National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, China.
Max Bergmann Center of Biomaterials, Leibniz Institute of Polymer Research Dresden, Dresden, 01069, Germany; Key Lab. for Advanced Technologies of Materials, Ministry of Education, School of Material Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China.
Biomaterials. 2021 Feb;269:120418. doi: 10.1016/j.biomaterials.2020.120418. Epub 2020 Oct 21.
In-stent restenosis after stenting is generally characterized by an inflammatory response, excessive proliferation of smooth muscle cells, and delayed healing of the endothelium layer. In this study, inspired by catechol/gallol surface chemistry, a sandwich-like layer-by-layer (LBL) coating was developed using chitosan and heparin as polyelectrolytes, along with the embedding of an epigallocatechin gallate/copper (EGCG/Cu) complex. The embedding of EGCG stabilized the coating by various intermolecular interactions in the LBL coating (e.g., π-π stacking, weak intermolecular crosslinking, and enriched hydrogen bonding) and supported the sustained release of the cargo heparin over 90 days. This design enabled a biomimetic endothelium function in terms of the sustained release of heparin and continuous in situ generation of nitric oxide, driven by the catalytic decomposition of endogenous S-nitrostothiols by copper ions. The result showed enhanced durability of anticoagulation and suppressed inflammatory response. Moreover, the "sandwich-like" coating supported the growth of endothelial cells and up-regulated the protein expression of vascular endothelial growth factor, while effectively suppressing the proliferation and migration of smooth muscle cells (SMCs) via the up-regulation of cyclic guanosine monophosphate. Ex vivo and in vivo experiments demonstrated the effectiveness of the sandwich-like coating in preventing thrombosis formation, suppressing the growth of SMCs, reducing the infiltration and activation of inflammatory cells, and ultimately achieving rapid in situ endothelialization. Hence, the EGCG-assisted sandwich-like coating might be used as a robust and versatile surface modification strategy for implantable cardiovascular devices.
支架内再狭窄是支架置入后普遍存在的问题，其特征通常是炎症反应、平滑肌细胞过度增殖和内皮细胞层延迟愈合。在这项研究中，受儿茶酚/没食子酸表面化学的启发，采用壳聚糖和肝素作为聚电解质，构建了一种三明治型层层（LBL）涂层，并嵌入表没食子儿茶素没食子酸酯/铜（EGCG/Cu）配合物。EGCG 的嵌入通过 LBL 涂层中的各种分子间相互作用（例如，π-π 堆积、弱分子间交联和丰富的氢键）稳定了涂层，并支持肝素载体的持续释放超过 90 天。这种设计使得肝素的持续释放和一氧化氮的原位持续产生具有仿生内皮功能，这是由铜离子催化分解内源性 S-亚硝基硫醇驱动的。结果表明，抗凝效果持久，炎症反应受到抑制。此外，“三明治”涂层支持内皮细胞的生长，并上调血管内皮生长因子的蛋白表达，同时通过环鸟苷单磷酸的上调有效抑制平滑肌细胞（SMCs）的增殖和迁移。体外和体内实验证明了三明治涂层在预防血栓形成、抑制 SMC 生长、减少炎症细胞浸润和激活以及最终实现快速原位内皮化方面的有效性。因此，EGCG 辅助的三明治涂层可能成为用于可植入心血管设备的强大且通用的表面改性策略。
