Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), State and Local Joint Engineering Laboratory for Vascular Implants (Chongqing), Bioengineering College of Chongqing University, Chongqing 400044, China.
Biomater Sci. 2017 Aug 22;5(9):1845-1857. doi: 10.1039/c7bm00417f.
Drug-eluting stents (DESs) can effectively control the harmful effects of coronary artery disease, because of their excellent ability to reduce in-stent restenosis. However, delayed re-endothelialization and late stent thrombosis have caused concern over the safety of DESs. In this study, according to time-ordered pathological responses after stent implantation, a hierarchical multiple drug-eluting stent was designed and prepared to overcome the existing DES limitations. A platelet membrane glycoprotein IIIa monoclonal antibody (SZ-21) and a vascular endothelial growth factor (VEGF) were loaded into the inner coating of 316L stainless steel (316L SS) stents to inhibit thrombosis and promote re-endothelialization; rapamycin (RAPA) was loaded into the third layer to inhibit intima hyperplasia; a drug-free poly-l-lactic acid coating was located on the second and fourth layers and used as sustained release layers. The results showed that the three drugs exhibited sequential release kinetics without significant burst release. RAPA released quickly at the early stage, while SZ-21 and VEGF achieved a slow and prolonged release. In vitro experiments showed that the stents had excellent hemocompatibility and anti-inflammatory properties, and promoted the proliferation and migration of endothelial cells while inhibiting the proliferation and migration of smooth muscle cells. Finally the stents were implanted in the carotid arteries of New Zealand white rabbits. In vivo results showed that compared to 316L SS stents, the multiple drug-eluting stents could accelerate re-endothelialization and inhibit thrombosis, inflammation and in-stent restenosis after 4 weeks (12.79 ± 2.45% vs. 25.27 ± 4.81%) and 12 weeks (15.87 ± 3.62% vs. 58.84 ± 6.87%). These results indicate that the novel drug-eluting stent with multiple layer coatings will have a highly potential clinical application.
药物洗脱支架 (DES) 可以有效控制冠状动脉疾病的有害影响，因为它们具有出色的减少支架内再狭窄的能力。然而，延迟的再内皮化和晚期支架血栓形成引起了对 DES 安全性的关注。在这项研究中，根据支架植入后的时间顺序病理反应，设计并制备了一种分层的多药物洗脱支架，以克服现有 DES 的局限性。将血小板膜糖蛋白 IIIa 单克隆抗体（SZ-21）和血管内皮生长因子（VEGF）载入 316L 不锈钢（316L SS）支架的内层涂层，以抑制血栓形成并促进再内皮化；将雷帕霉素（RAPA）载入第三层以抑制内膜增生；无药物的聚 L-乳酸涂层位于第二层和第四层，用作持续释放层。结果表明，三种药物表现出顺序释放动力学，没有明显的爆发释放。RAPA 在早期快速释放，而 SZ-21 和 VEGF 则实现了缓慢而持久的释放。体外实验表明，支架具有良好的血液相容性和抗炎特性，促进内皮细胞的增殖和迁移，同时抑制平滑肌细胞的增殖和迁移。最后将支架植入新西兰白兔的颈动脉中。体内结果表明，与 316L SS 支架相比，多药物洗脱支架可以在 4 周（12.79 ± 2.45%比 25.27 ± 4.81%）和 12 周（15.87 ± 3.62%比 58.84 ± 6.87%）后加速再内皮化并抑制血栓形成、炎症和支架内再狭窄。这些结果表明，具有多层涂层的新型多药物洗脱支架具有很高的临床应用潜力。
