原位催化持续、稳定、可控释放一氧化氮的内皮功能仿生涂层研究

The continuous release of nitric oxide (NO) by the native endothelium of blood vessels plays a substantial role in the cardiovascular physiology, as it influences important pathways of cardiovascular homeostasis, inhibits smooth muscle cell (SMC) proliferation, inhibits platelet and leukocyte activation, prevents atherosclerosis and promotes the healing of intima lesions. Based on the recognition of the complications such as thrombus, inflammatory response, intimal hyperplasia and restenosis caused by stent intervention, a NO-producing coating that mimics this endothelium functionality was presented as a hemocompatible stent-modified platform with potential to address the issue of such complications. The NO-producing coating was obtained through copolymerization of catechol and selenocystamine (SeCA) with glutathione peroxidase (GPx)-like catalytic activity to generate NO from S-nitrosothiols (RSNOs) via specific catalytic reaction in blood. By means of regulating the ratio of catechol to SeCA to adjust and control the content of SeCA, so as to accurately control the release rate of NO. The project will focus on investigating the effects of NO generated by NO-producing coating on hemocompatibility, growth behavior of endothelial cells (EC), SMCs and inflammatory cells, reduction in restenosis and late stent thrombosis to understand the relationship between the NO release kinetics and physiological function, so as to provide the basic knowledge and serve as a guide for the design of the new type of the NO-functionalized stents.

内皮细胞（EC）层持续释放的一氧化氮（NO）具有抗凝、抗炎、抑制平滑肌细胞（SMC）增殖以及促使受损内皮层自我修复等多重功能在维持和保护整个心血管系统正常运作中起到重要作用。基于此，项目针对血管支架在植入过程中存在的血栓、炎症反应、内膜增生、再狭窄等并发症的特点，提出在支架表面构建具有持续催化NO释放的内皮功能仿生涂层以实现病变血管的修复和治愈。项目应用儿茶酚具有与广谱材料的粘附能力以及与伯胺基的化学反应性的双重特性，通过与NO催化活性分子硒代胱胺（SeCA）在碱性条件下氧化聚合，在支架表面沉积NO-催化粘附涂层。通过调控SeCA与儿茶酚的化学计量比实现SeCA含量的精确调控，从而实现NO释放速率的调控。评价NO-催化涂层支架的NO催化活性、血液相容性以及对SMC、EC、炎性细胞、再狭窄及晚期血栓的综合影响，为NO-催化涂层在血管支架的应用提供理论指导和奠定技术基础。

晚期血栓和再狭窄是血管支架在临床上面临的两大并发症。提高支架生物相容性是降低支架内再狭窄和晚期血栓的有效手段之一。NO，主要是由ECs通过其分泌的一氧化氮合酶与精氨酸作用产生，持续释放的NO不仅是维持心血管体内平衡和调节血管舒张的一个关键因素，而且NO还有具有许多重要的生物学功能如：抑制血小板激活、抑制SMCs增殖及调控炎症反应等功能。除此之外，NO在动脉粥样硬化预防和治疗方面也有着极为重要的作用。值得一提的是，NO在EPCs动员、分化中同样起着重要的作用。NO所具有的这些独特的生物学功能使其成为修饰血液接触类材料或器械（如血管支架）的理想分子。为了实现血管支架表面模范内皮持续、稳定释放NO的功能，本项目基于贻贝灵感化学，发展出“酚-胺”及“金属-酚-胺”表面化学策略，选用植物多酚/儿茶酚，NO催化活性物质硒代胱胺（SeCA）和Cu2+为涂层制备前驱体，通过“一步分子/离子共组装”技术，在支架表面构建出具有长期、持续、稳定、可控NO催化释放功能的粘附涂层。改性血管支架通过原位催化内源性NO供体持续释放NO，显著地抑制了血栓形成、促进内皮快速再生修复，有效地抑制了支架再狭窄。该研究的重要意义在于，一方面为心血管支架表面构建仿生内皮长期、持续、稳定释放NO提供了全新策略，另一方面更为重要的是优化出最佳适宜心血管支架表面修饰的NO催化释放剂量，为基于NO催化释放的内皮功能仿生血管支架表面工程化设计提供理论指导和借鉴。