基于“巨噬细胞-MSCs交互对话”构建功能化中药给药体系参与心肌损伤修复的作用机制研究

Changes in the microenvironment of tissue damage after myocardial infarction play an important role in dilated remodeling and hyperfibrosis of the infarcted heart. The interaction between macrophages and MSCs is a key link in the regulation of tissue damage repairation. The preliminary experimental results of the research group showed that tanshinone IIA can promote the transformation of macrophages into repaired type m2-type macrophages. In order to regulate the interaction between macrophages and MSCs and solve the problem of local long-term drug administration of insoluble TanIIA, we used electrostatic spinning technology to prepare micro-fiber scaffold materials with different topological structures to load drugs, and planned to construct a functional Chinese medicine delivery system, so as to promote the repairation of infarcted myocardial tissue. This project intends to adopt the rat bone marrow macrophage and bone marrow mesenchymal stem cell co-culture model and rat myocardial infarction patch model to observe the effect of the functional Chinese medicine delivery system on the infarct myocardium from the perspective of regulating the "macrophage-MSCs interactive dialogue", and preliminarily explore the mechanism. This project innovatively combines traditional Chinese medicine monomers, biomaterials and synergistically regulated treatment strategies, which can not only provide experimental basis for the clinical transformation of this drug delivery system, but also have important significance for promoting the interdisciplinary cooperation between tissue engineering and clinical medicine of traditional Chinese medicine.

巨噬细胞与MSCs的交互作用位于调控心梗后组织损伤修复的关键环节。课题组的前期实验结果显示丹参酮IIA能促进巨噬细胞向修复型M2型巨噬细胞的转化。静电纺纤维是一种集细胞生长支架和药物载体为一体的多功能修复支架。 因此，为了调控巨噬细胞与MSCs相互作用并解决难溶性TanIIA局部长效给药的问题，我们利用静电纺丝技术制备具有拓扑结构的微米纤维材料来负载药物，拟构建一种功能化的中药给药体系，以期实现调控“ 巨噬细胞-MSCs交互对话”进而促进梗死心肌修复的作用。本项目拟采用大鼠骨髓巨噬细胞和骨髓间充质干细胞共培养模型和大鼠心梗补片模型的基础上，基于“中药单体-拓扑结构生物材料”协同调控“ 巨噬细胞-MSCs交互对话”的角度观察可释放TanIIA的微拓扑结构材料对梗死心肌的修复作用。此研究不仅可为该支架材料用于临床转化提供实验依据，而且对促进组织工程学与中医药临床医学的学术交叉合作具有重要意义。

本项目利用静电纺丝技术制备具有拓扑结构的微米纤维材料来负载药物，成功构建一种功能化的中药给药体系，首先实现了难溶性中药单体丹参酮IIA的原位缓释给药方式。在大鼠心梗补片缝合实验中显示AF-1支架可以改善心脏功能和心肌组织结构。通过后续的机制探究，我们发现该载药支架是通过调节巨噬细胞表型和抑制炎症反应，实现内源性干细胞募集和血管化。AF-1显著促进RAW 264.7巨噬细胞向M2表型极化。从AF-1支架上培养的巨噬细胞收集的条件培养基改善了BMSC的增殖和迁移，调节了其多种生物学功能，并促进了HUVEC的增殖、迁移和管形成。在大鼠皮下植入AF-1支架进一步证实了其招募内源性干细胞和增强体内血管化的能力。在这项研究中，我们开发了一种新型的生物活性材料，通过将传统的中药单体药物与纤维支架相结合来促进内源性再生。