电子束熔融技术3D打印金属模块嵌入肌腱干细胞外泌体精准保髋治疗股骨头坏死的疗效分析和生物学机制探索

The incidence of femoral head osteonecrosis showed younger trend. Using total hip arthroplasty prematurely may cause problems such as repeated revision. Therefore, hip-preserving treatment in the early stage is drawing more attention. We have used 3D printing technology to develop a Poly Ethylene( PE) module filling osteonecrotic area of the femoral head, to delay the collapse of the femoral head. However, due to material properties, deficiencies such as poor implant fixation and poor wear resistance were detected in the PE module. Electron beam melting (EBM) free form fabricated (FFF) technology used three-dimensional data model and electron beam to melt metal powder, to obtain the expected space configuration of metal parts, and in turn to meet the shape customization requirements. The tendon derived stem cells (TDSCs) had higher mRNA expression of cartilage and bone related markers than that of BMSCs, which suggested that TDSCs had stronger osteogenic and chondrogenic potentials to repair cartilage and subchondral bone of the femoral head. Exosomes derived from TDSCs have regenerative potential similar to TDSCs. Furthermore, they are small enough to reach injury location quickly and can avoid the risks of stem cell transplantation. The aims of this project were to develop a metal module for repairing the early osteonecrotic area of the femoral head using EBM FFF technology and 3D printing, and then to explore the curative effect and biological mechanism of repairing early stage femoral head osteonecrosis using the metal module, TDSC exosomes and a emu model. By this research, we try to find a new and more effective solution for the hip-preserving treatment of femoral head osteonecrosis.

股骨头坏死的发病逐渐趋于年轻化，过早使用人工全髋关节置换手术治疗将面临后期多次翻修的问题，早期保髋治疗越来越受到重视。我们曾用3D打印技术研发出聚乙烯模块填充股骨头坏死区域，达到延缓股骨头塌陷的效果。但由于材料特性，模块存在无法牢固固定、耐磨性差等缺陷。电子束熔融自由空间构型技术利用三维数据模型，通过熔融金属粉末构建预期的空间构型金属件，可满足形状定制化要求。肌腱干细胞中软骨、骨相关标记物表达水平均明显高于骨髓间充质干细胞，具有极大的成骨、成软骨分化潜能，其来源的外泌体具有组织再生修复等功能。外泌体直径小,可快速到达病损部位,并可避免干细胞移植带来的免疫排异、促肿瘤生长迁移等风险。本课题组拟用电子束熔融技术，3D打印出用于修补股骨头早期坏死区域的金属模块，结合肌腱干细胞外泌体，探索早期修复鸸鹋股骨头坏死的疗效和生物学机制。本课题的顺利实施将为股骨头坏死保髋治疗策略提供新的实验依据。

股骨头坏死导致髋关节功能丧失的主要是由于股骨头塌陷。如何抓住早期发现后的窗口期，防止股骨头塌陷是保髋治疗的切入点和难点，项目组主要围绕寻找一种安全有效的坏死区域替代治疗方案开展了系列特色研究。我们探索了肌腱干细胞外泌体对成骨细胞和破骨细胞的活性影响和组织再生修复功能，自主设计新型坏死区域金属修补块（ZL202130664465.8）以较小的手术干预预防股骨头塌陷，以及从“个性化治疗角度”入手，对人诱导多能干细胞来源的间充质干细胞、脂肪来源与脐带来源间充质干细胞等自身来源的干细胞进行了探索研究，丰富了骨关节疾病治疗的种子细胞来源。本项目完善了肌腱来源干细胞外泌体提取及鉴定体系，新的种子细胞也对股骨头坏死的治疗有积极的效果，局部应用iPSC-MSCs可以增加坏死股骨头的骨量，减少骨丢失，促进成骨和血管生成，同时在局部形成软骨类结构。个性化的金属修补块可按计划植入，但替代坏死区域的精准性还有待进一步研发个性化的导航工具。修补块光滑面边缘与股骨头软骨的匹配和衔接还不够完美，影响修补块的远期效果。项目实施期间，依托基金支持项目组已在国内外杂志发表文章14篇（SCI 4篇）；授权国际专利1项，国家专利14项；培养博士后1名，博士研究生4名，硕士研究生13名，一名博士研究生获评解放军医学院优秀博士学位论文。