CN117462770A - 一种抗凝血促内皮的血流导向装置及表面改性方法 - Google Patents
一种抗凝血促内皮的血流导向装置及表面改性方法 Download PDFInfo
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Abstract
本发明公开了一种抗凝血促内皮的血流导向装置及表面改性方法，包括以下步骤：步骤1：将血流导向装置放入去离子水和无水乙醇中各清洗3次，清洗干燥后备用；步骤2：将步骤1所得样品浸入铜离子、原儿茶酸、纳豆激酶的混合溶液中，并在常温下液相沉积一定时间；步骤3：将步骤2所得样品取出，常温干燥后得到抗凝血促内皮的血流导向装置。本发明制备了具有抗凝血促内皮功能的血流导向装置，包含存在于植物体内的天然小分子原儿茶酸和抗凝血药物纳豆激酶，基于自组装和共价接枝的原理，在装置表面形成了具有抗凝血促内皮的智能释放活性分子涂层。
Description
技术领域
本发明涉及智能响应的功能表面改性技术领域，具体涉及一种抗凝血促内皮的血流导向装置及表面改性方法。
背景技术
当前临床上医治颅内动脉瘤的主要措施是在动脉瘤所在患处植入血流导向装置(又称密网支架)，血流导向装置主要通过镍钛合金或钴铬合金丝材进行编织而成，血流导向装置植入载瘤动脉后，可改变动脉瘤内血流流速、流量及剪切力，因血流动力学变化在动脉瘤囊内逐步形成血栓，并促使动脉瘤处血管再内皮化，重塑患处血管正常功能。是当前治疗颅内动脉瘤的“最优选择”。但随着临床的大规模使用，逐步暴露出一些关键问题，如装置植入前期，易诱发急性血栓形成，在血流导向装置上形成血栓甚至发生支架内再狭窄。导致患者脑供血不足，甚至脑梗死等。由于植入后需服用双抗进行抗凝血治疗，故发生不明原因出血的风险增加，是植入血流导向装置后致死的主要原因。
因此，对血流导向装置进行表面功能改性以提高其抗凝性和再内皮化，减少血流导向装置内血栓形成和促进支架表面快速内皮化是当前对血流导向装置进行表面改性的关键。国内外有报道在血流导向装置表面构建仿生抗凝功能涂层；亲水性高分子涂层等。然而，仍然存在改性效果不显著等问题，特别是在抗急性凝血及促内皮快速再生方面不能满足临床需求。本发明针对血流导向装置表面抗凝及促内皮再生关键临床需求，构建抗凝促内皮生物活性分子的智能响应功能改性涂层，促进血流导向装置在体内服役期间发挥抗凝促进内皮再生功能，从而减少术后患者服用双抗药物的剂量，大大降低术后发生血栓及其他并发症风险。
发明内容
针对上述问题，本发明提供一种抗凝血促内皮的血流导向装置的表面改性方法，包括如下步骤：
步骤1：将血流导向装置清洗干燥后备用；
步骤2：将步骤1所得样品浸入铜离子、原儿茶酸、纳豆激酶的混合溶液中，并在常温下液相沉积一定时间；
步骤3：将步骤2所得样品取出，常温干燥后得到智能释放生物活性分子的血流导向装置。
进一步的，所述步骤1中清洗的具体方法为：用无水乙醇和去离子水依次进行清洗。
进一步的，所述铜离子、原儿茶酸、纳豆激酶的混合溶液中铜离子浓度0.01-0.1mg/ml，原儿茶酸0.01-1mg/ml，纳豆激酶0.01-5mg/ml的溶液中。
进一步的，所述液相沉积时间为5min-24h。
本发明的另一方面提供一种抗凝血促内皮的血流导向装置，所述装置表面形成的涂层均匀致密，覆盖完整，涂层厚度为4-40nm。
本发明的有益效果是：
本发明构建了具有抗凝血促内皮功能的智能释放活性分子涂层的血流导向装置，包含存在于植物体内的天然小分子原儿茶酸和抗凝血药物纳豆激酶，基于自组装和共价接枝原理，铜离子、原儿茶酸、纳豆激酶通过氢键、范德华力和化学共价结合形成稳定的抗凝血促内皮智能释放活性分子涂层，涂层厚度为4-40纳米，表明涂层有较好的表界面特性，有利于材料表面抗凝血促内皮。
附图说明
为了更清楚地说明本发明实施例的技术方案，下面将对实施例的附图作简单地介绍，显而易见地，下面描述中的附图仅仅涉及本发明的一些实施例，而非对本发明的限制。
图1为本发明镍钛合金片材改性前后形貌图(SEM及AFM)示意图，图中NiTi表示镍钛合金，Cu-PCA表示在镍钛合金上沉积Cu2+和原儿茶酸涂层，Cu-PCA&NK(0.01)、Cu-PCA&NK(0.1)、Cu-PCA&NK(1)表示Cu2+和原儿茶酸及不同浓度的纳豆激酶(0.01,0.1,1)沉积的涂层；
图2为本发明镍钛合金片材改性前后涂层厚度及亲水性示意图；
图3为本发明改性涂层模拟植入血管后催化释放NO活性分子速率示意图；
图4为本发明镍钛基密网支架改性前后血小板粘附荧光图、扫描电镜图及血小板粘附定量示意图；
图5为本发明镍钛材质密网支架改性前后溶血率及凝血时间示意图；
图6为本发明镍钛合金片材改性前后内皮细胞增殖情况荧光示意图；
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将结合本发明实施例的附图，对本发明实施例的技术方案进行清楚、完整地描述。显然，所描述的实施例是本发明的一部分实施例，而不是全部的实施例。基于所描述的本发明的实施例，本领域普通技术人员在无需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。
下面结合附图和实施例对本发明进一步说明。
如图1至图5所示，一种抗凝血促内皮的血流导向装置的表面改性方法，包括以下步骤：
步骤1：将血流导向装置清洗干燥后备用。
清洗的具体方法为：用无水乙醇和去离子水依次进行清洗。
步骤2：将步骤1所得样品浸入铜离子、原儿茶酸、纳豆激酶的混合溶液中，并在常温下液相沉积一定时间。
其中所述铜离子、原儿茶酸、纳豆激酶的混合溶液中铜离子浓度0.01-0.1mg/ml，原儿茶酸0.01-1mg/ml，纳豆激酶0.01-5mg/ml的溶液中；液相沉积一定时间为5min-24h。
步骤3：将步骤2所得样品取出，常温干燥后得到智能释放生物活性分子的血流导向装置。
具体的，所述装置表面形成的涂层均匀致密，覆盖完整，涂层厚度为4-40nm。
实施例1
步骤1：将血流导向装置用无水乙醇和去离子水依次进行清洗干燥后备用。
步骤2：将步骤1所得样品浸没在CuSO4浓度为0.1mg/mL，原儿茶酸浓度0.01mg/ml，纳豆激酶为5mg/ml的混合溶液中，沉积时间为5min。
步骤3：将步骤2中所得样品取出清洗，常温干燥即可。
实施例2
步骤1：将血流导向装置用无水乙醇和去离子水依次进行清洗干燥后备用。
步骤2：将步骤1所得样品浸没在CuSO4浓度为0.01mg/mL，原儿茶酸浓度1mg/ml，纳豆激酶浓度为0.1mg/ml的混合溶液中，沉积时间为1h。
步骤3：将步骤2中所得样品取出清洗，常温干燥即可，得到Cu-PCA&NK(0.1)。
实施例3
步骤1：将血流导向装置用无水乙醇和去离子水依次进行清洗干燥后备用。
步骤2：将步骤1所得样品浸没在CuSO4浓度为0.01mg/mL，原儿茶酸浓度1mg/ml，纳豆激酶浓度为0.01mg/ml的混合溶液中，沉积时间为1h。
步骤3：将步骤2中所得样品取出清洗，常温干燥即可，得到Cu-PCA&NK(0.01)。
实施例4
步骤1：将血流导向装置用无水乙醇和去离子水依次进行清洗干燥后备用。
步骤2：将步骤1所得样品浸没在CuSO4浓度为0.01mg/mL，原儿茶酸浓度1mg/ml，纳豆激酶浓度为1mg/ml的混合溶液中，沉积时间为1h。
步骤3：将步骤3中所得样品取出清洗，常温干燥即可，得到Cu-PCA&NK(1)。
实施例5
步骤1：将血流导向装置用无水乙醇和去离子水依次进行清洗干燥后备用。
步骤2：将步骤1所得样品浸没在CuSO4浓度为0.01mg/mL，原儿茶酸浓度1mg/ml，纳豆激酶浓度为0.1mg/ml的混合溶液中，沉积时间为24h。
步骤3：将步骤2中所得样品取出清洗，常温干燥即可。
对上述改性后得到的Cu-PCA&NK(0.01)、Cu-PCA&NK(0.1)、Cu-PCA&NK(1)进行相关表征，具体结果如下：
图1显示了制得的涂层的微观形貌，可以看出图中改性后形成的涂层均匀致密，覆盖完整，达到纳米级尺度，具有良好的表界面特征。
图2显示了制得的的抗凝血促内皮智能释放生物活性分子涂层的厚度和亲水性情况，由图2可见，涂层厚度为4-40纳米，表明涂层有较好的表界面特性，对材料表面抗凝血促内皮将有利。通过UP水滴对制得的涂层的表面亲疏水性进行演示，改性之后镍钛片材都表现出较好亲水性，改性后样品表面的水滴能铺展均匀。
图3为改性后涂层在达到稳定释放活性分子NO时的平均释放速率，采用NOA 280i一氧化氮实时检测仪来检测不同样品的NO催化释放能力，首先将四种不同涂层316L SS样品，剪切成尺寸为1cm×0.5cm大小的长方形，在反应室中预先加入5mL PBS溶液，10μM GSNO和10μM GSH反应溶液。等待基线平稳后，将涂层样品放入反应液中。反应器底部通入的N2会将样品催化产生的NO气体从反应室带入到检测室中，并与臭氧发生反应生成激发态的NO2，激发态的NO2释放光子从而转为基态。该光子波长在660-900nm之间，仪器通过感应该波段的光谱，从而间接得出样品实时催化释放NO的能力，说明涂层植入后可刺激血管内产生活性分子气体NO。
图4为装置改性前后血小板粘附荧光图、扫描电镜图及血小板粘附定量。具体实验操作过程如下：
1、本实验使用的血液为无名志愿者捐献。将新鲜血液与3.8％的柠檬酸钠按照10:1混合，在离心机上离心15min，转速为1500rpm，取上清液，即为富板浆(PRP)。
2、准备好的样品加入24孔板中，每个样品表面滴加100μL的富板浆，置于37℃恒温孵箱中孵化1h。
3、将孵化的样品取出用0.9％的氯化钠清洗三遍，并用2.5％的戊二醛固定4h。
本发明利用免疫荧光染色和扫面电镜对血小板的粘附形态和激活情况进行观察，免疫荧光染色步骤为：
1.用0.9％的氯化钠清洗3次固定后的样品。
2.在每个样品表面滴加70μL罗丹明(Rhodamine-phalloidin)溶液，避光条件放置15min。
3.用0.9％的氯化钠清洗染色样品3次并吹干，在荧光显微镜下观察。
电镜扫描观察血小板步骤：
1.上述样品进行脱水处理：将样品依次放于50％，75％，90％和100％的酒精溶液中，每次15min。
2.脱醇处理：将样品依次置于50％，75％，90％和100％的乙酸异戊酯溶液中，每次15min；
3、临界点干燥，并进行喷金处理，通过扫描电镜进行观察。
如图4所示，未改性的血流导向装置表面粘附较多的血小板，而改性后的样品表面只有少量甚至没有血小板的粘附，这充分说明了改性后的涂层具有良好的抗凝效果。样品表面血小板粘附扫描电镜显示，未改性的样品表面粘附了大量的血小板，改性后的样品表面光滑平整，几乎没有血小板的粘附，结果与荧光染色一致。血小板粘附定量结果也是如此。上述结果表明改性后样品具有良好的抗凝血能力。
如图5所示，考察制得的抗凝血促内皮智能释放生物活性分子涂层的体外溶血及凝血时间，未改性和改性后材料溶血率都低于5％，证明改性后材料表面具有良好的血液相容性，凝血时间测定(PT、TT、APTT)显示，改性后样品显著提高了样品的凝血时间，证明改性后材料表面具有良好的抗凝血特性。
如图6所示，考察制得的抗凝血促内皮智能释放生物活性分子涂层的释放生物活性小分子NO，促内皮细胞粘附和增殖情况，在加入NO供体(GSNO和GSH)后，1天和3天的内皮细胞直接培养结果可见改性后材料表面可促进内皮细胞的粘附和增殖，5天的培养结果更加显著。
以上所述，仅是本发明的较佳实施例而已，并非对本发明作任何形式上的限制，虽然本发明已以较佳实施例揭露如上，然而并非用以限定本发明，任何熟悉本专业的技术人员，在不脱离本发明技术方案范围内，当可利用上述揭示的技术内容作出些许更动或修饰为等同变化的等效实施例，但凡是未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所做的任何简单修改、等同变化与修饰，均仍属于本发明技术方案的范围内。
Claims (5)
1.一种抗凝血促内皮的血流导向装置的表面改性方法，其特征在于，包括如下步骤：
步骤1：将血流导向装置清洗干燥后备用；
步骤2：将步骤1所得样品浸入铜离子、原儿茶酸、纳豆激酶的混合溶液中，并在常温下液相沉积一定时间；
步骤3：将步骤2所得样品取出，常温干燥后得到抗凝血促内皮的血流导向装置。
2.根据权利要求1所述一种抗凝血促内皮的血流导向装置的表面改性方法，其特征在于，所述步骤1中清洗的具体方法为：用无水乙醇和去离子水依次进行清洗。
3.根据权利要求1所述一种抗凝血促内皮的血流导向装置的表面改性方法，其特征在于，所述铜离子、原儿茶酸、纳豆激酶的混合溶液中铜离子浓度0.01-0.1mg/ml，原儿茶酸0.01-1mg/ml，纳豆激酶0.01-5mg/ml的溶液中。
4.根据权利要求1所述一种抗凝血促内皮的血流导向装置的表面改性方法，其特征在于，所述液相沉积时间为5min-24h。
5.采用如权利要求1-4所述任一方法制备得到一种抗凝血促内皮的血流导向装置，其特征在于，所述装置表面形成的涂层均匀致密，覆盖完整，涂层厚度为4-40nm。
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| 李新兰等: "《保健食品开发及应用》", 31 October 1999, 华中理工大学出版社, pages: 179 * |
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