3D打印多孔钛合金填充辛伐他汀温敏性水凝胶促进骨和血管新生在脊柱融合中的研究

3D printing technology (Electron Beam Melting) is convenient to cast titanium alloys with irregular shape and porous trabecular structure, and the elastic modulus of the 3D printed porous titanium alloys is close to cancellous bone, which is especially suitable for spinal fusion. .In our previous studies, we found that the 3D printed porous titanium alloy is a suitable implant for spinal fusion and substitute of vertebrae in sheep, but the bone ingrown is not ideal than we expected. We also found that local injection of simvastatin hydrogel promote osteogenesis in OVX rats and minipigs. But the injectable thermosensitive hydrogel has poor mechanical properties. The 3D printed porous titanium alloy has good mechanical properties and internal lacuna characteristics. In this study, we are trying to have the two combined by filling thermosensitive simvastatin hydrogel into the 3D printing porous titanium alloy, and investigate its application in the spinal fusion..In this study, we first design 3D printed porous titanium alloy artificial vertebral body and intervertebral fusion. The printed porous titanium alloy were filled with different concentrations of simvastatin hydrogel and implanted into the experimental sheep. According to the effect of fusion, optimized simvastatin was used and the effect of angiogenesis promoted by simvastatin in spinal fusion was studied. We suppose that local simvastatin application promotes the expression of hypoxia factor 1a (HIF-1α), which acts on the special endothelial cell in bone tissue, the H endothelial cells. Induced H endothelial cells secrete more Noggin, which promote bone formation, and stimulate the release of endogenous VEGF secreted by osteoblasts and chondrocytes. When the implant was normal vascularization, and improved anoxic condition, the HIF-1α decreased to normal level. The bone remodeling and angiogenesis reached a homeostasis state. This study will highlight the molecular mechanism of simvastatin for promoting vascularization within plants and intensify the research in bone fusion..The research will provide preclinical evidence that the 3D printed porous titanium alloy filled with injectable simvastatin hydrogel can promote spinal fusion, clarify the mechanism that simvastatin promotes endogenous angiogenic factor secretion and regulates bone formation and vascularization of the implant through up-regulating HIF-1α. The study is of great theoretical significance and research value.

3D打印技术便于制造外形不规则、内部多孔、弹性模量接近松质骨的钛合金。但我们前期研究发现多孔钛合金内部骨长入不理想，辛伐他汀水凝胶促进成骨、成血管，但力学性能差；多孔钛合金提供了绝佳的给药腔隙。.本课题是在以往研究的基础上尝试将两者“合体”用于脊柱融合。设计打印多孔钛合金人工椎体和椎间融合器；填充辛伐他汀温敏性水凝胶，研究其促进脊柱融合的作用；结合siRNA及缺氧诱导因子1α（HIF-1α）拮抗剂，分别从体内外阐明辛伐他汀通过上调HIF-1α，释放内源性成骨、成血管因子，促进骨长入和血管新生，随着局部缺氧改善和辛伐他汀浓度降低，HIF-1α下调而重新达到骨重建平衡的分子机制。.研究不仅为3D打印多孔钛合金填充辛伐他汀水凝胶促进脊柱融合提供实验依据，还将阐明小分子化合物自适应调控HIF-1α，促进内源性成骨、成血管，诱导骨长入和血管长入，促进骨融合的机制，研究具有重要的应用前景和研究价值。

3D打印技术便于制造外形不规则、内部多孔、弹性模量接近松质骨的钛合金，但我们前期研究发现多孔钛合金内部骨长入不理想。辛伐他汀水凝胶促进成骨、成血管，但力学性能差;多孔钛合金提供了绝佳的给药腔隙。本课题是在以往研究的基础上尝试将两者“合体”用于脊柱融合。主要研究内容包括：设计打印多孔钛合金人工椎体和椎间融合器;填充辛伐他汀温敏性水凝胶，利用其脊柱力学环境与人类相似猕猴作为动物模型，研究其促进脊柱融合的作用；研究结果显示：根据影像学参数设计并3D打印的多孔椎间融合器与猕猴腰椎解剖结构匹配良好，术后假体位置良好，未发生明显松动、移位现象；辛伐他汀温敏性水凝胶单次使用可以促进3D打印多孔椎间融合器内部骨长入，加快骨形成速率，使其与周围骨实现良好的骨整合，提高力学性能，促进脊柱融合。研究结果作为封面文章于2020年发表在Biomaterials Science。另外，我们在研究中发现，骨内单次注射辛伐他汀通过动员内皮祖细胞、诱导血管新生促进糖尿病小鼠伤口愈合。辛伐他汀温敏性水凝胶和3D打印多孔椎间融合器首次在大型灵长类动物中使用，该实验结果可为其临床转化提供实验支持，具有重要的临床意义。

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