CN110180038A - 具药物缓释功能超高柔性涂层的锌合金血管支架材料 - Google Patents

具药物缓释功能超高柔性涂层的锌合金血管支架材料 Download PDF

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CN110180038A
CN110180038A CN201910542109.0A CN201910542109A CN110180038A CN 110180038 A CN110180038 A CN 110180038A CN 201910542109 A CN201910542109 A CN 201910542109A CN 110180038 A CN110180038 A CN 110180038A
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饶席
胡豪侣
杨济涵
张永平
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Abstract

本发明是一种具药物缓释功能超高柔性涂层的锌合金血管支架材料及制备方法，该血管支架材料由锌合金基体、富氨基官能团聚合涂层和载药聚乳酸‑羟基乙酸共聚物PLGA涂层组成。所述及的血管支架材料选用锌合金作为基体，具有药物缓释功能的高柔性涂层，由等离子体增强化学气相沉积技术PECVD和旋涂覆膜技术制备。其制备方法为：在Zn‑(2~4 at%)Li基体材料表面上，利用PECVD技术聚合化沉积富基官能团的3‑氨基丙基三乙氧基硅烷APTES涂层；同时，将目标药物及生化活性因子与PLGA加入二氯甲烷并混合均匀，然后使用旋涂技术将其涂覆于沉积有APTES的锌合金基体表面，经干燥、消毒后，即可得所述血管支架材料。

Description

具药物缓释功能超高柔性涂层的锌合金血管支架材料
技术领域
本发明涉及一种具药物缓释功能超高柔性涂层的锌合金血管支架材料,特别是涉及一种以锌合金为基体，其表面覆盖有由PECVD技术聚合化沉积的具有高密度氨基官能团的APTES涂层以及由旋涂技术接枝于其上的药物/生化活性因子/PLGA药物缓释层，具有自发降解、促进血管内皮化、防止再狭窄等有益作用，属于心血管植入材料领域。
背景技术
动脉粥样硬化所导致的冠心病、心肌梗塞、脑梗死等心脑血管顽疾是临床医学急需解决的热点问题。基于血管内介入治疗的理念，医学工作者们提出了在人体内植入异物支架为血管提供支撑的方法，从而帮助已堵塞或狭窄的血管完成血运重建，恢复正常的生理功能。
由于传统不可降解血管支架易诱发再狭窄，因此血管支架材料的研究重点转移到生物可降解吸收材料上。其中，可降解金属具有良好的力学性能，能在较小尺寸上提供支架材料所需的高径向支撑力，是当前研究的热点。
锌元素具有良好的抑制增生作用，有助于防止再狭窄。锌的标准电位为-0.763V，在人体环境中平均降解速度<50μm/year，可较好匹配受损血管的修复时间。研究表明，Zn-（2~4at%）Li合金在保持约14%的延伸率同时可提供接近400MPa的拉伸强度，能有效满足介入治疗对血管支架的力学性能要求。
为提高金属血管支架材料的血液相容性和生物相容性，学者们常对其进行表面改性，传统的金属改性方法多是通过物理化学手段在基体表面生长具有一定力学性能的刚性涂层。此类涂层虽然能提高基体的生物医学性能，却存在柔性不足的缺点。而血管支架在投送到指定部位后，需经球囊变形张开方可起到导通堵塞血管的作用，这常常导致硬质涂层开裂甚至失效。
在金属表面制备高柔性涂层，使其随支架张开而伸展、并在血管服役过程中始终覆盖于基体表面是解决此类问题的有效手段。（3-氨基丙基）三乙氧基硅烷（APTES）常用于材料表面功能化，其分子结构中的氨基官能团可为负载纳米级物质提供接枝点。最近有研究表明，APTES聚合化所形成的涂层具有良好的生物相容性，因此具有接枝负载药物缓释体的潜力。此外，高分子聚合形成的涂层具有良好的柔性和膜基结合力，既能满足血管支架植入服役时的展开变形需要，又可协同调控基体的腐蚀行为。
相较于传统的湿化学方法制备APTES涂层，等离子体增强化学气相沉积（PECVD）技术操作简单、沉积效率高、可控精度高，且在沉积过程伴随等离子体聚合反应提高涂层交联度，最终形成与基体结合紧密的APTES柔性涂层
聚乳酸-羟基乙酸共聚物（PLGA）常用作缓释药物或生化活性因子的载体，目前已广泛应用于药物递送领域。分子末端带有羧基官能团的PLGA可与氨基官能团通过两性电子进行接枝，并形成具有药物缓释功能的结合层。
本发明利用PECVD技术在锌合金表面制备富含高密度氨基的APTES涂层，随后将带羧基官能团的PLGA与药物混合并涂覆其上形成药物缓释层。所制备支架材料可随人体血管恢复重建而逐步被人体降解吸收。覆盖其上的涂层具有良好的柔性，在植入初期与基体结合良好，可以随支架形变而变形。同时，涂层在降解过程中可缓慢释放抗凝血、消炎、促进血管重建的药物及生化活性因子。
发明内容
血管支架工作在植入过程中，需经过一个球囊变形的过程，低柔性涂层常会在此过程中产生开裂甚至脱落，最后造成支架表面的生物相容性及血液相容性下降。本发明针对传统用于提高血管支架表面生物活性的刚性涂层结构的不足，提出的一种具药物缓释功能超高柔性涂层，并将其应用于可降解锌合金血管支架表面，达到调控支架降解速率、提高植入初期细胞相容性及血液相容性、并促进血管组织重建再生的目的。
锌元素具有良好的一直增生作用，有助于防止再狭窄。锌基合金的腐蚀为均匀腐蚀，可有效避免局部过度腐蚀造成的材料崩坏。以锌合金为基体血管支架，在其表面沉积具有高变形能力的柔性涂层，使其随血管支架形变发生变形且不产生脱落。所沉积的涂层具有较高生物相容性及细胞相容性、能调控基体腐蚀速率、可进行药物/生化活性因子负载及缓释。
本发明通过以下技术方案加以实现：
具药物缓释功能超高柔性涂层的锌合金血管支架材料，其特征在于，所述的具药物缓释功能超高柔性涂层的锌合金血管支架材料由锌合金基体和利用PECVD技术在基体表面聚合化沉积具有高密度氨基官能团的3-氨基丙基三乙氧基硅烷APTES涂层，以及使用旋涂技术接枝APTES-锌合金基体表面的药物/生化活性因子/ PLGA缓释层组成；所述的具药物缓释功能超高柔性涂层的锌合金血管支架材料的制备方法，其特征在于，包括如下步骤：
（1）提供一种Zn-(2~4 at%)Li合金作为基体；
（2）将基体表面抛光、清洗、干燥后置于PECVD设备，在Ar混合O2气氛中进行等离子体表面活化预处理；
（3）在基体材料完成表面活化预处理后，向反应腔室中鼓入3-氨基丙基三乙氧基硅烷APTES雾化单体，在Ar等离子体中聚合沉积具有高密度氨基官能团的APTES涂层；
（4）将PLGA溶于二氯甲烷中配制成所需要的PLGA溶液，再将目标药物与生化活性因子按照一定比例与PLGA溶液进行充分混合，得到目标药物/生化活性因子/PLGA溶液；
（5）将预沉积有APTES涂层的基体材料放置在旋涂机上进行旋涂，以一定转速旋转样品，待转速稳定后，缓慢将由步骤（4）制备的目标药物/生化活性因子/PLGA溶液滴在旋转样品表面；经过一定时间反应，关闭旋涂机电源，将样品干燥、消毒，即可得具药物缓释功能超高柔性涂层的锌合金血管支架材料。
进一步，所述步骤（2）中的Ar混合O2气氛为在Ar中混合0~5% O2，所述的等离子体表面活化预处理的参数为：电压5~20W，腔内压力0.2~1.0mbar，总气流量5~20sccm，处理时间5~120s。
进一步，所述步骤（3）中的在Ar等离子体聚合沉积具有高密度氨基官能团的APTES涂层的参数设置为：电压5~40W，腔内压力0.5~1.5mbar，总气流量5~50sccm,沉积时间5~30s。
进一步，所述步骤（4）中的PLGA溶液的浓度为10mg/mL, 所述的目标药物为地塞米松、肝素中的一种或几种，生化活性因子为内皮细胞异性靶向GREDVY多肽、VEGF血管内皮生长因子中的一种或几种，所述的目标药物/生化活性因子/PLGA溶液中目标药物的浓度为0.05~0.5% wt。
进一步，所述步骤（5）中的旋涂过程参数为：转速1000r/min,旋转时间为60s, 目标药物/生化活性因子/PLGA溶液滴加量为100~200μL。
附图说明
图1为实施例1中PECVD技术在锌合金表面所沉积的具有高密度氨基官能团的APTES涂层的XPS C1s高分辨图谱。
图2为实施例1中PECVD技术在锌合金表面所沉积的具有高密度氨基官能团的APTES涂层的细胞毒性实验结果。
图3 为实施例1中表面具有目标药物/生化活性因子/PLGA缓释涂层的锌合金进行弯曲后的界面的SEM图。
图4为实施例2中表面具有目标药物/生化活性因子/PLGA缓释涂层的锌合金进行弯曲后的界面的SEM图。
具体实施方式
下面将对本发明的优选实例进行详细的描述。
实施例1
（1）提供一种Zn-(2~4 at%)Li合金作为基体。
（2）将基体表面抛光、清洗、干燥后置于PECVD设备，在Ar中混合5% O2形成Ar/O2气氛中进行等离子体表面活化预处理,其中参数设置为：电压10W，腔内压力0.5mbar，总气流量10sccm，处理时间60s。
（3）在基体材料完成表面活化预处理后，向反应腔室中鼓入3-氨基丙基三乙氧基硅烷（APTES）雾化单体，在Ar等离子体中聚合沉积具有高密度氨基官能团的APTES涂层，其中参数设置为：电压20W，腔内压力1.0mbar,总气流量20sccm,处理时间30s; 如图1所示的PECVD技术在锌合金表面所沉积的具有高密度氨基官能团的APTES涂层的XPS C1s高分辨图谱，说明APTES涂层完好的沉积在了锌合金基体表面，C-N峰的出现证明了氨基官能团的存在；将PECVD技术在锌合金表面所沉积的具有高密度氨基官能团的APTES涂层进行细胞毒性测试，结果如图2所示，说明APTES涂层有良好的生物相容性和血液相容性。
（4）将PLGA溶于二氯甲烷中配制成本实验需要的PLGA溶液，PLGA在二氯甲烷中的浓度为10mg/mL。再将0.1%wt的肝素及内皮细胞异性靶向GREDVY多肽与PLGA/二氯甲烷溶液进行充分混合，得到肝素/内皮细胞异性靶向GREDVY多肽/PLGA溶液。
（5）将预沉积有APTES涂层的基体材料放置在旋涂机，以1000r/min的速度旋转样品，旋转时间为60s。待转速稳定后，缓慢将200μL由步骤（4）制备的肝素/内皮细胞异性靶向GREDVY多肽/PLGA溶液滴在旋转样品表面。经过一定时间反应，关闭旋涂机电源，将样品干燥、消毒，即可得具药物缓释功能超高柔性涂层的锌合金血管支架材料。
（6）将得到的支架进行弯曲测试，其SEM图的结果如图3所示，说明所制备的具药物缓释功能的锌血管支架材料具有超高的柔性。
实施例2
（1）提供一种Zn-(2~4 at%)Li合金作为基体。
（2）将基体表面抛光、清洗、干燥后置于PECVD设备，在Ar中混合5% O2形成Ar/O2气氛中进行等离子体表面活化预处理,其中参数设置为：电压10W，腔内压力0.5mbar,总气流量10sccm,处理时间60s。
（3）在基体材料完成表面活化预处理后，向反应腔室中鼓入（3-氨基丙基）三乙氧基硅烷（APTES）雾化单体，在Ar等离子体中聚合沉积具有高密度氨基官能团的APTES涂层，其中参数设置为：电压20W，腔内压力1.0mbar,总气流量20sccm,处理时间30s。
（4）将PLGA溶于二氯甲烷中配制成本实验需要的PLGA溶液，PLGA在二氯甲烷中的浓度为10mg/mL。再将0.1%wt的地塞米松及内皮细胞异性靶向GREDVY多肽与生化活性因子与PLGA/二氯甲烷溶液进行充分混合，得到地塞米松/VEGF血管内皮生长因子/PLGA溶液。
（5）将预沉积有APTES涂层的基体材料放置在旋涂机，以1000r/min的速度旋转样品，旋转时间为60s。待转速稳定后，缓慢将200μL由步骤（4）制备的地塞米松/VEGF血管内皮生长因子/PLGA溶液滴在旋转样品表面。经过一定时间反应，关闭旋涂机电源，将样品干燥、消毒，即可得具药物缓释功能超高柔性涂层的锌合金血管支架材料。
（6）将得到的支架进行弯曲测试，其SEM图的结果如图4所示，说明所制备的具药物缓释功能的锌血管支架材料具有超高的柔性。

Claims (5)

1.具药物缓释功能超高柔性涂层的锌合金血管支架材料，其特征在于，所述的具药物缓释功能超高柔性涂层的锌合金血管支架材料由锌合金基体和利用等离子体增强化学气相沉积PECVD技术在基体表面聚合化沉积具有高密度氨基官能团的3-氨基丙基三乙氧基硅烷APTES涂层，以及使用旋涂技术接枝于APTES-锌合金基体表面的目标药物/生化活性因子/聚乳酸-羟基乙酸共聚物 PLGA缓释层组成；所述的具药物缓释功能超高柔性涂层的锌合金血管支架材料的制备方法，其特征在于，包括如下步骤：
（1）提供一种Zn-(2~4 at%)Li合金作为基体；
（2）将基体表面抛光、清洗、干燥后置于PECVD设备，在Ar混合O2气氛中进行等离子体表面活化预处理；
（3）在基体材料完成表面活化预处理后，向反应腔室中鼓入3-氨基丙基三乙氧基硅烷APTES雾化单体，在Ar等离子体中聚合沉积具有高密度氨基官能团的APTES涂层；
（4）将PLGA溶于二氯甲烷中配制成所需要的PLGA溶液，再将目标药物与生化活性因子按照一定比例与PLGA溶液进行充分混合，得到目标药物/生化活性因子/PLGA溶液；
（5）将预沉积有APTES涂层的基体材料放置在旋涂机上进行旋涂，以一定转速旋转样品，待转速稳定后，缓慢将由步骤（4）制备的目标药物/生化活性因子/PLGA溶液滴在旋转样品表面；经过一定时间反应，关闭旋涂机电源，将样品干燥、消毒，即可得具药物缓释功能超高柔性涂层的锌合金血管支架材料。
2.根据权利要求1所述的具药物缓释功能超高柔性涂层的锌合金血管支架材料的制备方法，其特征在于，所述步骤（2）中的Ar混合O2气氛为在Ar中混合0~5% O2，所述的等离子体表面活化预处理的参数为：电压5~20W，腔内压力0.2~1.0mbar，总气流量5~20sccm，处理时间5~120s。
3.根据权利要求1所述的具药物缓释功能超高柔性涂层的锌合金血管支架材料的制备方法，其特征在于，所述步骤（3）中的在Ar等离子体聚合沉积具有高密度氨基官能团的APTES涂层的参数设置为：电压5~40W，腔内压力0.5~1.5mbar，总气流量5~50sccm,沉积时间5~30s。
4.根据权利要求1所述的具药物缓释功能超高柔性涂层的锌合金血管支架材料的制备方法，其特征在于，所述步骤（4）中的PLGA溶液的浓度为10mg/mL, 所述的目标药物包括地塞米松、肝素的一种或几种，所述生化活性因子包括内皮细胞异性靶向GREDVY多肽、VEGF血管内皮生长因子中的一种或几种，所述的目标药物/生化活性因子/PLGA溶液中目标药物的浓度为0.05~0.5% wt。
5.根据权利要求1所述的具药物缓释功能超高柔性涂层的锌合金血管支架材料的制备方法，其特征在于，所述步骤（5）中的旋涂过程参数为：转速1000r/min,旋转时间为60s, 目标药物/生化活性因子/PLGA溶液滴加量为100~200μL。
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