掺锶微纳米棒组合结构修饰羟基磷灰石陶瓷调控骨质疏松大鼠骨缺损修复及机理研究

Osteoporosis has become one of common diseases that affect the health of residents in China. It is still a great challenge for osteoporosis to repair the complicating fractures or bone defects due to tumors, trauma and inflammation, etc. Due to impaired abilities of osteogenesis, angiogenesis and remodeling in vivo, traditional bone graft materials may achieve limited effect for osteoporosis. Design of new biomaterials with the abilities to rapidly induce the osteogenesis and angiogenesis, may be the key to achieve bone defect repairing and remodeling for osteoporosis. In present project, the strontium element with multiple functions of stimulating osteogenesis/angiogenesis and inhibiting osteoclastogenesis will be further doped into the micro-nano-hybrid structured hydroxyapatite bioceramics with osteoindutivity, which has been identified as the optimal surface topography in our recent studies. Then the synergistic effect of the micro-nano-hybrid structure modification and strontium substitution on biological function of the bone marrow stromal cells derived from ovariectomized rats and osteoclasts, as well as its association with ERK, PI3K/AKT and JAK/STAT3 signaling pathways and cascade will be further systematically evaluated. Moreover, this new type fabricated materials will be applied to repair mandibular critical-size bone defects in ovariectomized rats to reveal the coordinately regulatory pattern of the micro-nano-hybrid structure and strontium on the performance of bone repair in vivo. The present study may provide an ideal new bone graft material for repairing bone defects in the state of osteoporosis disease. Moreover, it may provide a new strategy to design the new bioactive bone repair materials for specific diseases.

骨质疏松症已成为影响我国国民健康常见疾病之一，其并发骨折或肿瘤、外伤、炎症等造成的骨缺损修复面临巨大挑战。由于该疾病下体内成骨/成血管及骨重塑能力受损，使得传统骨修复材料疗效有限。设计具有快速诱导成骨/成血管的新型生物材料是实现骨质疏松骨缺损修复及骨重塑的关键。本项目拟在前期筛选具有良好诱导成骨活性的微纳米棒组合结构修饰羟基磷灰石陶瓷基础上，进一步掺杂具有促成骨/成血管和抑制破骨多重功能的锶元素。系统研究羟基磷灰石微纳米棒组合结构修饰与锶元素掺杂协同调控骨质疏松大鼠来源骨髓基质细胞及破骨细胞的生物学功能及其与ERK、PI3K/AKT及JAK/STAT3信号通路关联及级联反应。进而应用该材料修复骨质疏松大鼠颌骨标准缺损，揭示微纳米棒组合结构和锶元素协同调控体内骨修复性能规律。本研究可望为骨质疏松疾病下骨缺损修复提供理想的新型植骨材料，并为设计新型特定疾病状态下骨修复生物活性材料提供新的策略。

骨质疏松症已成为影响我国国民健康常见疾病之一，其并发骨折或肿瘤、外伤、炎症等造成的骨缺损修复面临巨大挑战。由于该疾病下体内成骨/成血管及骨重塑能力受损，使得传统骨修复材料疗效有限。设计具有快速诱导成骨/成血管的新型生物材料是实现骨质疏松骨缺损修复及骨重塑的关键。项目通过前驱水热转化技术装制备法制备锶元素掺杂微纳米棒组合结构修饰HA多孔支架；系统开展掺锶微纳米棒组合结构修饰HA多孔支架材料细胞学效应研究，在大鼠颅骨标准缺损动物模型中研究掺锶微纳米棒组合结构修饰HA多孔支架材料体内成骨及成血管效应；探讨骨质疏松疾病状态下锶与硅元素协同调控成骨、破骨及成血管体内外效应。研究证实在微纳米棒组合结构修饰基础上进一步掺杂锶元素可进一步促进BMSCs增殖、成骨分化及成血管因子表达，并在此基础上筛选出10%掺锶浓度与微纳米棒组合结构协同作用最佳；体内研究证实锶元素与微纳米棒组合结构具有协同促进体内成骨及成血管效应；研究发现锶硅元素掺杂生物活性陶瓷材料可促进骨质疏松大鼠来源BMSCs（OVX-BMSCs）成骨分化和成血管基因表达；并可进一步早期提升OVX-BMSCs OPG/RANKL 比值，晚期抑制RANKL诱导破骨细胞形成及破骨相关基因表达；进一步单纯离子作用研究证实锶元素在成血管及抑制破骨中发挥着主导作用；在骨质疏松大鼠颌骨圆形标准缺损动物模型中，发现锶硅元素掺杂生物活性陶瓷材料相比于传统生物陶瓷材料β-TCP，可明显促进体内新骨形成和矿化；研究初步发现在骨质疏松大鼠颌骨标准缺损动物模型中初步发现掺锶微纳米棒组合结构修饰HA多孔可促进体内新骨形成。本研究通过借助微纳米棒组合结构修饰及锶元素掺杂协同设计提升HA陶瓷成骨/成血管诱导活性，从而为骨质疏松疾病下骨组织再生提供更为理想的新型植骨材料，并为设计新型特定疾病状态下骨修复生物活性材料提供新的策略。