力学-生化学耦合作用下关节软骨成熟发育机理及缺损修复的研究

The cartilage tissue engineering has not become a conventional surgical method in clinical application now. The fibrillated cartilage and bad interfacial integration are the urgent problems in tissue engineering application. The repairing and reconstructing mechanism of defects for articular cartilage under mechanical-biochemical coupling signals is investigated based on the influence rule of cartilage maturity under these coupling signals since the mature process of immature cartilage is same as the repairing process of defect by artificial cartilage. The growth models from immature to mature cartilage are built under the coupling conditions of growth factor and mechanical loads including compressive, rolling and sliding loads. It is investigated for the grade of manurity of cartilage such as the mechanical property, chemical composition, histologic evaluation and so on under these coupling signals. The best coupling signal is determined. The repairing models for cartilage in vivo and vitro are built by using artificial cartilage constructed in 3D printing scaffold and the related experiments are conducted. The repair and integration aspects of immature and mature cartilage are studied including the proliferation, differentiation and migration of cell and the mechanical properties of tissue. The appropriate grade of manurity for artificial cartilage is obtained by investigating the effect of grade of manurity on integration of repaired tissue. This research work will contribute to solve the repair problems of cartilage defects in tissue engineering application.

软骨组织工程还没有成为临床上常规手术方法，其修复过程中还存在软骨纤维化及“缝隙”界面等急需解决的挑战。未成熟软骨向成熟发育的过程与植入缺损人工软骨的修复重建阶段类似，因此，首先研究力学-生化学耦合信号对软骨成熟发育的影响规律，然后探索该耦合信号作用下关节软骨缺损修复重建的机理。在压缩、滚动或滑动载荷及生长因子条件下建立未成熟关节软骨（天然和人工）加速向成年软骨转变模型，研究力学-生化学耦合作用下软骨发育的成熟度（机械性能、生化构成、组织学评价、细胞指标），确定成熟发育的耦合条件。采用3D打印支架为基础的人工软骨，开展体外/体内软骨缺损修复模型实验，研究未成熟软骨缺损修复、发育以及成年软骨缺损修复整合，包括细胞增殖、分化、迁移行为，组织宏微观力学性能测试及本构模型预测等；探索人工软骨不同成熟度对修复整合的影响，获得合适软骨成熟度指标。研究将有助于解决组织工程修复软骨缺损难题，推动其临床应用。

软骨组织工程还没有成为临床上常规手术方法，其修复过程中还存在软骨纤维化及“缝隙 ”界面等急需解决的挑战。未成熟软骨向成熟发育的过程与植入缺损人工软骨的修复重建阶段类似，因此，项目首先研究了力学-生化学耦合信号对软骨成熟发育的影响规律，然后探索了该耦合信号作用下关节软骨缺损修复重建的机理。采用3D打印技术制备了II型胶原-丝素蛋白人工软骨支架，通过测试支架的降解性能、生物相容性及力学性能，获得了优化的人工软骨支架。基于此支架，建立了力学-生化学耦合作用下软骨培养、发育模型，检测了耦合信号作用下软骨培养、发育过程中的细胞增殖、分化，以及组织、结构、性能的变化；同时，采用实验测试和理论预测研究了不同力学载荷下未成熟天然软骨与成年软骨的性能，将人工软骨与天然软骨的研究结果作对比，总结了力学-生化学耦合信号对软骨成熟发育的影响规律。建立了力学载荷下体外未成熟（幼年）软骨和成年软骨缺损模型，考察了缺损尺寸及力学载荷对两种缺损软骨性能的影响，获得了幼年和成年软骨自我修复的极限缺损尺寸；研究了含裂纹缺损软骨的力学性能及裂纹扩展行为，获得了软骨的裂纹扩展规律。建立了力学载荷下体外软骨缺损修复模型，研究了不同力学载荷下宿主软骨、修复界面及人工软骨区域的应力应变分布，探究了不同缺损形状修复后关节软骨力学行为的变化及修复区域的压力分布情况，分析了力学载荷对软骨缺损修复、界面整合的影响。将体外培养的人工软骨植入动物膝关节软骨缺损处，建立了力学载荷下关节软骨缺损修复动物模型，采用Micro-CT、HE染色、免疫组化等手段检测了修复不同时间时软骨缺损修复情况，分析了力学载荷和构建的人工软骨对体内软骨缺损修复、重建的影响。结合体内、外研究结果，总结了力学-生化学耦合信号对关节软骨发育、缺损修复、重建的作用机理。该研究将有助于解决组织工程修复软骨缺损难题，推动其临床应用。

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