缓释小分子化合物Kartogenin水凝胶重建软骨及软骨下骨缺损的机制研究

The incidence of osteochondral defect is very high. There are more than 30 million patients in China. There is huge social and economic benefits to treat the osteochondral defect. Although various methods have been applied in the treatment of osteochondral defect, there is still no useful way to overcome this problem. What’s more, almost all the attention was paid to the repair of the cartilage injury, there is almost no study to find out the mechanism of osteochondral defect reconstruction especially the mechanism of subchondral bone reconstruction. Our team have used a photo-cross-linked scaffold with kartogenin (KGN) encapsulated nanoparticles for cartilage regeneration. Hyaline-like cartilage tissue was reconstructed, and the subchondral bone defect was also reconstructed (ASC nano, 2016). This project will focus on the mechanism of osteochondral reconstruction using the photo-cross-linked hydrogel with KGN. Cell and animal models will be used in this study. The following three questions will be studied: 1. the mechanism of subchondral bone reconstruction, 2. how to restore the cartilage and subchondral bone defect using one same hydrogel by one surgery? 3. find out the type and size of the defect that can be repaired using this method. Our team hope to find out the mechanism of osteochondral defect reconstruction through this study, so that the osteochondral defect can be better restored in the future.

骨软骨损伤的发病率非常高，我国骨软骨损伤患者达3000万以上。治疗此类疾病有巨大的社会和经济效益。目前，多种方法用于骨软骨损伤的治疗研究，但均仍存在各种不足之处。而且，对骨软骨损伤的研究更多的关注于软骨层的修复。尚无研究揭示骨软骨损伤的重建机制，尤其是软骨下骨的重建机制。课题组之前使用缓释小分子有机化合物Kartogenin的透明质酸凝胶在骨软骨缺损处再生出类天然软骨组织，并重建出了软骨下骨（ACS nano, 2016）。但作用机制仍不清楚。本项目将在前期工作的基础上重点研究阐明重建软骨及软骨下骨的机制。本项目将采用细胞模型及骨软骨损伤的动物模型进行相关研究，重点解决以下三个问题：1.缓释KGN凝胶重建软骨下骨缺损的机制；2.同一种凝胶可同时重建软骨层及软骨下骨层的机制；3.缓释KGN凝胶可修复的骨软骨损伤的类型和大小。拟通过研究阐明骨软骨损伤重建的机制，以更好的促进骨软骨损损伤修复。

骨软骨损伤作为一种常见的骨关节疾病，为我国社会医疗资源带来了沉重的负担。在课题组前期工作中发现，缓释含小分子化合物Kartogenin（KGN）凝胶可在骨软骨缺损处重建软骨-软骨下骨界面，在本项目中，课题组针对KGN凝胶在促进软骨及软骨下骨重建的机制及转化展开了相关工作，综合应用组织工程学、生物医学、分子生物学等技术，深入探讨了KGN修复骨软骨缺损及在软骨与软骨下骨区域分别形成软骨和软骨下骨的机制。在此基础上，团队利用小型猪骨软骨缺损动物模型证实KGN凝胶在大动物模型中修复骨软骨缺损的可行性，并阐明缓释KGN凝胶可修复重建的骨软骨缺损类型和大小。总的来说，在项目实施过程中，申请人团队证明了KGN可通过降解为4-ABP和OPA两部分，原位调控软骨与软骨下骨再生，从而在骨软骨缺损中达到近似天然的软骨-软骨下骨界面修复，同时在小型猪模型上验证了含KGN凝胶修复软骨及软骨下骨的可行性，并证明了含KGN凝胶对直径较小的骨软骨缺损和全层骨软骨缺损（累及软骨下骨）修复效果更佳。该项目的实施有助于进一步理解KGN修复骨软骨缺损的作用机制，推动其向临床的应用转化。