3D打印三相一体化支架缓释DMOG激活HIF-1α信号通路治疗骨软骨缺损

The treatment of osteochondral defects is a major challenge in orthopedic surgery, while the development of tissue engineering brings new hope, in which preparing tri-layer monolithic scaffolds and promoting vascularization is a hotspot. Hypoxia inducible factor-1α (HIF-1α) is s key regulator for cell in response to hypoxia, and studies have shown that it plays an important role in coupling osteogenesis and angiogenesis during bone regeneration. The use of inhibitors of prolyl hydroxylase (PHD), such as dimethyloxaloylglycine (DMOG), can stabilize HIF-1α expression and promote angiogenic effect. Our research group found mesoporous bioactive glasses have excellent biocompatibility, bioactivity, controllable drug loading and releasing properties. Based on previous studies, we fabricate tri-layer DMOG releasing MBG/Alginate scaffolds by 3D-printing technology, planning to validate whether MBG/Alginate scaffolds can promote osteogenic, chondrogenic and angiogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and repair osteochondral defects. Furthermore, we plan to clarify the molecular mechanisms that how MBG/Alginate scaffolds activate of HIF-1α signaling pathway and promote osteochondral regeneration. This proposed study taking advantage of material science and 3D-printing technique will provide new ideas and scientific basis for the treatment of osteochondral defects in future.

骨软骨缺损的治疗一直是骨科医生面临的棘手问题，组织工程学的发展为其治疗带来了新的希望，其中制备三相一体化支架并促进其血管化是该领域的研究热点。低氧诱导因子-1α（HIF-1α）是一个细胞对缺氧反应调节的关键因子，研究显示它在骨再生时成骨和成血管偶联反应中发挥了重要作用，而通过使用脯氨酰羟化酶（PHD）抑制剂，如二甲氧乙二酰甘氨酸（DMOG）,可以稳定HIF-1α表达并产生成血管效应。本课题组长期致力于介孔生物玻璃（MBG）的研究，发现其具有良好的生物相容性、成骨活性和可控的药物装载等优点。在此基础上，我们利用3D打印技术制备MBG/Alginate三相一体化支架，并缓释DMOG，验证该支架促进骨髓间充质干细胞（BMSCs）成骨、成软骨和成血管分化以及对骨软骨缺损的修复作用，阐明其通过激活HIF-1α信号通路实现骨软骨再生的分子机制。该课题的顺利实施，将为骨软骨缺损的治疗提供新的思路和依据。

软骨缺损的治疗一直是骨科面临的难题。目前常用的各种治疗软骨缺损的方法，包括微骨折术、自体软骨细胞移植术、干细胞移植技术等。然而，这些治疗方法都有各自的缺陷。相比人骨髓间充质干细胞和人脂肪间充质干细胞，脐带间充质干细胞的增殖，分化能力更强，并且具有来源丰富，无伦理学争议等优点。但是潜在的免疫原性限制了其进一步的临床应用。最近研究表明脐带干细胞来源的外泌体(hUC-MSCs-Exos)能将干细胞的生物活性物质及信息传递至效应细胞从而发挥与hUC-MSCs类似的生物学功能，且无免疫原性，提示hUC-MSCs-Exos可能成为修复软骨缺损的新方法。此外，hUC-MSCs-Exos治疗软骨缺损的研究鲜有报道。水凝胶作为一种仿生材料，具有类似软骨细胞外基质的纤维丝状结构，广泛应用于软骨组织工程。利用水凝胶填充软骨缺损区域，防止软骨进一步磨损，同时负载外泌体促进软骨再生。该课题有望为治疗软骨缺损提供新的思路和理论依据。