基于抗纤维包囊导电水凝胶的可注射性心肌组织工程研究

Myocardial tissue engineering based on injectable hydrogels provides a promising therapy for myocardial infarction. However, the lack of electroactivity and the formation of biofilm after in vivo implantation make traditional hydrogels pursuing a better long-term therapeutic effect. This project proposes to prepare injectable hydrogels with both conductivity and anti-biofilm capacity and to further study their regulation on the biological behaviors of MSCs, their repair effect of damaged myocardium and the molecular mechanism behind. First, superhydrophilic zwitterionic groups are to be introduced in polythiophene and thiophene based zwitterionic polymers (PThSB) will be prepared to increase their electroactivity and overcome the issue of biofilm formation. Thermosensitive xyloglucan (XG) can endow the PTHSB-XG hydrogels with injectability. Combined with the click chemistry, homogeneous conductive hydrogels will be then achieved. On this basis, MSCs will be encapsulated in the hydrogels to study the regulation mechanism of hydrogel mechanical properties on the biological behaviors of MSCs. Finally, in vivo experiment will be carried out to further evaluate the effect of anti-biofilm formation and the repair of damaged myocardium. Thus, the mechanism of MSCs differentiation and paracrine in the cardiac repair will be revealed. The study results will provide the repair of damaged myocardium with theoretical basis and experimental evidences.

基于可注射性水凝胶的心肌组织工程策略是一种极具潜力的心梗治疗方法，但传统水凝胶缺乏导电活性及体内植入后易形成纤维包囊，使其长期治疗效果有待进一步提高。本项目拟研制兼具导电和抗纤维包囊的可注射水凝胶，并探索其对间充质干细胞(MSCs)生物学行为的调控及对受损心肌的修复作用及相关分子机制。首先，将具有超亲水特征的两性离子基团引入噻吩基聚合物中，制备噻吩基两性离子聚合物(PThSB)，提高其导电活性并有效解决纤维包囊问题。而具有温敏凝胶特性的木葡聚糖(XG)则赋予PThSB-XG凝胶可注射性，通过点击化学协同温敏性获得结构连续均一的导电水凝胶。在此基础上，将MSCs装载于凝胶中，探索凝胶的理化性能对MSCs生物学行为的调控作用机制。通过体内实验，评价其抗纤维包囊及对受损心肌修复的效果，揭示MSCs分化及旁分泌行为在心肌修复中的作用机制。研究结果将为坏死心肌的修复提供理论基础和实验依据。

针对传统导电聚合物的强疏水性而使其在水凝胶中的分布离散且不均匀，导致导电聚合物水凝胶结构不均一、导电活性及力学性能差，以及由于蛋白质非特异性吸附而使材料植入体内后易被纤维化包囊的问题。本项目旨在研制结构连续均一、具有抗纤维包囊及导电特性的可注射性水凝胶，并探索水凝胶结构对MSCs 增殖、分化及旁分泌行为的调控，研究其对梗死心肌组织的修复机制。. 项目研究过程中，成功合成了结构连续均一的多糖基两性离子聚合物水凝胶、纯两性离子聚合物水凝胶、多功能改性聚苯胺基水凝胶及天然多糖掺杂的PEDOT基水凝胶，详细研究了所制备水凝胶的结构、可注射性能、力学性能、导电性能等理化性能；通过细胞包埋实验，证明了水凝胶对干细胞的高效增殖活性及优异的干性维持性能；通过动物实验，证明了所制备水凝胶良好的抗纤维包囊性能及促进受损心肌修复的功能。结果表明所制备的导电聚合物水凝胶与心肌组织具有优异的机电耦合作用，协同干细胞旁分泌调节微环境，可有效抑制心室恶性纤维化、扩张、变薄，促进梗死区血运重建，辅助电传导和同步搏动功能。研究结果为推动水凝胶联合干细胞组织工程策略在心肌梗死治疗中的应用提供理论指导和实验基础。