基于miRNA分子递送水凝胶材料的可注射性心肌组织工程研究

The expression of miRNA changes significantly after myocardial infarction. Exogenous administration of miRNA could regulate myocardial microenvironment and repair cardiac injury. However, delivery of naked miRNA is accompanied with shortcomings of low retention, stability and efficacy, et al. Delivery of miRNA with hydrogel is promising to realize the target delivery, controlled release as well as activity protection of miRNA, presenting a wide prospect. The project will investigate the temporal-spatial expression of endogenous miRNA, then design and synthesize exogenous miRNA targeting these target miRNA; Novel bionics materials will be prepared based on chitosan and OPF hydrogels. After that, miRNA-hydrogel compound is prepared by package or adsorption mehods. miRNA-delivering functional hydrogels with the capacity of myocardial repair will be screened through in vivo and in vitro cardiac ischemic models. Based on the above work, we will in-depth investigate the effects and underlying mechanisms of injectable cardiac tissues based on miRNA-delivering hydrogel and iPSC to repair myocardial infarction, the aim is to effectively repair injured myocardium based on the regulation of myocardial microenvironment. The project is valuable for miRNA-based therapy of myocardial infarction. Simultaneously, it will set basis for pulling the injectable cardiac tissue engineering forward toward clinical practice.

心梗后miRNA表达明显变化，外源性给予miRNA可发挥心梗微环境调控与损伤修复作用。然而，裸miRNA体内递送存在滞留率低、稳定性差及作用效率低等不足。基于水凝胶生物材料的miRNA递送系统有望实现miRNA靶向运输、缓释及活性保护，应用前景广阔。本项目拟在探索心梗后内源性miRNA时空表达规律的过程中，针对筛选的治疗性靶标miRNA设计与合成相应外源性miRNA；仿生制备基于壳聚糖、OPF的新型水凝胶材料；采用包裹、吸附等方法制备miRNA-水凝胶复合物，利用体内外心肌缺血模型筛选出具有心梗治疗作用的功能性miRNA水凝胶递送体系；在此基础上，深入开展基于miRNA递送水凝胶与诱导多能干细胞的可注射性心肌移植修复心梗的作用与机制研究，以期在有效调控心梗微环境的基础上实现损伤心肌的修复。本项目对基于miRNA的心梗治疗研究具有重要价值，并为推动可注射性心肌组织工程未来的临床应用奠定基础。

心梗后外源性给予 miRNA 可发挥心梗微环境调控与损伤修复作用。基于水凝胶生物材料的 miRNA 递送系统有望实现 miRNA 靶向运输、缓释及活性保护， 应用前景广阔。本课题开展了水凝胶与干细胞的可注射性心肌移植修复心梗的作用与机制研究，以期在有效调控心梗微环境的基础上实现损伤心肌的修复。此外，由于心肌组织独有的电传导特性，导电纳米材料已被用于构建工程化心肌组织来提高心肌兴奋收缩偶联特性，并初步用于心梗治疗改善心脏传导阻。本课题研究了基于碳纳米管、氧化石墨烯等导电纳米材料与细胞的相互作用，并从多个角度解析导电纳米材料对心肌细胞的调控功能并对促进细胞增殖和成熟的规律研究，寻找到引起变化的关键信号通路蛋白和基因。本课题对基于心梗治疗研究具有重要价值，并为推动可注射性心肌组织工程未来的临床应用奠定基础。本课题执行期间共发表SCI论文4篇，其中，Biomaterials（IF：8.402）1篇， JCMM（IF: 4.499）1篇，Plos one（IF：2.806）1篇，Stem Cell International（IF：3.540）1篇，影响因子总计19.247；待投稿SCI文章2篇。共培养博士研究生3名。