CN113855864A - 一种具有抗凝血涂层的支架的制备方法及支架 - Google Patents

一种具有抗凝血涂层的支架的制备方法及支架 Download PDF

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CN113855864A
CN113855864A CN202111130705.1A CN202111130705A CN113855864A CN 113855864 A CN113855864 A CN 113855864A CN 202111130705 A CN202111130705 A CN 202111130705A CN 113855864 A CN113855864 A CN 113855864A
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stent
anticoagulant
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drying
cleaning
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高飞
徐兰馨
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Chengdu bairuihengtong Medical Technology Co.,Ltd.
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Abstract

本发明涉及血管支架，提供了一种具有抗凝血涂层的支架的制备方法，包括如下制备步骤：(1)将合金片和合金支架进行清洗并干燥；(2)将步骤(1)中的样品浸没在硅烷偶联剂溶液中，并调节pH为3.5‑5.5，浸泡时间为1.5‑2.5h，然后将其取出、清洗干净并干燥；(3)将步骤(2)中的样品分别交替浸没在抗凝药物和含铜离子的溶液中，然后将其取出，清洗干净并干燥。本发明还提供了一种基于上述制备方法制备得到的支架。本发明的具有抗凝血涂层的支架的制备方法，具有显著的抗凝血性能。

Description

一种具有抗凝血涂层的支架的制备方法及支架
技术领域
本发明涉及血管支架的技术领域，具体而言，涉及一种具有抗凝血涂层的支架的制备方法及支架。
背景技术
动脉瘤是一种较为常见的心血管疾病。主要是由于动脉血管壁自身病变或损伤，形成动脉壁局限性或弥漫性扩张或膨出的表现，以膨胀性、搏动性肿块为主要表现，动脉瘤是患者体内“定时炸弹”，随时都有可能破裂，易产生大出血威胁到患者的生命健康。针对动脉瘤的治疗方法主要有：一是传统的外科夹闭手术；二是植入弹簧圈或者密网支架及二者的结合应用。外科手术存在风险大、创伤大且伴有并发症，一般情况患者和医生都将审慎选择。神经介入弹簧圈栓塞术是传统外科夹闭术的一大进步和发展，在治疗动脉瘤方面发挥较大功用，但临床应用中发现其对治疗宽径动脉瘤、夹层动脉瘤、梭形动脉瘤等效果欠佳。当前，神经介入植入密网支架治疗动脉瘤是治疗动脉瘤的优先选择，通过植入该装置可显著降低进入动脉瘤的血液流速和流量，逐步在动脉瘤内形成血栓，并进一步重构健康的动脉血管，其具有安全性更高、适用症范围更广、操作更便捷等诸多优势。
当前临床使用的镍钛合金密网支架仍然存在一些突出问题：一是支架植入后，由于支架与血流接触面积大，容易导致密网支架上血小板的粘附和激活，形成血栓，进而导致脑供血不足、脑梗死等风险。二是植入中后期患者出血风险相对增加，自发性脑出血(IPH)是植入后最可怕的并发症，可能会对患者造成严重的神经功能损害甚至患者死亡。当前解决的方法主要是患者术后服用双抗药物，但这不仅会增加出血的风险，而且对患者而言是巨大的心理压力和经济负担。
因此，对镍钛密网支架进行表面改性以提高其抗凝功能，减少血管再狭窄风险。当前也有针对密网支架的抗凝血的改性，如在密网支架表面构建抗凝小分子功能涂层；构建亲水性高分子涂层改善支架表面的抗凝能力。然而，仍然存在研究较少，改性效果不显著等问题。
发明内容
本发明的目的在于提供一种具有抗凝血涂层的支架的制备方法，及通过该制备方法制备得到的支架，其具有显著的抗凝血性能。
本发明的实施例通过以下技术方案实现：本发明具有抗凝血涂层的支架的制备方法，包括如下制备步骤：
(1)将合金片和合金支架进行清洗并干燥；
(2)将步骤(1)中的样品浸没在硅烷偶联剂溶液中，并调节pH为3.5-5.5，浸泡时间为1.5-2.5h，然后将其取出、清洗干净并干燥；
(3)将步骤(2)中的样品分别交替浸没在抗凝药物和含铜离子的溶液中，然后将其取出，清洗干净并干燥。
更为具体的，步骤(1)中的合金为镍钛合金、钴铬合金中的一种。
进一步地，步骤(2)中的硅烷偶联剂浓度为0.5％-3％。
进一步地，步骤(2)中使用醋酸来调节溶液pH。更为具体的，调节溶液pH为4.5，浸没时间为2h。
进一步地，步骤(3)中抗凝药物为阿司匹林和肝素中的一种。更为具体的，抗凝药物浓度为0.01-0.05mg/mL。
进一步地，步骤(3)中含铜离子的溶液为氯化铜和硫酸铜中的一种，铜离子浓度为0.01mM。
进一步地，步骤(3)中样品在抗凝药物和含铜离子溶液中各浸泡3次，每次浸泡时间为15分钟。
此外，本发明还提供了通过上述制备方法制备得到的支架。
本发明实施例的技术方案至少具有如下优点和有益效果：本发明的具有抗凝血涂层的支架的制备方法，通过在金属表面进行硅烷化处理，赋予金属基材表面氨基等官能团，基于金属离子螯合、共价接枝原理，与抗凝药物产生共价键或者氢键，将抗凝药物牢牢固定在基底表面，形成具有抗凝血功能的改性涂层。
区别于传统载药涂层体系，本发明中通过金属离子螯合、共价接枝作用使固定在表面的抗凝药物更加稳定，区别于基底载药并通过缓释发生作用，此方法可持续发挥抗凝血功用。
附图说明
图1为本发明试验例1提供的密网支架改性前后亲水性演示结果；
图2为本发明试验例2提供的镍钛合金片材改性前后血小板粘附和激活荧光染色图；
图3为本发明试验例2提供的镍钛合金片材改性前后血小板粘附和激活形貌图；
图4为本发明试验例2提供的镍钛合金支架改性前后血小板粘附和激活形貌图；
图5为本发明试验例3提供的镍钛合金片材改性前后全血浸泡形貌图；
图6为本发明试验例3提供的镍钛合金支架改性前后全血浸泡形貌图；
图7为本发明试验例4提供的镍钛合金密网支架改性后半体实验效果。
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，下面将对本发明实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
实施例1
本实施例的具有抗凝血涂层的支架的制备方法，包括如下制备步骤：
(1)对镍钛合金和镍钛密网支架进行清洗并干燥；
(2)在常温条件下将步骤(1)所得样品浸没在浓度为0.5％硅烷偶联剂溶液(KH550)中，加入醋酸将pH调为3.5，浸没时间为2h，取出洗净并干燥；
(3)将步骤(2)中所得的样品在常温条件下分别浸入0.01mg/mL的阿司匹林溶液和0.01mM的氯化铜溶液中，交替沉积3次，每次15min，取出清洗干燥即可。
实施例2
本实施例的具有抗凝血涂层的支架的制备方法，包括如下制备步骤：
(1)对镍钛合金和镍钛密网支架进行清洗并干燥；
(2)在常温条件下将步骤(1)所得样品浸没在浓度为3％硅烷偶联剂溶液(KH550)中，加入醋酸将pH调为3.5，浸没时间为2h，取出洗净并干燥；
(3)将步骤(2)中所得的样品在常温条件下分别浸入0.01mg/mL的阿司匹林溶液和0.01mM的氯化铜溶液中，交替沉积3次，每次15min，取出清洗干燥即可。
实施例3
本实施例的具有抗凝血涂层的支架的制备方法，包括如下制备步骤：
(1)对镍钛合金和镍钛密网支架进行清洗并干燥；
(2)在常温条件下将步骤(1)所得样品浸没在浓度为3％硅烷偶联剂溶液(KH550)中，加入醋酸将pH调为5.5，浸没时间为2h，取出洗净并干燥；
(3)将步骤(2)中所得的样品在常温条件下分别浸入0.01mg/mL的阿司匹林溶液和0.01mM的氯化铜溶液中，交替沉积3次，每次15min，取出清洗干燥即可。
实施例4
本实施例的具有抗凝血涂层的支架的制备方法，包括如下制备步骤：
(1)对镍钛合金和镍钛密网支架进行清洗并干燥；
(2)在常温条件下将步骤(1)所得样品浸没在浓度为3％硅烷偶联剂溶液(KH550)中，加入醋酸将pH调为3.5，浸没时间为2h，取出洗净并干燥；
(3)将步骤(2)中所得的样品在常温条件下分别浸入0.05mg/mL的阿司匹林溶液和0.01mM的氯化铜溶液中，交替沉积3次，每次15min，取出清洗干燥即可。
实施例5
本实施例的具有抗凝血涂层的支架的制备方法，包括如下制备步骤：
(1)对镍钛合金和镍钛密网支架进行清洗并干燥；
(2)在常温条件下将步骤(1)所得样品浸没在浓度为3％硅烷偶联剂溶液(KH550)中，加入醋酸将pH调为3.5，浸没时间为2h，取出洗净并干燥；
(3)将步骤(2)中所得的样品在常温条件下分别浸入0.05mg/mL的阿司匹林溶液和0.01mM的硫酸铜溶液中，交替沉积3次，每次15min，取出清洗干燥即可。
试验例1-4
试验例1-4均使用实施例1的制备方法制备得到的样品作为实验样，并命名为NiTi@KH550@ASP(ASP表示阿司匹林)。将未经任何处理的镍钛合金片和镍钛合金支架作为对照样，并命名为NiTi。
试验例1
通过UP水滴对实验样以及对照样进行演示。结果如附图1所示，通过附图1可以看出，改性后密网支架表现出更好的亲水性，样品表面的水滴能铺展均匀。
试验例2
验证制得的抗凝血功能涂层的体外血小板粘附和激活情况。实验步骤如下：
(1)本实施例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)准备好的样品加入置于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。
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。
本实施例制得的样品表面血小板粘附和激活荧光染色如附图2所示，可以看出，未改性的镍钛合金片材表面粘附了大片的血小板，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。
本实施例制得的样品表面血小板粘附和激活扫描电镜如附图3和附图4所示，未改性的镍钛片材(附图3)和镍钛合金密网支架(附图4)表面粘附了大量的血小板，改性后的片材和密网支架表面光滑平整，几乎没有血小板的粘附和激活，结果与荧光染色一致。上述结果表面我们的抗凝血改性涂层具有良好的抗凝能力。
试验例3
验证制得的抗凝血功能涂层的全血浸泡情况。实验步骤如下：
(1)本实施例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；
(2)准备好的样品置于24孔板中，每个样品表面滴加100μL的全血，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，干燥处理后进行形貌观察。
本实施例制得的样品表面全血浸泡后扫描电镜如附图5和附图6所示，未改性的镍钛片材(附图5)和密网支架(附图6)表面粘附了大量的蛋白细胞等物质，改性后的片材和密网支架表面光滑平整，几乎没有物质的粘附，上述结果说明我们的抗凝血改性涂层具有良好的抗凝能力。
试验例4
验证抗凝血涂层在动物模型中的抗凝性能。本实验所选模型为兔模型，实验分以下几步进行：
(1)选取健康的新西兰白兔作为模型。配置一定浓度的麻药，按照体积与兔子重量1mL:1kg的当量比将对应剂量的麻药通过耳缘静脉部位注射到兔子体内，使兔子麻醉。在兔子颈部动静脉所在皮肤处进行褪毛处理，方便接下来的手术操作。
(2)将镍钛密网支架样品装入组装好的PVC四通导管中，向其中注射生理盐水直至充满导管，轻弹导管，除去导管中滞留的气泡，将两端用止血钳夹紧待用。
(3)划开兔子颈部皮肤之后，逐层剥离肌肉组织，直到露出动静脉血管。小心分离出血管，随后将无菌留置针浸润后穿入剥离固定好的颈部动脉和静脉之中，然后将动静脉两端的留置针分别与组装好的四通导管两端相连，与白兔体内血管形成闭合血液循环回路。
(4)取下动静脉两端止血钳后，血液由白兔流向装有样品的四通管中并往复循环，记录此时时间作为实验开始节点，实验开始0.5h后，用血管钳固定动静脉，停止血液循环并取下导管装置，用生理盐水进行冲洗。实验样品取出后置于戊二醛(2.5％)溶液中固定，随后进行形貌观察。
本实施例制得的镍钛合金密网支架半体动物实验后光镜和扫描电镜如附图7所示，光镜显示未改性的镍钛合金密网支架堵塞较为严重，改性后的密网支架畅通，SEM显示，未改性的密网支架表面有较多物质粘附，而改性后的密网支架则相反，上述结果说明我们的抗凝血改性涂层具有良好的抗凝能力。
以上仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

1.一种具有抗凝血涂层的支架的制备方法，其特征在于，包括如下制备步骤：
(1)将合金片和合金支架进行清洗并干燥；
(2)将步骤(1)中的样品浸没在硅烷偶联剂溶液中，并调节pH为3.5-5.5，浸泡时间为1.5-2.5h，然后将其取出、清洗干净并干燥；
(3)将步骤(2)中的样品分别交替浸没在抗凝药物和含铜离子的溶液中，然后将其取出，清洗干净并干燥。
2.根据权利要求1所述的具有抗凝血涂层的支架的制备方法，其特征在于，步骤(1)中的合金为镍钛合金、钴铬合金中的一种。
3.根据权利要求1所述的具有抗凝血涂层的支架的制备方法，其特征在于，步骤(2)中的硅烷偶联剂浓度为0.5％-3％。
4.根据权利要求1所述的具有抗凝血涂层的支架的制备方法，其特征在于，步骤(2)中使用醋酸来调节溶液pH。
5.根据权利要求1所述的具有抗凝血涂层的支架的制备方法，其特征在于，步骤(2)中调节溶液pH为4.5，浸没时间为2h。
6.根据权利要求1所述的具有抗凝血涂层的支架的制备方法，其特征在于，步骤(3)中抗凝药物为阿司匹林和肝素中的一种。
7.根据权利要求6所述的具有抗凝血涂层的支架的制备方法，其特征在于，步骤(3)中抗凝药物浓度为0.01-0.05mg/mL。
8.根据权利要求7所述的具有抗凝血涂层的支架的制备方法，其特征在于，步骤(3)中含铜离子的溶液为氯化铜和硫酸铜中的一种，铜离子浓度为0.01mM。
9.根据权利要求8所述的具有抗凝血涂层的支架的制备方法，其特征在于，步骤(3)中样品每次浸泡时间为15分钟。
10.根据权利要求1-9任一所述的具有抗凝血涂层的支架的制备方法所制备得到的支架。
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