可注射导电水凝胶的构建及其在心肌梗死治疗中的应用

After a myocardial infarction (MI), cardiomyocytes die and cardiac muscle is replaced by a thick scar, which cannot pump blood like normal tissue. These result in total heart failure and death in those patients who survive the initial MI. Injectable hydrogels for myocardial regeneration are suitable for clinical applications due to the minimally invasive surgery to the patients, which have become one of the hottest topics in myocardial regeneration. Numerous researches have focused on the improving the bioactivity of injectable hydrogels, while the myocardial tissue passes and responds to the mechanical and electrophysiological signals during cardiac contractility and relaxation, but there has been no systematical research on different myocardial regeneration caused by the different mechanical and electrical properties of injectable hydrogels. Considering the excellent mechanical and electrical properties of graphene, this project intends to construct a dextran/graphene hybrid injectable hydrogel. The mechanical and conductive properties of the hydrogel can be controlled by the regulation of the composition of the network and the chemical structure. After injection into the MI area, the hydrogel can compensate the heart contraction function; participate contraction in coordinated with the heart and pass electrophysiological signals, thus preventing expansion of ventricle. In addition, graphene can bind the positively charged stromal cells derived factor-1 (SDF-1) in physiological environment, thereby increasing the stability of SDF-1 which could be released with degradation of the hydrogel. The in situ delivery of SDF-1 will be effective to mobilize and recruit the stem cells and then promote myocardial regeneration in vivo. The mechanisms underlying the effect of gel's mechanical and electrical conductivity on myocardial regeneration behavior will offer beneficial insight into to the regeneration of muscle and nerve tissue.

心肌梗死引起的心肌损伤是导致心力衰竭的主要因素。可注射水凝胶对患者创伤小而易于临床应用，已成为心肌再生领域研究的热点。目前对可注射水凝胶的研究集中于改善凝胶的生物活性，实际上心肌组织在收缩舒张过程中能迅速地响应并传导机械和电生理信号，而目前对可注射凝胶的力学和电性能对心肌再生的影响尚无系统的研究。基于石墨烯良好的力学及导电性，本项目拟通过迈克尔加成反应构建葡聚糖/石墨烯可注射水凝胶，通过调控其结构和网络组成优化水凝胶的力学和导电性能，将其注射到心梗区补偿心肌功能，参与心脏的协同收缩并传递电生理信号，抑制心室膨胀。并且，石墨烯能够和生理环境中带正电的基质细胞衍生因子-1（SDF-1）结合，使得SDF-1在体内稳定存在并随水凝胶降解释放，有效地募集干细胞归巢，促进心肌再生。本项目所揭示的力学和导电性对心肌再生的影响规律，对肌肉和神经组织的再生都具有重要的指导意义。

心肌梗死是全世界最首要的致死原因，心肌组织的再生潜能极其有限，而用于心脏移植的供体器官严重缺乏。针对心肌梗死的临床需求及心肌组织工程在心梗治疗中存在的问题，在本项目的支持下完成了大量研究工作，并取得了系列创新性研究成果，主要体现在三个方面：(1) 创建了一系列水凝胶功能化的新途径，针对心梗病灶微环境建立了干细胞/基因/导电水凝胶的组织工程化体系，明确了该体系对受损心肌的治疗性作用；(2) 拓展了非共价键调控水凝胶力学强度的新方法，提出了柔软导电水凝胶促进心肌功能重建的新思路；(3) 发展了超支化聚合物合成的新技术，发明了免缝合型“心脏创可贴”的新策略。本项目支持下在Progress in Polymer Science (IF=24.558)，Advanced Materials (IF=20.950)，Biomaterials (IF=8.806)，Chemical Science (IF=9.063)等杂志发表SCI检索科技论文10篇，申请中国发明专利11项（授权1项）。研究成果受到了国内外学者的广泛关注，被Chem Rev (IF=47.928)，等著名SCI期刊引用及正面评价。项目负责人在本项目的支持下获得2018年度国家优秀青年基金（心肌组织工程，编号：31822020）的支持，同时本项目培养硕士研究生三名。本项目基于再生医学的方法修复受损的心肌组织，对改善心梗后心肌功能具有重要意义，为组织工程手段治疗心肌梗死提供材料学储备。