基于"主动炎症调节"的骨组织工程技术的研究与机制探讨

骨组织工程（BTE）技术有望满足我国骨科治疗巨大临床需求，但其临床转化瓶颈在于组织工程骨植入体内后由于剧烈炎症反应及血供不足，细胞存活率低、疗效有限。基于预实验发现适量抗炎因子IL-4注射可调节炎症反应、促进骨再生，我们首次提出基于“主动炎症调节”的BTE技术新理念：首先移植复合IL-4的功能型多孔支架材料，调节局部炎症反应，促进血管化，构建适宜再生的微环境；然后注射移植微型组织工程骨（uTEBG），促进骨再生。我们拟建立基于“主动炎症调节”BTE技术，并研究其作用机理：①应用3D打印技术制备复合IL-4的功能型支架材料，优化三维结构及IL-4载药量；②探索uTEBG最优构建条件与注射移植时间点及剂量；③与现有BTE技术对比，从组织、细胞、分子水平研究其作用机理。基于“主动炎症调节”BTE技术可提高疗效，减少个体差异，加速临床转化；是现有BTE理论的重要补充，对其他组织修复有重要借鉴意义。

Mesenchymal stem cell (MSC) based bone tissue engineering (BTE) strategy can fulfil the ever-increasing clinical need for the bone defect treatment in China. However, the major bottlenecking problem for the clinical translation of BTE is the poor cellular survival rate of tissue engineered bone graft (TEBG) after the in vivo transplantation, due to the strong inflammation reaction and lack of sufficient vascularization, which leads to the compromised defect healing efficacy. Based on our preliminary study showing that the local injection of cytokine IL-4 can help to modulate the inflammatory response, and resulted in the better defect healing. Thus we propose a novel “inflammation modulation” based bone tissue engineering strategy, where the first step aims to implant a bioactive scaffold with sustained release of IL-4 from the scaffold to modulate the inflammatory response and construct a pro-healing microenvironment for bone regeneration and the second step aims to develop a micro-sized bone tissue engineering graft（uTEBG）and deliver the uTEBG with pro-osteogenic treatment to the defect site after sufficient vascular network has been generated in order to supplement osteogenic cell pools for bone regeneration. In this study, we will develop and optimize this “inflammation modulation” BTE transplantation strategy and investigate its underlying mechanism: (1) to develop a bioactive scaffold incorporating IL-4 using 3D printing technique, and optimize the three dimensional structure of scaffold and amount of IL-4 within the scaffold; (2) to optimize the construction conditions of TEBG and investigate the optimal time point and dosage for uTEBG transplantation by injection; and (3) to investigate its underlying mechanism by comparing it with current BTE strategy at the tissue, cell and molecular levels. The development of “inflammation modulation” based new bone tissue engineering technique will help to boost up the healing efficacy of BTE technology, minimize the individual variation of BTE treatment and promote its fast clinical translation, on the other hand, it can supplement the current knowledge of BTE research and serve as a useful reference for developing tissue engineering strategies for other tissue defect treatment.