CN116808316A - 药物洗脱支架表面载药和抗凝血复合涂层的制备方法及心脏支架 - Google Patents
药物洗脱支架表面载药和抗凝血复合涂层的制备方法及心脏支架 Download PDFInfo
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Abstract
本发明涉及一种药物洗脱支架表面载药和抗凝血复合涂层的制备方法及心脏支架，包括如下步骤：S1，将药物洗脱支架的基体表面进行活化；S2，载药涂层的制备；S3，表面亲水涂层的制备，同时公开了采用该方法制得的心脏支架。该发明改善了支架表面的亲水性，提高了支架的生物相容性，通过药物涂层药物释放和表面亲水涂层亲水的协同作用,减少表面血液蛋白的黏附和血栓的形成，减少支架置入后血液流动的阻力，降低血栓和血管狭窄的风险。
Description
技术领域
本发明涉及药物洗脱支架表面生物相容性改性领域，尤其是一种药物洗脱支架表面载药和抗凝血复合涂层的制备方法及心脏支架。
背景技术
21世纪以来，随着药物洗脱支架集采，药物载体以及抗增生药物的发展，药物洗脱支架行业迎来了较快的发展。支架技术多次创新，相关产品不断更迭。药物洗脱支架(DrugElutingStent)，又称药物释放支架，利用裸金属或可降解聚合物如聚左旋乳酸(PLLA)为基体，携带抗血管内膜增生的药物，将支架置入血管病变部位后，药物自聚合物涂层洗脱释放至心血管壁组织，通过干扰平滑肌增殖，有效防止手术后血管再狭窄。目前市场上采用的主流药物洗脱支架为第二代产品，其基体多为铬钴合金或316L不锈钢，基体表面有经过优化的聚合物载药涂层以改善生物相容性和机械完整性，并达到改善洗脱支架植入后安全性的问题。
但是在将支架置入血管病变部位后，会面临血管平滑肌细胞增殖和血液内的血小板覆盖两大挑战，前者会再次导致血管内腔狭窄，进而引起支架失效。后者可能引发血栓危及生命。因此抗平滑肌细胞增殖和抗凝血是置入药物洗脱支架亟待解决的两个问题。在临床及实际应用中，多采取聚合物包裹抗增殖药物(如雷帕霉素、紫杉醇等)涂层来抑制平滑肌细胞黏附及生长；用肝素涂层或口服抗凝血/抗血小板药物如氯吡格雷、波立维等药物抑制血栓形成。尽管抗增殖药物涂层可将血管内壁狭窄发生概率降低至10％，且口服抗凝血药物治疗方案也已成熟；但仍无法完全避免血管内壁再狭窄的风险，如过早的停用双重抗凝血药物，抗增殖药物的副作用导致血管内皮功能异常和局部炎症反应。并且，由于聚合物表面的疏水性，会导致血液蛋白的黏附从而形成血栓，疏水表面也会导致血液形成涡流增加流动阻力，减缓血液流速，增加血栓风险。不论是第二代洗脱支架还是第三代可降解支架，术后的血栓形成，都是支架手术亟待解决的临床风险。
发明内容
针对现有的不足，本发明提供一种药物洗脱支架表面载药和抗凝血复合涂层的制备方法及心脏支架。
本发明解决其技术问题所采用的技术方案是：一种药物洗脱支架表面载药和抗凝血复合涂层的制备方法，包括如下步骤：
S1，将药物洗脱支架的基体表面进行活化；
S2，载药涂层的制备，将环氧树脂、脂肪胺类固化剂、需要释放的抗增殖药物分别溶解在有机溶剂中制得医用环氧树脂溶液、医用固化剂溶液、待释放药物溶液；将活化后的基体依次浸泡于医用环氧树脂溶液、待释放药物溶液和医用固化剂溶液中浸涂，并反复多次形成载药涂层；
S3，表面亲水涂层的制备，将热引发剂溶于有机溶剂中制得引发剂溶液；将形成有载药涂层的基体依次浸泡在医用环氧树脂溶液、引发剂溶液、医用固化剂溶液形成引发剂涂层，并在室温下静置固化；固化后将基体浸泡于亲水性单体溶液中，并加热制得亲水涂层。
作为优选，所述基体表面活化包含如下步骤：
S1a，将基体依次用去离子水、酒精超声清洗，清洗后用氮气吹干；
S1b，将洗净后的基体在等离子活化仪中活化。
作为优选，所述等离子活化仪活化用的气体是压缩空气、氮气、氩气、氧气中的任意一种，活化时间是1-10min，活化功率为1-2000W。
作为优选，所述医用环氧树脂溶液、医用固化剂溶液、待释放药物溶液在有机溶剂中的质量浓度均为1-15％。
作为优选，所述有机溶剂是丙酮。
作为优选，所述热引发剂在有机溶剂中的质量浓度为1-20％。
作为优选，所述亲水性单体是聚乙二醇类化合物或者是具有两性离子的有机化合物。
作为优选，所述亲水性单体是聚(乙二醇)甲基丙烯酸酯、[2-(甲基丙烯酰氧基)乙基]二甲基-(3-磺丙基)氢氧化铵、甲基丙烯酰氧基乙基磷酸胆碱中的任意一种。
作为优选，所述热引发剂是偶氮类引发剂。
一种心脏支架，所述心脏支架上具有如前任意一项所述的药物洗脱支架表面载药和抗凝血复合涂层的制备方法制备的多功能复合涂层。
本发明的有益效果在于：该发明通过在支架表面形成一个具有亲水性的表层，提高了支架的生物相容性，有效阻止血液蛋白质的黏附，达到抗凝血和抗平滑肌细胞黏附的目的，从而降低血栓的形成和内腔变窄的概率。同时，该复合涂层底层为聚合物载药涂层，可释放抑制平滑肌增生的药物，通过药物涂层药物释放和表面亲水涂层亲水的协同作用，减少支架置入后血液流动的阻力，减少支架置入后血液流动的阻力，降低血栓和血管狭窄的风险，可广泛方便的地应用于各种基体的药物洗脱支架的改性。
附图说明
图1是本发明实施例复合涂层制备流程示意图；
图2是本发明实施例1、2、3的心脏支架和裸金属药物洗脱支架的横截面扫描电镜图的对照示意图；
图3是本发明实施例1的心脏支架亲水性测试示意图；
图4是本发明实施例2的心脏支架亲水性测试示意图；
图5是本发明实施例3的心脏支架亲水性测试示意图；
图6是本发明实施例心脏支架抗蛋白黏附测试；
图7是本发明实施例新西兰兔静脉血培养后血液细胞以及表皮细胞在心脏支架表面的黏附。
具体实施方式
下面将结合实施例对本发明作进一步说明，进行清楚、完整的描述，应理解，这些实施例是用于说明本发明而不限于限制本发明的范围。实施例中采用的实施条件可以根据具体厂家的条件做进一步调整，未注明的实施条件通常为常规实验中的条件。
本发明实施例，一种药物洗脱支架表面载药和抗凝血复合涂层的制备方法及心脏支架，实施例中的药物洗脱支架选择金属心脏支架，如图1中所示，包括如下步骤：
S1，将药物洗脱支架的基体(基材)表面进行活化，活化时，
S1a，将金属心脏支架依次用去离子水，酒精超声清洗10分钟后，用氮气吹干；
S1b，将洗净后的心脏支架在等离子活化仪中活化1-10分钟，此时，等离子活化仪活化用的气体是压缩空气、氮气、氩气、氧气中的任意一种，活化时间是1-10min，活化功率为1-2000W；
S2，载药涂层的制备，将环氧树脂、脂肪胺类固化剂、需要释放的抗增殖药物分别溶解在有机溶剂中制得医用环氧树脂溶液、医用固化剂溶液、待释放药物溶液，有机溶剂是丙酮，抗增殖的药物选用雷帕霉素或紫杉醇等类似药物，将环氧树脂、脂肪胺类固化剂、需要释放的抗增殖药物分别溶解在丙酮中形成质量浓度在1-15％的医用环氧树脂溶液、医用固化剂溶液、待释放药物溶液，优选它们的浓度均为10％；在制备好各种溶液后，将活化后的基体依次浸泡于医用环氧树脂溶液、待释放药物溶液和医用固化剂溶液中浸涂，并反复多次形成载药涂层，即先将活化后的基体浸泡在医用环氧树脂溶液中，然后再浸泡在待释放药物溶液中，最后浸泡在医用固化剂溶液中形成一个动作周期，之后就多次重复这个动作周期，直至在基体表面形成载药涂层；
S3，表面亲水涂层的制备，将热引发剂溶于有机溶剂中制得引发剂溶液，热引发剂选用偶氮类引发剂，如AIBN,有机溶剂和前一步骤中各溶液制备时所使用的有机溶剂相同，如丙酮，引发剂溶液的质量浓度为1-20％，如浓度为13％的引发剂溶液；将形成有载药涂层的基体依次浸泡在医用环氧树脂溶液、引发剂溶液、医用固化剂溶液形成引发剂涂层，也就是说将前一步骤中形成有载药涂层的基体先浸泡在医用环氧树脂溶液中，之后再浸泡在引发剂溶液中，最后浸泡在医用固化剂溶液中形成一个流程以引入引发剂，重复该流程多次直至形成引发剂涂层，浸泡完毕后后将其在室温下静置固化，静置时间以引发剂涂层完全牢固的固化为止，如室温下静置固化24小时；固化后将基体浸泡于亲水性单体溶液中，并加热制得亲水涂层，加热就引发表面聚合反应形成亲水涂层，亲水性单体溶液的亲水性单体是聚乙二醇类化合物或者是具有两性离子的有机化合物，如聚(乙二醇)甲基丙烯酸酯、[2-(甲基丙烯酰氧基)乙基]二甲基-(3-磺丙基)氢氧化铵(SBMA)、甲基丙烯酰氧基乙基磷酸胆碱(MPC)中的任意一种。
这样的心脏支架表面得到了改性，可广泛应用于不同基材的心脏药物洗脱支架，提高生物相容性，从而实现与血液接触的支架无肝素自抗凝血，可有效地降低肝素，枸橼酸钠等抗凝血的使用，从而减轻其副作用，如易出血，高血钾症，低血钙症等，实现了涂层的牢固定植，延长了支架表面自抗凝的时效；同时由于亲水性抗蛋白黏附涂层的引入，可有效降低表面蛋白质的黏附，降低免疫反应和平滑肌细胞的附着。
具体实施例如下：
实施例1：在裸金属钛合金心脏支架表面复合涂层的制备
[1]载药涂层的制备
将环氧树脂和脂肪胺类固化剂(汉高乐泰LoctiteEAM-21hp)分别溶解在丙酮中制成质量浓度为10％的医用环氧树脂溶液、医用固化剂溶液；将需要释放雷帕霉素(Sirolimus)溶解于丙酮中制成质量浓度为10％的雷帕霉素溶液；之后将裸金属钛合金心脏支架依次浸泡于医用环氧树脂溶液、雷帕霉素溶液和医用固化剂溶液中浸涂，并反复多次，以形成载药涂层。
[2]亲水涂层的制备
将热引发剂AIBN溶于丙酮中制成质量浓度为13％的引发剂溶液，将改性的心脏支架也就是前一步骤形成的具有载药涂层的心脏支架依次浸泡于医用环氧树脂溶液、引发剂溶液和医用固化剂溶液中以引入引发剂，可反复多次形成引发剂涂层；之后将具备引发剂涂层的心脏支架在室温下静置24小时以达到涂层完全牢固的固化；固化完成后将具备引发剂涂层的心脏支架浸泡于聚(乙二醇)甲基丙烯酸酯(PEGMA)单体的溶液中，并加热引发表面聚合反应形成亲水性涂层，得到最终产品，记为S-PEGMA。
实施例2：采用与实施例1相同的步骤，只是将聚(乙二醇)甲基丙烯酸酯(PEGMA)替换为[2-(甲基丙烯酰氧基)乙基]二甲基-(3-磺丙基)氢氧化铵(SBMA)，记作S-SBMA。
实施例3：采用与实施例1相同的步骤，只是将聚(乙二醇)甲基丙烯酸酯(PEGMA)替换为甲基丙烯酰氧基乙基磷酸胆碱(MPS)，记作S-MPC。
对心脏支架的复合涂层进行表征：
所有经过涂覆改性的基体，如心脏支架，可用扫描电镜直接观测横截面并测量出涂层的结构，厚度和均一性，同时将具有该复合涂层的心脏支架与其它同类材质的心脏支架进行亲水性测试验证。
对心脏支架的复合涂层和作为对照组的裸金属支架分别进行测试比较：
对改性心脏支架抗蛋白黏附测试和体外抗凝血测试可直观的模拟出实际应用中基体表面与含蛋白质的人体血液长期接触的情况；由于清白蛋白、纤维蛋白原两种蛋白质在人体血液中广泛存在，并是血栓形成的主要诱因，首先进行的体外蛋白质黏附测试可证明基体表面涂层的抗血栓效果；当基体置于体内以后，人体体液内的更复杂的多糖及蛋白质会缓慢的黏附在基材表面，血液接触实验就会更准确的模拟出涂层的抗凝血效。
将实施例1、2、3中制得的心脏支架(亦即改性好的心脏支架)以及作为对照组的裸金属支架分别进行如下测试来进行比较，测试方法如下：
1)抗蛋白黏附测试
将心脏支架在磷酸(PBS)缓冲液放置12小时以保证表面水层完全形成后，将磷酸缓冲液排出，并注入1％的待测蛋白，如牛血清白蛋白，纤维蛋白原等血液中常见的蛋白质，并在37℃培养24小时。之后，用PBS缓冲液将心脏支架冲洗三次，以洗净心脏支架表面游离的蛋白质；再浸泡于1％的十二烷基硫酸钠(SDS)溶液中，超声15分钟，以洗下黏附在心脏支架上的的蛋白质，收集在96孔板中，用二辛可宁酸测定(BCA)测定蛋白浓度。
2)抗血细胞黏附测试
在新西兰白兔颈静脉取10毫升静脉血，并分装在2毫升的小离心管中，将血液与心脏支架共同在37℃下培养2小时；之后用PBS缓冲液将心脏支架冲洗三次；再用SDS洗脱支架表面黏附细胞，并用流式细胞仪确认细胞属性及浓度。
结果分析：
如图2中所示是支架横截面的扫描电镜图，在仅附着医用环氧树脂载药涂层而无亲水层的裸金属药物洗脱支架(心脏支架+载药涂层)，其表面可形成一层10微米厚的均匀载药涂层；在实施例1、2、3中，在表面引发亲水性单体聚合后，载药层表面定植了一层明显的亲水性涂层，在扫描电镜下，改性的心脏支架截面呈现出明显的两层涂层结构，证明了本方法可在心脏支架表面均匀涂覆载药和亲水性的复合涂层。同时，该复合涂层的亲水性也得到了验证，如图3至5中所示，改性的钛合金心脏支架亲水性变化对照示意图中所示，实施例1采用PEG涂层的钛金属片接触角降低到23.78°，实施例2的接触角降低到了10.60°，实施例3的接触角降低到了11.28°，达到了超亲水的效果。
由于涂层良好的亲水性，在与水接触时，会瞬间形成一层牢固致密的水膜，从而阻挡血液中蛋白质和细胞的黏附。在与血清蛋白和纤维蛋白原共同培养的实验中，如图6心脏支架抗蛋白黏附测试中所示，对照组为裸金属支架，实施例1(S-PEGMA涂层)可以实现60-80％的抗血清蛋白和纤维蛋白原的效果；而实施例2和3，则可以达到接近或大于95％抗血清蛋白和纤维蛋白原效果。
新西兰兔血液常用于检测医疗耗材中的过敏原或病原体，在与新西兰兔静脉血体外共同培养的实验中，如图7新西兰兔静脉血培养后血液细胞以及表皮细胞在心脏支架表面的黏附中所示，对照组为裸金属支架，实施例1，2，3表面的血细胞黏附对比裸金属心脏支架有了明显的减少，其中单核细胞为血液中直径较大的细胞，而淋巴细胞为人体内主要的免疫细胞。该实验证实了复合涂层良好的血细胞相容性和免疫相容性。除血细胞和淋巴细胞外，血液中也会有游离的表皮细胞，若定植在植入的心脏支架后，可能会形成平滑肌的增生从而加快血管狭窄化。而实施例2、3显示出了比实施例1聚乙二醇涂层更加优异的抗表皮细胞黏附效果，其抗表皮细胞黏附效果可达90％；在和雷帕霉素的协同作用下，该复合涂层可以达到更好的抗血管增生，抗血栓效果。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.一种药物洗脱支架表面载药和抗凝血复合涂层的制备方法，其特征在于：包括如下步骤：
S1，将药物洗脱支架的基体表面进行活化；
S2，载药涂层的制备，将环氧树脂、脂肪胺类固化剂、需要释放的抗增殖药物分别溶解在有机溶剂中制得医用环氧树脂溶液、医用固化剂溶液、待释放药物溶液；将活化后的基体依次浸泡于医用环氧树脂溶液、待释放药物溶液和医用固化剂溶液中浸涂，并反复多次形成载药涂层；
S3，表面亲水涂层的制备，将热引发剂溶于有机溶剂中制得引发剂溶液；将形成有载药涂层的基体依次浸泡在医用环氧树脂溶液、引发剂溶液、医用固化剂溶液形成引发剂涂层，并在室温下静置固化；固化后将基体浸泡于亲水性单体溶液中，并加热制得亲水涂层。
2.根据权利要求1所述药物洗脱支架表面载药和抗凝血复合涂层的制备方法，其特征在于:所述基体表面活化包含如下步骤：
S1a，将基体依次用去离子水、酒精超声清洗，清洗后用氮气吹干；
S1b，将洗净后的基体在等离子活化仪中活化。
3.根据权利要求2所述药物洗脱支架表面载药和抗凝血复合涂层的制备方法，其特征在于:所述等离子活化仪活化用的气体是压缩空气、氮气、氩气、氧气中的任意一种，活化时间是1-10min，活化功率为1-2000W。
4.根据权利要求1所述药物洗脱支架表面载药和抗凝血复合涂层的制备方法，其特征在于:所述医用环氧树脂溶液、医用固化剂溶液、待释放药物溶液在有机溶剂中的质量浓度均为1-15％。
5.根据权利要求1所述药物洗脱支架表面载药和抗凝血复合涂层的制备方法，其特征在于:所述有机溶剂是丙酮。
6.根据权利要求1所述药物洗脱支架表面载药和抗凝血复合涂层的制备方法，其特征在于:所述热引发剂在有机溶剂中的质量浓度为1-20％。
7.根据权利要求1所述药物洗脱支架表面载药和抗凝血复合涂层的制备方法，其特征在于：所述亲水性单体是聚乙二醇类化合物或者是具有两性离子的有机化合物。
8.根据权利要求7所述药物洗脱支架表面载药和抗凝血复合涂层的制备方法，其特征在于:所述亲水性单体是聚(乙二醇)甲基丙烯酸酯、[2-(甲基丙烯酰氧基)乙基]二甲基-(3-磺丙基)氢氧化铵、甲基丙烯酰氧基乙基磷酸胆碱中的任意一种。
9.根据权利要求1所述药物洗脱支架表面载药和抗凝血复合涂层的制备方法，其特征在于:所述热引发剂是偶氮类引发剂。
10.一种心脏支架，其特征在于：所述心脏支架上具有如权利要求1-9任意一项所述的药物洗脱支架表面载药和抗凝血复合涂层的制备方法制备的多功能复合涂层。
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