新型多维可控3D打印复合材料修复大段骨缺损的研究

High-energy trauma, bone tumors, osteomyelitis often lead to large bone defects, which is a major challenge for the orthopedic surgeon. Bone grafts are limited by donor supply and clinical complications. Clinical efficacy of in vitro tissue engineering is still unsatisfied. However, the bone shortening-lengthening technique needs a prolonged treatment period and high cost, moreover, this technique has the risk of pin-tract loosening and infection. . Recently, in-situ tissue engineering technology is a hot research arena. A novel PLGA/TCP/Mg composite material designed by our group has the features of excellent biocompatibility and osteogenic activity, which promote osteogenic differentiation of MSCs. It would be feasible to further modify this new composite material, to improve its ability of promoting or accelerating the repair of large bone defects. .In this study, the multi-dimensional structure of the scaffold will be designed optimally to balance the degradation and mechanical strength. Furthermore, it will be infused with different concentrations of cell growth factors（CGF） by low temperature in 3D printing technique. The physical and chemical properties, biological performance and osteogenic ability of this new composite material will be checked in vitro and in vivo. The curve of scaffold gradient degradation and CGFs dynamic release will be analyzed. The best spatial multidimensional structure and the best temporal concentration gradient will be optimized to synchronize the bone defects` physiological repair process in vivo, which may promote the process of bone regeneration (4D printing). This research may help to overcome the clinical obstacle of larger bone defects reparation.

高能量创伤、骨肿瘤、骨髓炎常导致大段骨缺损，治疗十分困难，植骨所需的骨移植材料来源有限、并发症多，体外组织工程技术临床疗效仍欠佳。而骨延长骨搬运技术存在治疗时间长、费用高、钉道松动、感染等风险。原位组织诱导再生技术为近年研究热点，本课题组前期创新设计PLGA/TCP/Mg复合材料，具有良好的生物相容性和促成骨活性，可促进间充质细胞骨向分化，进一步设计能否使其具备促进或加速大段骨缺损的修复能力意义重大。本研究拟对该支架材料进行多维空间构象优化打印设计，实现材料的降解性能与力学强度的平衡，同时3D低温打印复合不同浓度的生长因子，体内外实验检测该多维复合支架的理化性能、生物学性能及成骨能力，分析支架梯度降解、生长因子梯度释放动态曲线，找出最佳多维空间构象与梯度，使该材料具备与体内骨缺损生理修复过程相匹配的梯度降解、梯度释放及促骨诱导骨再生性能（4D打印），为解决临床大段骨缺损修复的难题奠定基础。

高能量创伤、骨肿瘤、骨髓炎常导致大段骨缺损，治疗十分困难，植骨所需的骨移植材料来源有限，体外组织工程技术临床疗效仍欠佳，原位组织诱导再生技术为近年研究热点。在本课题组前期创新设计PLGA/TCP/Mg复合材料的基础上，本项目设计制备了三种新型3D打印复合支架材料：（1）负载可缓释BMP-2的壳核微球的3D打印聚己内酯支架，结果表明该支架可很大程度保留BMP-2的活性，赋予支架系统与骨再生重建相匹配的BMP-2释放性能，显著提升高分子三维支架材料的骨修复效率；（2）3D低温打印PLGA/MgO/PDA 复合支架，结果表明该复合支架具有良好的生物安全性和物理性能，可以有效的促进成骨分化，加速体内骨骼生成；（3）可梯度释放BMP-2和VEGF双生长因子的3D打印GelMA复合支架，结果表明该3D打印GelMA复合支架具有促进骨缺损骨修复的能力，可以用作新型的骨修复材料。同时，本项目也研制出了一种新型自固化可注射水凝胶体系（四臂PEG复合水凝胶），结果表明该新型水凝胶具备可注射性、自固化性及良好的生物相容性，力学强度高，同时也是BMP-2的优良载体，可显著促进大鼠股骨髁缺损修复，该新型水凝胶在骨缺损修复中具备优良应用前景。.综上所述，本项目创新设计制备了三种新型3D打印复合支架材料和一种新型自固化可注射水凝胶体系。体内外实验表明，这些新型材料实现了降解性能与力学强度的平衡，并且具备与体内骨缺损修复过程相匹配的梯度降解、生长因子梯度释放与骨诱导再生性能，能够促进骨缺损的修复，为解决临床大段骨缺损修复的难题提供了新材料。本项目共发表SCI论文3篇、中文核心期刊论文5篇和申请专利4项，培养博士后5名、博士研究生7名和硕士研究生11名。