新型生物可降解单面刻槽载药靶向支架对冠状动脉内膜增生的影响

doi:10.3969/j.issn.2095-4344.2017.26.021

摘要/Abstract

摘要：

文章快速阅读：

文题释义：

Firehawk支架：是在原Firebird药物洗脱支架基础上改进的新型冠状动脉雷帕霉素靶向洗脱支架系统，采用生物可降解的药物涂层及外表面单面刻槽载药技术，与传统的不可降解药物涂层药物洗脱支架相比，理论上可避免长期存在的药物涂层对局部血管壁的致炎作用，减少药物剂量，减少血栓形成的可能性，减轻管腔狭窄。

Firehawk支架的优势：与传统药物洗脱支架不同，Firehawk支架具有更低的药物量和聚合物量，即药物涂层仅储存于支架外表面的凹槽内，支架扩张后药物仅向血管壁释放且药物释放速度得到聚合物的有效控制，达到用更小的药物量，却使其在血管内能较长时间保持有效治疗浓度效果。因此，Firehawk支架系统是更为安全有效的新一代药物支架系统。

背景：理论上，新型生物可降解单面刻槽载药靶向支架可避免长期存在药物涂层对局部血管壁的致炎作用，减少药物剂量，减少血栓形成的可能性，减轻管腔狭窄。

目的：评价生物可降解新型单面刻槽载药支架对健康小型猪冠状动脉内膜增生的影响。

方法：将18只健康小型猪随机分为裸支架组、Firebird 2支架组和Firehawk支架组，分别植入L605钴铬合金裸金属支架、L605钴铬合金不可降解涂层雷帕霉素支架和L605钴铬合金可降解单面刻槽涂层雷帕霉素靶向洗脱支架，于左前降支和右冠状动脉各植入相同支架1枚。支架植入后1，3个月时复查冠状动脉造影并处死取材，观察内膜增生情况。

结果与结论：①冠状动脉造影结果：植入1，3个月时，3组支架段冠状动脉均无狭窄发生，支架段血管均通畅，见血栓及动脉瘤等影像学表现；植入后1，3个月时，Firebird 2支架组、Firehawk支架组管腔丢失均低于裸支架组(P < 0.05)，Firebird 2支架组与Firehawk支架组管腔丢失比较差异无显著性意义；②组织病理学结果：3组均未见支架段冠状动脉管壁组织坏死或管腔内血栓形成；支架植入后1，3个月时，Firebird 2支架组、Firehawk支架组新生内膜面积及面积狭窄百分比低于裸支架组(P < 0.05)，残余管腔面积、内弹力板面积高于裸支架组(P < 0.05)。Firebird 2支架组与Firehawk支架组上述各指标比较差异无显著性意义；③结果表明：生物可降解新型单面刻槽载药支架可有效抑制冠状动脉内膜增生，预防冠状动脉支架内狭窄，效果与不可降解涂层雷帕霉素支架相当，长期效果仍有待进一步观察。

ORCID: 0000-0003-2162-4384(金慧)
中国组织工程研究杂志出版内容重点：生物材料；骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性；组织工程

关键词: 生物材料, 材料相容性, 药物洗脱支架, 雷帕霉素, 聚乳酸, 生物可降解, 内膜增生

Abstract:

BACKGROUND: Theoretically, a novel single-sided groove target release biodegradable stent can avoid drug-induced inflammation of the local vessel wall, reduce drug dose, decrease the likelihood of thrombosis, and relieve stenosis.

OBJECTIVE: To evaluate the influence of the novel single-sided groove target release biodegradable stent on intimal hyperplasia in a healthy porcine coronary artery model.

METHODS: Eighteen healthy pigs were randomly divided into three groups, bare metal stent group, Firebird metal stent group and Firehawk stent group, which were implanted with L605 cobalt chromium alloy bare metal stents and L605 cobalt chromium alloy non-biodegradable rapamycin-eluting stent and L605 cobalt chromium alloy biodegradable rapamycin-eluting stent, respectively. Two same stents were implanted into the left anterior descending artery and the right coronary artery of each pig, respectively. After 1 and 3 months of follow-up, coronary angiography was performed, and the pigs were killed to take coronary artery samples for detection of intima hyperplasia.

RESULTS AND CONCLUSION: At 1 and 3 months after stent implantation, no stenosis, thrombosis and aneurysm occurred in the three groups shown by the coronary angiography; the lumen loss was significantly lower in the Firebird metal stent group and Firehawk stent group than the bare metal stent group (P < 0.05), while there was no difference between the Firebird metal stent group and Firehawk stent group. Histopatologically, there was no coronary arterial tissue necrosis or luminal thrombosis in the three groups. Compared with the bare metal stent group, at 1 and 3 months after stent implantation, the neointimal area and the percentage of stenosis were significantly lower in the Firebird metal stent group and Firehawk stent group (P < 0.05), while the residual lumen area and internal elastic lamina area were significantly higher (P < 0.05). Additionally, there was no significant difference between the Firebird metal stent group and Firehawk stent group. Overall, the Firehawk stent that achieves the same clinical efficacy as the non-biodegradable rapamycin-eluting stent effectively inhibits intimal hyperplasia, and prevents stent restenosis after stent implantation. However, future investigations on the long-term effect are warranted.

中国组织工程研究杂志出版内容重点：生物材料；骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性；组织工程

Key words: Drug-Eluting Stents, Sirolimus, Tissue Engineering

中图分类号:

R318

金慧，李猛. 新型生物可降解单面刻槽载药靶向支架对冠状动脉内膜增生的影响[J]. 中国组织工程研究, 2017, 21(26): 4222-4227.

Jin Hui, Li Meng.

A novel single-sided groove target release biodegradable stent inhibits coronary artery intimal hyperplasia [J]. Chinese Journal of Tissue Engineering Research, 2017, 21(26): 4222-4227.

图/表（结果） 4

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引言

材料方法

1.1 设计随机对照动物实验。

1.2 时间及地点实验于2016年8至10月在包头市中心医院实验室完成。

1.3 材料

实验动物：纳入普通级6-9月龄健康中华小型猪18只，雌雄不拘，体质量25-30 kg，由包头市中心医院实验动物中心提供。动物按随机数字法随机分为裸支架组、Firebird 2支架组和Firehawk支架组，每组6只。

Firehawk支架：是微创公司研发的新一代冠状动脉支架系统，在原Firebird药物洗脱支架基础上加以改进，以L605钴铬合金为支架骨架，利用激光在支架丝血管壁面单面刻槽，槽中填充生物可降解的聚乳酸并携带雷帕霉素(图1)，医疗器械注册证号：国食药监械(准)字2014第3460190号。涂层暴露面积仅为支架表面积的20%，药物体内释放时间超过90 d，聚合物涂层9个月内可完全降解，平均金属覆盖率14.0%-16.1%，为全球最低载药量支架，只有同类产品1/3的载药量，并可获得相同的有效性。

Firebird 2支架：购自微创医疗器械(上海)有限公司，医疗器械注册证号：国食药监械(准)字2010第3460480号，支架显影性好，金属覆盖率为11.9%-13.6%，该产品由带涂层的支架和输送系统两部分组成(图2)，支架材料为L605钴基合金，支架上的涂层由雷帕霉素药物和高分子生物材料(苯乙烯丁烯共聚物，不可降解)组成，支架含药量为120-305 μg；输送系统为快速交换式球囊扩张导管，由Pebax33、Nylon12、304L不锈钢、Poyolefin、PC等制成，有PVP亲水涂层和显影点。

1.4 实验方法裸支架组植入L605钴铬合金裸金属支架，Firebird 2支架组植入L605钴铬合金不可降解涂层雷帕霉素支架Firebird 2，Firehawk支架组植入L605钴铬合金可降解涂层雷帕霉素靶向洗脱支架Firehawk，每只猪植入相同支架2枚，所有支架均购自微创医疗器械(上海)有限公司。

支架植入的操作及抗血小板药物的应用参照邱洪等^[4]报道的方法进行。动物于支架植入前2 d开始给予双联抗血小板药物治疗(阿司匹林300 mg/d+氯吡格雷75 mg/d)，并维持给药直至处死动物。常规麻醉动物，穿刺猪股动脉并植入6F动脉鞘管，经鞘管送入引导导管，分别送入至左右冠状动脉行冠状动脉造影。以指引导管直径作为参考，测量预植入血管直径。按照支架∶血管1.1∶1的标准沿Pilot导丝将支架先后送至左前降支及右冠状动脉后释放，并再次冠状动脉造影。同一动物左前降支及右冠状动脉分别植入同种支架各1枚。支架植入后复查冠状动脉造影，测量计算管腔丢失情况，管腔丢失=支架植入后获得管腔直径-末次随访最小管腔直径。术后3 d予以抗生素预防感染。

1.5 主要观察指标

取材及血管组织内膜增生的定量评价：支架植入后1，3个月，复查冠状动脉造影后麻醉处死动物，每组每个时间点处死3只。取出心脏，分离出支架段血管，40 g/L多聚甲醛固定48 h后硬塑料包埋、切片，行苏木精-伊红染色，行光镜形态学观察，使用医学图像分析软件LEICA Qwin Plus V3.2.1计算相关指标：残余管腔面积、内弹力板面积、新生内膜面积(内弹力板面积-残余管腔面积)、面积狭窄百分比(新生内膜面积/内弹力板面积×100%)。面积狭窄百分比≥50%定义为支架内狭窄。其余部分冠状动脉行扫描电镜观察。参考文献[5]方法，对组织切片进行半定量内皮化组织病理学评价，并观察有无血栓形成。

1.6 统计学分析采用SPSS 18.0统计学软件进行统计分析。计量数据用x(_)±s表示，多组之间均数比较用方差分析，两组均数比较采用t 检验，P < 0.05为差异有显著性意义。

中国组织工程研究杂志出版内容重点：生物材料；骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性；组织工程

讨论

冠状动脉介入目前已成为冠心病常规治疗重要手段，其中药物洗脱支架的出现更是意义重大，支架内再狭窄率从裸金属支架的20%-35%降低到目前的5%-10%。尽管不可降解聚合物涂层药物洗脱支架具有不可否认的临床疗效，但其长期安全性引起了人们的关注。有关药物洗脱支架植入后发生支架内血栓形成，特别是晚期和极晚期血栓形成的顾虑，已成为医学界的一个重要问题，这也促进了学者对新一代药物洗脱支架的研制^[6-10]。

多个学者的研究结果显示，与金属裸支架相比，药物洗脱支架的晚期血栓发生率略有升高，但并不增加甚至可能减少患者整体死亡和心肌梗死风险。而一旦发生晚期血栓，患者预后往往不良。药物洗脱支架晚期血栓形成的机制目前尚无定论，很大程度上与药物洗脱支架覆盖的不可降解聚合物有关，其可能引起血管壁慢性持续性炎症和血管愈合延迟，形成促栓环境^[11-15]。

为进一步避免金属支架对血管壁的长期异物刺激，发展全降解药物洗脱支架使其在完成防止血管弹性回缩和药物洗脱的历史使命后，从血管壁中被完全降解吸收，是新型药物洗脱支架发展的趋势之一^[15-18]。实验应用的新型冠脉雷帕霉素靶向洗脱支架系统是第3代药物洗脱支架，其优势如下：①在裸金属支架表面覆盖了可降解聚合物涂层——聚乳酸，其在体内最终可经三羧酸循环分解为CO₂和H₂O排出体外，不仅可降低血管再狭窄发生率，同时又能有效降低支架植入后晚期血栓及血管瘤的形成，保证支架植入后远期临床安全性和生物相容性；②支架采用外表面单面刻槽载药，支架的侧面和内表面都没有药物，药物含量以Firebird 和Firebird 2为参考，对应规格载药量小于Firebird 2载药量的1/2。综合上述两方面优点，Firehawk支架可避免长期存在的非降解涂层对局部血管壁的致炎作用；减少药物剂量，在不降低临床有效性前提下，也可能减少血管局部炎症反应，减少血栓形成的可能性^[19-25]。

中国组织工程研究杂志出版内容重点：生物材料；骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性；组织工程