原位注射bFGF-ECM-HP温敏性水凝胶治疗脊髓损伤的作用和机制研究

Currently, spinal cord injury is the most terrible central nervous system damage, which with high rate of incidence and disability, the treatment of second injury is the key of prognosis, but still short for efficient strategy. Based on our previous studies, this project constructed a synthetic material heparin - poloxamer (HP) to prepare a novel HP hydrogel, combine with tissue repairable extracellular matrix (ECM) and efficient neuroprotective factor basic fibroblast growth factor (bFGF), to establish the bFGF-ECM-HP temperature-sensitive hydrogel. Combined with in situ injection administration, bFGF-ECM-HP hydrogel can attach closely on the tissue cavity and form a three-dimensional supporting gel. With comprehensive evaluation system including modern cytology, pharmacology, imaging and molecular biology, the multiple repairment effects and mechanism of bFGF-ECM-HP temperature-sensitive hydrogel for spinal cord injury model animals will be investigated. Further more, base on our previous studies, to investigate the molecular mechanism with autophagy and others. This project will combine these techniques effectively --"Biological graft material", "biological factor", "targeted delivery system". To overcome the limitation of existing therapies andsatisfy the ideal requirement of safe, efficient and specific treatment to realize.multiple repair effects. Through our study, a novel strategy with high efficiency and safety will be developed to improve the effect and control release technology for the recovery and regeneration of spinal cord injury.

脊髓损伤是当今社会发病率、致残率极高的中枢神经系统严重的创伤之一，其继发性损伤的治疗是影响预后的关键，但迄今尚缺乏安全有效治疗策略。本项目自主合成肝素-泊洛沙姆水凝胶，联合具有组织修复再生活性的去细胞化组织基质ECM，和具有良好神经保护作用的碱性成纤维细胞生长因子(bFGF)，构建bFGF-ECM-HP温敏型水凝胶，原位注射到脊髓损伤区域，形成紧贴组织空洞的三维支撑型凝胶，通过多角度细胞生物学、药理学、影像学、分子生物学等综合评价方法， 研究原位注射bFGF-ECM-HP温敏型水凝胶对于脊髓损伤模型动物的治疗效果，并基于前期工作，探讨自噬等相关作用机制的变化。本项目将生物支架/移植材料、高效治疗因子、制剂新技术多学科技术融合，克服已有药物治疗半衰期短、给药频繁的局限，提高基因工程药物的药效和控释技术水平，实现安全、高效的脊髓损伤修复和功能再生。

脊髓损伤是当今社会发病率、致残率极高的中枢神经系统严重的创伤之一，其继发性损伤的治疗是影响预后的关键，但迄今尚缺乏安全有效治疗策略。应用生长因子(GFs)治疗慢性脊髓损伤已被证明可以促进轴突再生和功能恢复。然而，GFs在损伤部位直接给药后因快速降解和稀释而受到应用限制。并且治疗脊髓损伤是一个复杂过程，需要多种GFs参与组织再生。因此，我们设计了一种基于GFs的药物递送系统(GFs-HP水凝胶)，并发现GFs-HP的神经保护和神经再生作用可能与激活PI3K/Akt以及MAPK/ERK信号通路相关。除此以外，基于课题组前期研究，我们还研发了一种新型水凝胶，UCMSC-bFGF-ECM-HP温敏型水凝胶，通过体内体外实验验证其对脊髓损伤的修复作用及具体分子作用机制。本课题的研究结果对于设计水凝胶等生物支架材料联合干细胞、生长因子等药物的协同治疗脊髓损伤有重要的参考意义，有望进一步推动水凝胶支架修复脊髓损伤的临床应用。