基于抗过氧化药物小分子水凝胶体系的构建及其在心肌组织工程中的应用研究

In recent years, myocardial tissue engineering has made great progress in the area of post-myocardial infarction. Peroxidation plays a vital role in ventricular remodeling and stem cell therapy after myocardial infarction. In this study, three kinds of flavonoid hydrogels (FG) with antiperoxidation property were prepared. Free radicals in the infarcted zone were removed by the local release of flavonoids to protect the transplanted stem cells from damage under peroxidation environment, therefore to improve the survival of transplantating cells. The hydrogels we prepared would play the important role of anti-peroxidation and to regulate stem cell survival in the local hypoxic enviroment. The flavonoids-short peptide hydrogels have unique biodegradable degradability, which has more pronounced advantages over other hydrogels in improving local peroxidation microenvironment, carrying biologically active substances and regulating stem cell behavior. In this study, the following work will be carried out: the rational construction and functional characterization of flavonoid-short peptide hydrogel that simulating the microenvironment of the myocardium in vivo will be investigated, and the ability and mechanism of flavonoid-peptide self-assembly hydrogel to protect cells against anti-peroxidation in vitro will be explored. Finally, the in vivo study of flavonoid-short peptide hydrogel carrying MSCs will be transplanted into rat model of myocardial infarction and its role and mechanism will be clarified. This study is expected to provide a method for the reasonable construction of bioactive materials and the treatment of myocardial infarction in the area of injectable myocardium tissue engineering.

心肌组织工程近年在心肌梗死后的研究中取得长足进展，成为研究热点。过氧化在心梗后心肌重构及干细胞治疗中发挥至关重要的作用。本研究拟制备三种具有抗过氧化作用的黄酮类药物小分子水凝胶，通过在心梗局部水凝胶中黄酮类药物的释放以清除自由基，保护过氧化环境下的移植干细胞，从而发挥抗过氧化调控干细胞存活的作用，解决移植细胞存活率低的难题。我们采用的黄酮药物-小分子水凝胶具备独特的生物可调控降解性，在改善局部过氧化微环境、携带生物活性物质及干预干细胞的行为等方面较其他水凝胶有更明显的优势。课题如获资助，拟开展以下工作：黄酮药物-短肽小分子水凝胶的合理构建及表征；体外模拟心肌过氧化微环境，探讨水凝胶保护细胞抗过氧化能力及其机制；体内水凝胶携带MSCs进行大鼠心肌梗死模型移植，观察其对心功能及心室重构的影响并尝试阐明其作用机制，本研究有望为生物活性材料的合理构建及可注射性心肌组织工程策略治疗心梗提供参考。

心肌组织工程在心肌梗死中的应用是近年的研究热点，心梗后的氧化应激微环境损伤是导致移植干细胞存活和滞留不足的重要因素；本课题针对此问题成功构建并获得一系列具有抗过氧化性能的生物活性纳米材料体系，包括葛根素水凝胶、磷酸化糖肽葛根素水凝胶、黄芩苷水凝胶、紫檀芪水凝胶、维生素E-Ang1-7两亲肽水凝胶、替米沙坦-血管紧张素1-7双药纳米体系等，该给药体系具有自组装能力强、合成方便、生物相容性好、性能及成胶条件可控、药物释放稳定持续时间长等优势、与心肌组织具有较好的组织相容性；在体外实验中可抑制过氧化或缺氧环境下的细胞损伤、降低过氧化水平、减少细胞凋亡；应用于动物心梗模型可促进移植细胞滞留，减少移植细胞凋亡，从而增加梗死区室壁厚度、减少心肌纤维化程度、减少心梗面积，增加心肌血管新生，促进心脏射血分数保留的作用。其机制可能是通过炎症通路、细胞凋亡相关通路等发挥作用。该课题证实了抗过氧化生物材料在心肌组织工程中的重要作用，可望为此类生物材料的开发和临床应用提供理论依据，又可望为心肌组织工程的应用拓展思路。