CN117018305A - 抗凝血抗炎活性ecmo体外循环通道设备及其制备方法 - Google Patents
抗凝血抗炎活性ecmo体外循环通道设备及其制备方法 Download PDFInfo
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- CN117018305A CN117018305A CN202310969777.8A CN202310969777A CN117018305A CN 117018305 A CN117018305 A CN 117018305A CN 202310969777 A CN202310969777 A CN 202310969777A CN 117018305 A CN117018305 A CN 117018305A
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Abstract
本发明公开了一种抗凝血抗炎活性ECMO体外循环通道设备及其制备方法，包括复合抗凝血抗炎涂层修饰的ECMO体外循环管道，所述复合抗凝血抗炎涂层为复合多糖涂层，所述复合多糖涂层为多种硫酸化多糖和氧化多糖的混合物。本发明采用上述一种抗凝血抗炎活性ECMO体外循环通道设备及其制备方法，能适应多种类型和材质的血液体外循环管道抗凝血抗炎修饰，具有抗蛋白质吸附、减少血小板黏附和聚集、抑制内源性凝血因子活化、抑制血栓形成、促进材料伪内膜化等特点；基于共价键结合的抗凝血修饰、抗炎修饰的ECMO管道，具有良好的材料安全性、良好的血液相容性、以及不易脱落稳定性高的特点、兼具抗凝血抗炎双重功效、适宜较长时间的体外循环。
Description
技术领域
本发明涉及ECMO体外循环通道技术领域，尤其是涉及一种抗凝血抗炎活性ECMO体外循环通道设备及其制备方法。
背景技术
在医学领域中，医用高分子材料及医疗器械主要用于诊断和治疗，每天有成千上万的病人使用血液接触类器械，如ECMO体外循环管路、血液透析循环管路、中心静脉导管、血管移植物、心脏瓣膜等。该类器械直接与血液接触时会发生一系列反应，血浆蛋白首先会瞬间吸附于材料表面，然后血小板会在血浆蛋白表面黏附、聚集，进而使血小板激活、凝血级联及补体激活，最终导致血栓形成。
由于血栓形成导致的死亡率高达80％，严重威胁着人类的健康及生命安全。临床上，通常需要口服抗血小板药物或抗凝剂来抑制器械表面血栓形成，但同时会增加出血的风险。因此，在医用材料器械表面设计及构建安全有效的抗凝血表面至关重要。
为了赋予医用材料表面抗凝血性能，需有针对性地设计和构建抗凝血表面。目前构建策略主要分为以下两类：生物惰性涂层、生物活性涂层。
生物惰性涂层可以阻止血液与器械表面之间的相互作用，尤其是非特异性蛋白质吸附。目前主要有两种构建方法：(1)构建聚乙二醇(PEG)或两性离子聚合物等亲水刷或水凝胶，抑制蛋白质、血小板等的吸附；(2)构建滑移表面，抑制水分子或血液润湿从而阻碍蛋白质、血小板等在材料/器械表面吸附。尽管PEG涂层在短期应用中展现出了较好的非特异性黏附和抗凝性，但在长期体内实验中，该涂层表面的链段易被氧化分解，且PEG层的链长和表面密度逐渐减少，更适合短期使用的血液接触类器械。
生物活性涂层是在高分子材料表面引入生物活性物质，如肝素、一氧化氮(NO)、抗凝药物等形成生物活性涂层，预防凝血和血栓形成。这些活性物质可以选择性吸附或结合特定的生物大分子，抑制血液中凝血酶的产生。
目前最常见的生物活性涂层主要有：肝素钠盐涂层、抗凝药物涂层和一氧化氮涂层。肝素钠虽然抗凝血性良好，但肝素钠在高分子材料表面固定后生物活性会降低，通常在其表面接枝PEG亲水性钝化层作为间隔臂来提高肝素活性、减少血浆蛋白和血小板的黏附，从而保证其优异的抗凝性能。
抗凝药物涂层是将具有抗凝机制的药物涂层在血液接触器械上，以增强抗血栓能力，这些药物包括玉米胰蛋白酶抑制剂(CTI)、血栓调节蛋白(TM)、直接凝血酶抑制剂水蛭素等，虽然CTI、TM和水蛭素涂层表面在体外较稳定且能显著降低血小板黏附、活化和血栓形成，但前期处理与保存及后期合成过程较为繁琐复杂，不易制备。
NO涂层技术，NO作为一种重要的信号分子在许多生物活动过程中被发现，其中包括作为杀菌剂和抗血栓剂的这两种优异性能。其主要是由一氧化氮合酶(NOS)催化氧化L-精氨酸末端胍基中的氮而产生，是正常血管内皮细胞释放的一种舒张血管的重要活性物质，可使血管张力得到调节，维持正常的血液流动。
其抗凝机制是：NO经内皮细胞释放后迅速在细胞外液中弥散，并与该受体相结合，激活血小板等靶细胞，促使三磷酸鸟苷环化酶生成环磷酸鸟苷(cGMP)，使cGMP的量增加并降低血小板激活所需要的钙离子浓度，从而抑制血小板激活和集聚的功能。
虽然NO作为供体在生物应用中有着良好的抗炎和抗凝血性，但其主要缺点就是不稳定易分解，且随着时间的推移涂层表面的量逐渐减少。因此，该涂层在长期应用中会失去其抗凝血性能。
医用高分子材料及器械抗凝血表面构建研究虽取得了一定进展，但目前抗凝血策略仍存在一些不足，亟待在以下3方面进行突破：(1)材料/器械抗凝表面改性新方法和新技术的建立；(2)材料/器械表面抗凝性能提高的同时，在表面固定的生物活性物质以及涂层的稳定性和生物相容性对于器械长期应用也十分重要；(3)加快开发复合型抗凝涂层，如：兼备抗凝血、抗炎等多功能复合涂层技术。
发明内容
本发明的目的是提供一种抗凝血抗炎活性ECMO体外循环通道设备及其制备方法，提高ECMO体外循环通道设备表面抗凝血性能和抗炎性能，同时提高其生物相容性。
为实现上述目的，本发明提供了一种抗凝血抗炎活性ECMO体外循环通道设备，包括复合抗凝血抗炎涂层修饰的ECMO体外循环管道，所述复合抗凝血抗炎涂层为复合多糖涂层，所述复合多糖为多种硫酸化多糖和氧化多糖的混合物。
优选的，所述复合多糖包括38.33％硫酸化葛根多糖、26.67％硫酸化白芨多糖、20.00％硫酸化糖胺聚糖片段、15.00％氧化蛋白聚糖片段。
一种抗凝血抗炎活性ECMO体外循环通道设备的制备方法，包括以下步骤：
(1)医用高分子材料的预处理：量取30mL-70ml98％浓硫酸，加入到54mL-72ml水中，称取0.3g-0.5gKMnO4，配制成质量分数为36.36％-48.52％酸化溶液；将医用高分子材料浸入到所述酸化溶液中，酸化处理2min-10min，用蒸馏水冲洗干净，真空干燥；
(2)医用高分子材料表面氨基化处理：将预处理后的医用高分子材料与质量分数为0.01-0.08％的亚胺聚合物溶液进行氨基化反应，终止反应后分别将医用高分子材料取出，用蒸馏水清洗干净，真空干燥；
(3)医用高分子材料表面抗凝血抗炎修饰：45℃-55℃恒温水浴条件下，浓度为0.8g/L-2.5g/L复合多糖和表面氨基化处理的医用高分子材料在催化剂的作用下，发生Schiff-base交联反应，反应2-6小时，在医用高分子材料表面交联形成稳定的有抗凝血抗炎活性表面。
优选的，所述医用高分子材料为硅橡胶、聚丙烯、聚乙烯、聚偏氟乙烯、聚氯乙烯、聚苯乙烯、聚酯、聚氨酯、聚碳酸酯中的一种。
优选的，所述催化剂为KCN、NaSH、CH3BNNa中的一种。
优选的，所述催化剂质量分数为0.05-0.15％。
医用高分子材料与血液接触时，在相接触的界面发生一系列复杂的相互作用，首先是医用高分子材料表面吸附血浆中的蛋白质形成蛋白质吸附层，具体被吸附蛋白的种类和数量取决于所接触医用高分子材料的表面理化性质。
发生吸附现象后，血浆蛋白分子的构象迅速发生变化，引发内源性凝血(凝血因子活化造成凝血酶原变为凝血酶，纤维蛋白原变为纤维蛋白)和外源性凝血(血浆蛋白质诱导血小板枯附、聚集并激活)，进而发生血液的凝血反应以及血栓的形成。
与血液接触的医用高分子材料表面电荷、化学组成(官能团)、亲疏水性和表面形貌等因素都对其血液相容性有直接影响。与血液直接接触的医用高分子材料，必须具备良好的血液相容性，包括抗凝血性、不溶血、不激发血小板、不影响血中脂蛋白、不改变电解质平衡等。
最常用的医用高分子材料为硅橡胶(SR)、聚氯乙烯(PVC)以及聚氨酯(PU)，虽然具有一定的生物功能性，但其血液相容性尚不能满足临床上的需求，需要对其进行抗凝血改性。
目前，对体外循环材料进行抗凝血修饰应用最广泛的抗凝剂是肝素。以离子键的形式将肝素固定于体外循环材料，肝素无法稳定存在于体外循环材料表面，在使用过程中会被血液成分带走而很快耗尽，从而导致抗凝血功能丧失。通过共价键的形式也能将肝素接枝于体外循环材料表面，其稳定性大大提高，但这种形式严重影响了肝素在体外循环材料表面的抗凝血性能。另外，体外循环管道与人体接触的创口处容易发炎，严重时甚至给机体造成严重的损伤，因此，对体外医用材料进行抗炎改性是很有必要的。
真实的医疗环境是复杂的，对医用材料的特性需求也是多样的。与血液接触类材料既要具备优异的血液相容性以防止血栓，同时也需要一定的抗炎性能以防止治疗过程中可能的感染；抗炎抗凝血改性应多管齐下，提高医用材料的血液相容性。
因此，本发明采用上述一种抗凝血抗炎活性ECMO体外循环通道设备及其制备方法，具有如下技术效果：
(1)能适应多种类型和材质的血液体外循环管道抗凝血抗炎修饰，具有抗蛋白质吸附、减少血小板黏附和聚集、抑制内源性凝血因子活化、抑制血栓形成、促进材料伪内膜化等特点；
(2)基于共价键结合的抗凝血修饰、抗炎修饰的ECMO管道，具有良好的材料安全性、良好的血液相容性、以及不易脱落稳定性高的特点、兼具抗凝血抗炎双重功效、适宜较长时间的体外循环；
(3)有望降低医疗费用，产生良好的经济效益和社会效益。
下面通过附图和实施例，对本发明的技术方案做进一步的详细描述。
附图说明
为了更清楚地说明本发明的实施方式或现有技术中的技术方案，下面将对实施方式或现有技术描述中所需要使用的附图作简单地介绍。
图1为实施例二中ECMO体外循环通道的红外吸收光谱；
图2为实施例四中ECMO体外循环通道的红外吸收光谱；
图3为实施例五中ECMO体外循环通道的红外吸收光谱；
图4为未涂层修饰ECMO体外循环通道的红外吸收光谱；
图5为实施例一～实施例三中的抗凝血抗炎活性ECMO体外循环通道的电镜图；
图6为未经复合多糖修饰的SR、PU、PVC材料的ECMO体外循环通道的电镜图。
具体实施方式
以下通过附图和实施例对本发明的技术方案作进一步说明。
除非另外定义，本发明使用的技术术语或者科学术语应当为本发明所属领域内具有一般技能的人士所理解的通常意义。实施例一
一种具有抗凝血抗炎活性ECMO体外循环通道设备，包括复合抗凝血抗炎涂层修饰的ECMO体外循环管道。复合抗凝血抗炎涂层为复合多糖涂层，复合多糖包括38.33％硫酸化葛根多糖、26.67％硫酸化白芨多糖、20.00％硫酸化糖胺聚糖片段、15.00％氧化蛋白聚糖片段。
一种抗凝血抗炎活性ECMO体外循环通道设备的制备方法，包括以下步骤：(1)高分子材料硅橡胶的预处理：量取38ml98％浓硫酸，加入到55ml水中，称取0.35gKMnO4，配制成质量分数为40.42％酸化溶液；将高分子材料硅橡胶浸入到所述酸化溶液中，酸化处理6min，用蒸馏水冲洗干净，真空干燥；
(2)高分子材料硅橡胶表面氨基化处理：将预处理后的高分子材料硅橡胶与质量分数为0.06％的亚胺聚合物溶液进行氨基化反应，终止反应后分别将高分子材料硅橡胶取出，用蒸馏水清洗干净，真空干燥；
(3)高分子材料硅橡胶表面抗凝血抗炎修饰：45℃恒温水浴条件下，浓度为1.2g/L复合多糖和表面氨基化处理的高分子材料硅橡胶在质量分数为0.09％催化剂KCN的作用下，发生Schiff-base交联反应，反应4小时，在高分子材料硅橡胶表面交联形成稳定的有抗凝血抗炎活性表面。
实施例二
一种抗凝血抗炎活性ECMO体外循环通道设备的制备方法，包括以下步骤：
(1)聚氯乙烯的预处理：量取58ml98％浓硫酸，加入到70ml水中，称取0.3gKMnO4，配制成质量分数为44.64％酸化溶液；将高分子材料硅橡胶浸入到所述酸化溶液中，酸化处理5min，用蒸馏水冲洗干净，真空干燥；
(2)聚氯乙烯表面氨基化处理：将预处理后的高分子材料硅橡胶与质量分数为0.07％的亚胺聚合物溶液进行氨基化反应，终止反应后分别将高分子材料硅橡胶取出，用蒸馏水清洗干净，真空干燥；
(3)聚氯乙烯表面抗凝血抗炎修饰：47℃恒温水浴条件下，浓度为1.2g/L复合多糖和表面氨基化处理的高分子材料硅橡胶在质量分数为0.12％催化剂NaSH的作用下，发生Schiff-base交联反应，反应6小时，在聚氯乙烯表面交联形成稳定的有抗凝血抗炎活性表面。
复合多糖包括38.33％硫酸化葛根多糖、26.67％硫酸化白芨多糖、20.00％硫酸化糖胺聚糖片段、15.00％氧化蛋白聚糖片段。
实施例三
一种抗凝血抗炎活性ECMO体外循环通道设备的制备方法，包括以下步骤：(1)聚氨酯的预处理：量取42ml98％浓硫酸，加入到66ml水中，称取0.43gKMnO4，配制成质量分数为38.50％酸化溶液；将高分子材料硅橡胶浸入到所述酸化溶液中，酸化处理8min，用蒸馏水冲洗干净，真空干燥；
(2)聚氨酯表面氨基化处理：将预处理后的高分子材料硅橡胶与质量分数为0.06％的亚胺聚合物溶液进行氨基化反应，终止反应后分别将高分子材料硅橡胶取出，用蒸馏水清洗干净，真空干燥；
(3)聚氨酯表面抗凝血抗炎修饰：48℃恒温水浴条件下，浓度为1.2g/L复合多糖和表面氨基化处理的高分子材料硅橡胶在质量分数为0.08％催化剂CH3BNNa的作用下，发生Schiff-base交联反应，反应5小时，在聚氨酯表面交联形成稳定的有抗凝血抗炎活性表面。
复合多糖包括38.33％硫酸化葛根多糖、26.67％硫酸化白芨多糖、20.00％硫酸化糖胺聚糖片段、15.00％氧化蛋白聚糖片段。
实施例四
一种抗凝血抗炎活性ECMO体外循环通道设备的制备方法，采用实施例二的制备方法，不同之处在于复合多糖的浓度为0.8g/L。
实施例五
一种抗凝血抗炎活性ECMO体外循环通道设备的制备方法，采用实施例二的制备方法，不同之处在于复合多糖的浓度为2.5g/L。
对比例一
一种抗凝血抗炎活性ECMO体外循环通道设备的制备方法，采用实施例二的制备方法，不同之处在于没有对聚氯乙烯进行预处理。
试验测试
(1)抗凝血抗炎涂层表面功能基团特性分析：
通过红外光谱法检测，检测对象为实施例二、实施例四、实施例五、对比例一中的抗凝血抗炎活性ECMO体外循环通道和未经复合多糖涂层修饰过的ECMO体外循环通道。
其中实施例二、实施例四、实施例五中的抗凝血抗炎活性ECMO体外循环通道在3350nm处均有一个宽且较浅的醛基吸收峰，而未经预处理和涂层的ECMO体外循环通道没有这个吸收峰，表明复合多糖已成功通过醛基固定在管路材料表面。
波长为1025-1210nm处为硫酸根基团(-SO3)的反对称伸缩振荡吸收峰，通过红外光谱可以看出，实施例二、实施例四、实施例五具有硫酸根基团的吸收峰，而对比例一和未经复合多糖涂层修饰过的ECMO体外循环通道没有，说明通过硫酸化处理后的多糖硫酸酯已经固定于材料表面。
图1为实施例二中ECMO体外循环通道的红外吸收光谱；
图2为实施例四中ECMO体外循环通道的红外吸收光谱；
图3为实施例五中ECMO体外循环通道的红外吸收光谱；
图4为未涂层修饰ECMO体外循环通道的红外吸收光谱。
(2)对实施例一～实施例三中制备的ECMO体外循环通道和未进行复合多糖修饰的ECMO体外循环通道进行凝血性检测，检测结果如表1所示。
SR、PVC、PU复合多糖涂层凝血四项指标(x±s,n＝6,s)
(3)SEM检测
对实施例一～实施例三中的抗凝血抗炎活性ECMO体外循环通道和未经复合多糖修饰的SR、PU、PVC材料的ECMO体外循环通道进行电镜扫描。
其中，实施例一的电镜图为图5中A部分，实施例二的电镜图见图5中B部分，实施例三的电镜图见图5中C部分。
未经复合多糖修饰的SR材料的ECMO体外循环通道电镜图见图6中A部分，未经复合多糖修饰的PVC材料的ECMO体外循环通道电镜图见图6中B部分，未经复合多糖修饰的PU材料的ECMO体外循环通道电镜图见图6中C部分。
因此，本发明采用上述一种具有抗凝血抗炎活性ECMO体外循环通道设备及其制备方法，能适应多种类型和材质的血液体外循环管道抗凝血抗炎修饰，具有抗蛋白质吸附、减少血小板黏附和聚集、抑制内源性凝血因子活化、抑制血栓形成、促进材料伪内膜化等特点；基于共价键结合的抗凝血修饰、抗炎修饰的ECMO管道，具有良好的材料安全性、良好的血液相容性、以及不易脱落稳定性高的特点、兼具抗凝血抗炎双重功效、适宜较长时间的体外循环；有望降低医疗费用，产生良好的经济效益和社会效益。
最后应说明的是：以上实施例仅用以说明本发明的技术方案而非对其进行限制，尽管参照较佳实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对本发明的技术方案进行修改或者等同替换，而这些修改或者等同替换亦不能使修改后的技术方案脱离本发明技术方案的精神和范围。
Claims (7)
1.一种抗凝血抗炎活性ECMO体外循环通道设备，其特征在于：包括复合抗凝血抗炎涂层修饰的ECMO体外循环管道，所述复合抗凝血抗炎涂层为复合多糖涂层，所述复合多糖涂层为多种硫酸化多糖和氧化多糖的混合物。
2.根据权利要求1所述的一种抗凝血抗炎活性ECMO体外循环通道设备，其特征在于：所述多糖包括植物多糖、动物多糖和海洋多糖中至少一种，较佳地包括植物多糖和动物多糖；较佳地，所述植物多糖包括葛根多糖和/或白芨多糖和/或黄芪多糖；较佳地，所述动物多糖包括糖胺聚糖和/或蛋白聚糖；较佳地，所述海洋多糖包括海藻酸钠。
3.根据权利要求2所述的一种抗凝血抗炎活性ECMO体外循环通道设备，其特征在于：所述复合多糖包括38.33％硫酸化葛根多糖、26.67％硫酸化白芨多糖、20.00％硫酸化糖胺聚糖片段、15.00％氧化蛋白聚糖片段。
4.一种如权利要求1～3任一项所述的抗凝血抗炎活性ECMO体外循环通道设备的制备方法，其特征在于，包括以下步骤：
(1)医用高分子材料的预处理：量取30mL-70ml 98％浓硫酸，加入到54mL-72ml水中，称取0.3g-0.5g KMnO4，配制成质量分数为36.36％-48.52％酸化溶液；将医用高分子材料浸入到所述酸化溶液中，酸化处理2min-10min，用蒸馏水冲洗干净，真空干燥；
(2)医用高分子材料表面氨基化处理：将预处理后的医用高分子材料与质量分数为0.01-0.08％的亚胺聚合物溶液进行氨基化反应，终止反应后分别将医用高分子材料取出，用蒸馏水清洗干净，真空干燥；
(3)医用高分子材料表面抗凝血抗炎修饰：45℃-55℃恒温水浴条件下，浓度为0.8g/L-2.5g/L复合多糖和表面氨基化处理的医用高分子材料在催化剂的作用下，发生Schiff-base交联反应，反应2-6小时，在医用高分子材料表面交联形成稳定的有抗凝血抗炎活性表面。
5.根据权利要求4所述的一种抗凝血抗炎活性ECMO体外循环通道设备的制备方法，其特征在于：所述医用高分子材料为硅橡胶、聚丙烯、聚乙烯、聚偏氟乙烯、聚氯乙烯、聚苯乙烯、聚酯、聚氨酯、聚碳酸酯中的一种。
6.根据权利要求4所述的一种抗凝血抗炎活性ECMO体外循环通道设备的制备方法，其特征在于：所述催化剂为KCN、NaSH、CH3BNNa中的一种。
7.根据权利要求4所述的一种抗凝血抗炎活性ECMO体外循环通道设备的制备方法，其特征在于：所述催化剂质量分数为0.05％-0.15％。
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