与心包膜进行化学结合而成。进一步的，所述双键氟化物具体为：烯丙基五氟苯(CAS号：1736-60-3)，1H,1H,2H-全氟-1-辛烯(CAS号：25291-17-2)，1H,1H,2H-全氟-1-十二烯(CAS号：30389-25-4)，2-(全氟辛基)乙基甲基丙烯酸酯(CAS号：1996-88-9)中的一种或几种。所述双键氟化物容易通过双键与生物心脏瓣膜材料表面的活性基团反应形成稳定的化学结合。
作为可选方式，在上述人工心脏瓣膜材料中，所述润滑剂为全氟萘烷或五氟苯酚二乙基三甲基烯酯。所述润滑剂具有良好的生物安全性和生物相容性。
本发明还提供了一种上述的人工心脏瓣膜材料的制备方法，其特征在于，包括以下步骤：
a.将戊二醛交联的生物心脏瓣膜材料，浸入氧自由基活化剂溶液中，进行基团活化；
b.加入对应的氟化物，使其通过步骤a中的被活化的基团与生物心脏瓣膜材料进行化学结合，从而在生物心脏瓣膜材料表面形成氟化物超润滑抗凝涂层；
c.加入润滑剂使其保持在所述氟化物超润滑抗凝涂层中；
d.漂洗后采用抑菌溶剂保存或采用醇溶液脱水干燥后保存。
作为可选方式，在上述制备方法中，步骤a中所述戊二醛交联具体为将心包膜浸泡于0.2-2.5v％的戊二醛溶液中1-7天。
作为可选方式，在所述步骤a中，将戊二醛交联的生物心脏瓣膜材料浸泡在5-500mM氧自由基活化剂溶液中1-24h。
作为可选方式，所述氧自由基活化剂包括：过硫酸铵(CAS号：7727-54-0)/亚硫酸氢钠(CAS号：7631-90-5)，硝酸铈铵(CAS号：16774-21-3)。所述过硫酸铵可以产生活性氧自由基，亚硫酸氢钠进一步增强产生活性氧自由基的数量及效率。
作为可选方式，在所述步骤b中，通过化学气相沉积或液相沉积将三氯硅烷氟化物与生物心脏瓣膜材料进行化学结合，或加入双键氟化物与生物心脏瓣膜材料进行化学结合。
作为可选方式，在所述步骤c中，将润滑剂溶液完全浸没材料保持1-24h。
作为可选方式，步骤的d中可选用去离子水等常用的漂洗液漂洗，更优选为采用生理盐水或PBS漂洗。
作为可选方式，步骤的d中所述抑菌溶剂保存具体为：将瓣膜材料浸泡于20-100vt％的异丙醇或70-100vt％的乙醇水溶液中保存。
作为可选方式，步骤的d中所述醇溶液脱水干燥后保存具体为：将生物瓣膜材料浸泡于10-30vt％甘油与70-90vt％乙醇等体积混合的混合溶液或10-30vt％甘油、35-45vt％乙醇与35-45vt％异丙醇等体积混合的混合溶液中4-24h，干燥。所述干燥步骤优选为自然风干。
本发明还提供了一种上述的人工心脏瓣膜材料的应用，其特征在于，将其用于制作人工主动脉瓣膜、肺动脉瓣膜、静脉瓣膜、二尖瓣膜或三尖瓣膜。
本说明书中公开的所有特征，或公开的所有方法或过程中的步骤，除了互相排斥的特征和/或步骤以外，均可以以任何方式组合。
本发明的有益效果：
(1)本发明所述抗凝血的人工心脏瓣膜材料，通过在生物心脏瓣膜材料表面构建氟化物超润滑抗凝涂层，能够显著减小血小板黏附以及全血黏附，大幅提高材料的抗凝血性能。
(2)本发明选用的氟化物已经被美国FDA批准用于血液接触材料，具有较好的生物安全性。
(3)本发明中氟化物涂层制备方法简单，只需要简单地溶液浸泡或气相沉积，对动物心包膜生物瓣膜材料的损伤较小，额外引入或残留的化学试剂少，有利于保持材料良好的生物相容性。
(4)本发明构建的氟化物涂层结构对各种简单和复杂的液体都具有良好排斥抗黏附作用，具有良好的、稳定的抗凝作用。
附图说明：
图1为本发明实施例所述技术路线1的示意图；
图2为本发明实施例所述技术路线2的示意图；
图3为本发明实验例所述材料对应的全血黏附照片。
具体实施方式：
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明，即所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。
因此，以下对提供的本发明的实施例的详细描述并非旨在限制要求保护的本发明的范围，而是仅仅表示本发明的选定实施例。基于本发明的实施例，本领域技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。
以下结合实施例对本发明的特征和性能作进一步的详细描述。本发明采用了两种技术路线：(1)氧自由基活化剂活化心包膜表面后三氯硅烷氟化物化学修饰(图1)。(2)氧自由基活化剂活化心包膜表面后双键氟化物化学修饰心包膜(图2)。
本发明对基底材料没有限制，由于心包膜是目前已经广泛验证使用效果较好的人工心脏瓣膜材料，以下实施例中主要以心包膜为例对本发明进行展示，本领域技术人员可以很容易地将其替换为瓣膜、肠膜、脑膜、肺膜、血管、皮肤或韧带等其他生物组织。
实施例1
具体步骤如下：
a.将0.625v％戊二醛交联的10cm*10cm猪心包膜浸入50mM过硫酸铵/50mM亚硫酸氢钠溶液中，进行基团活化2h；
b.通过液相沉积将三氯(1H,1H,2H,2H-全氟辛基)硅烷与心包膜进行化学结合,即将100毫升10v％三氯(1H,1H,2H,2H-全氟辛基)硅烷溶液于60摄氏度浸泡10cm*10cm心包膜24h；
c.加入10毫升全氟萘烷润滑剂24h；
d.漂洗后采用25％异丙醇水溶液保存。
实施例2
具体步骤如下：
a.将0.625v％戊二醛交联的10cm*10cm猪心包膜浸入50mM过硫酸铵/50mM亚硫酸氢钠溶液中，进行基团活化2h；
b.将100毫升10v％烯丙基五氟苯溶液于室温浸泡10cm*10cm心包膜24h；
c.加入10毫升全氟萘烷润滑剂24h；
d.漂洗后采用25％异丙醇水溶液保存。
实施例3
具体步骤如下：
a.将0.625v％戊二醛交联的10cm*10cm猪心包膜浸入50mM硝酸铈铵溶液中，进行基团活化2h；
b.将100毫升10v％1H,1H,2H-全氟-1-辛烯溶液于室温浸泡10cm*10cm心包膜24h；
c.加入10毫升全氟萘烷润滑剂24h；
d.漂洗后采用25％异丙醇水溶液保存。
实施例4
具体步骤如下：
a.将0.625v％戊二醛交联的10cm*10cm猪心包膜浸入50mM硝酸铈铵溶液中，进行基团活化2h；
b.将100毫升10v％1H,1H,2H-全氟-1-十二烯溶液于室温浸泡10cm*10cm心包膜24h；
c.加入10毫升五氟苯酚二乙基三甲基烯酯润滑剂24h；
d.漂洗后采用25％异丙醇水溶液保存。
实验例
设置对照组与实施例制得的材料分别进行血小板及全血黏附测试。
对照组：将猪心包膜浸泡于0.625vt％的戊二醛溶液中交联1天。漂洗后采用25％异丙醇水溶液保存。
(1)全血黏附测试
使用枸橼酸钠采血管采集兔血，将样品(直径为12mm)浸泡在1mL全血中，37℃孵化2小时，之后吸出全血并采用1mL的PBS溶液清洗三次，每次5分钟，之后对全血黏附情况进行拍照分析。
结果如图3所示，实施例1-4组的全血黏附相比戊二醛对照组明显减少。
(2)血小板黏附测试
新鲜枸橼酸钠抗凝的兔血以1500rpm离心15分钟以获得富含血小板的上清液(PRP)。实验样品裁剪为12mm圆片并用PBS溶液清洗三次后，光滑面向上放置于24孔板中，并在每孔中加入1mL新鲜富血小板血浆后37摄氏度孵育1个小时(纯PRP被设置为阳性对照组)。孵育完成后，样品用PBS清洗三次以除去体系中未黏附的血小板，并使用LDH细胞毒性试剂盒测量细胞释放的LDH间接定量黏附在材料表面的血小板数量。反应完成后用酶标仪测量490nm处的吸光度，设置PBS为阴性对照。血小板的相对黏附量＝(测试样品490nm吸光度-阴性对照490nm吸光度)/(阳性对照490nm吸光度-阴性对照490nm吸光度)。
结果如表1所示，实施例1-4组的血小板黏附相比戊二醛对照组明显减少。
表1血小板黏附相对含量。
上述实施例仅为本发明的优选实施方式之一，不应当用于限制本发明的保护范围，但凡在本发明的主体设计思想和精神上作出的毫无实质意义的改动或润色，其所解决的技术问题仍然与本发明一致的，均应当包含在本发明的保护范围之内。
Claims (9)
1.一种人工心脏瓣膜材料的制备方法，其特征在于，包括以下步骤：
a．将戊二醛交联的生物心脏瓣膜材料，浸入氧自由基活化剂溶液中，进行基团活化；
b．加入双键氟化物，使其通过双键与生物心脏瓣膜材料表面的活性基团反应形成稳定的化学结合，从而在生物心脏瓣膜材料表面形成氟化物超润滑抗凝涂层，所述氟化物超润滑抗凝涂层是通过将双键氟化物与生物心脏瓣膜材料进行化学结合而成，双键氟化物具体为：烯丙基五氟苯、1H,1H,2H-全氟-1-辛烯、1H,1H,2H-全氟-1-十二烯、2-(全氟辛基)乙基甲基丙烯酸酯中的一种或几种；
c．加入润滑剂使其保持在所述氟化物超润滑抗凝涂层中；
d．漂洗后采用抑菌溶剂保存或采用醇溶液脱水干燥后保存。
2.根据权利要求1所述的制备方法，其特征在于，在所述步骤a中，将戊二醛交联的生物心脏瓣膜材料浸泡在5-500mM氧自由基活化剂溶液中1-24h。
3.根据权利要求1所述的制备方法，其特征在于，步骤a中所述氧自由基活化剂为过硫酸铵/亚硫酸氢钠或硝酸铈铵。
4.根据权利要求1所述的制备方法，其特征在于，步骤c中所述润滑剂为全氟萘烷或五氟苯酚二乙基三甲基烯酯。
5.根据权利要求1所述的制备方法，其特征在于，在所述步骤c中，将润滑剂溶液完全浸没材料保持1-24h。
6.根据权利要求1所述的制备方法，其特征在于，步骤d中所述抑菌溶剂保存具体为：将瓣膜材料浸泡于20-100vt%的异丙醇或70-100vt%的乙醇水溶液中保存。
7.根据权利要求1所述的制备方法，其特征在于，步骤d中所述醇溶液脱水干燥后保存具体为：将生物瓣膜材料浸泡于10-30vt%甘油与70-90vt%乙醇等体积混合的混合溶液或10-30vt%甘油、35-45vt%乙醇与35-45vt%异丙醇等体积混合的混合溶液中4-24h，干燥。
8.一种采用权利要求1所述方法制备的抗凝血的人工心脏瓣膜材料，其特征在于，包括生物心脏瓣膜材料、与所述生物心脏瓣膜材料化学结合的氟化物超润滑抗凝涂层、保持在所述氟化物超润滑抗凝涂层中的润滑剂。
9.一种如权利要求8所述的人工心脏瓣膜材料的应用，其特征在于，将其用于制作人工主动脉瓣膜、肺动脉瓣膜、静脉瓣膜、二尖瓣膜或三尖瓣膜。
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