基于新型股骨头坏死塌陷模型及靶向双膦酸盐/miR-431-5p/TGFβ/SMADs轴的缓释系统预防早期塌陷的多层次研究

股骨头坏死(ONFH)致残率极高，是关节外科医生面临的巨大挑战。目前，髓芯减压联合支架植入是临床早期干预、延缓或避免股骨头塌陷的主要途径。但现有的ONFH模型难以重现疾病自然进程，植入材料生物活性或力学性能欠佳，缺乏高效促骨形成活性的细胞、生长因子或药物等问题已成为限制ONFH疗效提升的瓶颈。基于此，本项目拟利用激素冲击联合髋臼内置股骨头仿生加压装置构建新型ONFH动物模型，通过高通量测序结合生信方法筛选ONFH关键miRNA分子和双膦酸盐(BP)相关的靶点并探究BP/miR-431-5p/TGFβ/SMADs轴的作用机制，将关键miRNA转染BMSCs后与BP共同加载于具有优良缓释特性与生物相容性的可注射自适应PCL缓释系统。髓芯减压后，将该系统注射入隧道自适应填充空腔并固化形成力学支撑，并持续、稳定发挥促成骨、抑破骨功能，终止或逆转股骨头坏死进程，避免股骨头塌陷的发生。

Osteonecrosis of femoral head (ONFH) is a huge challenge for orthopaedic surgeons because of extremely high disability rate. At present, core decompression combined with scaffolds implantation is the main approach as early clinical intervention may delay or even avoid the collapse of the femoral head. However, the existing ONFH model can hardly reproduce the natural progress of the disease. Besides, the biological activity or mechanical properties of the implant materials are not satisfactory for the clinical application. In addition, there is lack of effective treatment method based on cells, growth factors or drugs in promoting bone formation. These factors have become a bottleneck that limits the improvement of the ONFH therapeutic effect. In response to the above problems, this study intends to use the high-dose corticosteroid intervention combined with the acetabular built-in femoral head biomimetic compression device to build a new ONFH animal model and meanwhile screen common key miRNAs of ONFH and bisphosphate-treatment based on high-throughput sequencing and bioinformatic analysis. Subsequently, we will explore and verify the molecular mechanism of bisphosphate/miR-431-5p/TGFβ/SMADs axis. Then, after the key miRNAs were transfected into BMSCs, they were co-loaded with bisphosphonates in an injectable adaptive PCL sustained-release system. After core decompressing, the material is injected into the bone defect. The material can adaptively fill the bone defect and solidify to form a mechanical support. The material loaded with miRNA-transfected BMSCs and bisphosphonates can sustainably and stably promote bone formation, inhibit osteoclast function, and finally detain or reverse the process of osteonecrosis, avoiding the occurrence of femoral head collapse.