模拟低氧应答的高活性钙磷基骨修复材料用于骨质疏松性缺损修复

Osteoporosis induced by low estrogen is prone to fractures, and its difficulty and high recurrence rate of defect repair are the leading cause of death and disability for the postmenopausal women. OP is routinely treated with hormone drugs, mostly poor targeted and more side effects. Dimethyloxaloylglycine（DMOG）, simulating hypoxia to regulate the bone differentiation of stem cells, adjusts bone metabolism imbalance. However, DMOG has burst release, potential toxicity and no repair effect. Therefore, based on the drug-loaded large pore size of mesoporous silica, highly bioactive multi-porous bone scaffold was printed by 3D printer along with calcium phosphate cement and polyester. The key print technology at room temperature of bone repair materials with multi-component, coexisting of multilevel pore structure and biological activity is to be explored. The efficiency of drugs to fasten bone differentiation of stem cells, activation the signaling pathways and transcription factors of osteogenesis is analysized under normal oxygen. From different levels (composition, multi-level structure, mesoporous effect, degradation products）the effect of drug-loaded scaffold on the drug release, cell response, inhibition the osteoclasts absorption, stimulating new bone formation and accelerate vascularization is to be examined. The repair effect is conducted by animal model. The synergistic mechanism of the biomaterial and drug to repair bone defect is to be explored. The study will broaden the treatment options of bone defect repair, and provide the guidance for the design of biomaterial with the function of treatment and repair.

雌激素缺乏诱发的骨质疏松（OP）易骨折，其难愈合和高再发率是绝经后妇女致死、致残的主要原因。目前OP治疗大多采用激素类药物，靶向性差，副作用多。二甲基乙二酰甘氨酸（DMOG）模拟低氧调控干细胞骨向分化，具有潜在的促成骨成血管能力，有望逆转骨质疏松，但其突释、潜在毒性大且对大段缺损无修复作用。为此，项目在大孔径介孔硅装载DMOG的基础上，将其与钙磷骨水泥浆体、柠檬酸-1，8辛二醇酯预聚体进行3D打印，构建高活性钙磷基多级结构骨修复材料。探索室温打印多组分、多级孔结构并存且生物活性、保型性良好的骨修复材料的关键技术。分析常氧下药物在干细胞骨向分化、信号通路激活及成骨相关因子转录的效能。从不同角度（组成、多级结构、介孔效应、药物、体内转归、孔连通等）研究材料对药物响应性释放、调控细胞行为、抑制骨吸收、促新骨形成、加速血管化的影响因素，评价材料药物协同修复效果及其快速修复机制，为临床应用提供指导。

雌激素缺乏诱发的骨质疏松（OP）易骨折，其难愈合和高再发率是绝经后妇女致死、致残的主要原因。激素类药物靶向性差，活性因子BMP易突释且对大段缺损无修复作用。为此，项目在充分探讨DMOG、雷尼酸锶和续断及其与rhBMP-2上调成骨和成血管相关基因表达、诱导早期成骨分化、抑制骨吸收作用的基础上，将其活性装载到大孔径的介孔硅基的基础上，与钙磷基骨水泥、柠檬酸-1，8辛二醇酯预聚体/PLGA进行3D打印，制备出了可控图案化CPC/POC基复合支架、模拟低氧应答的高活性钙磷基多孔骨支架、高成骨活性和抑制骨吸收的钙磷基复合支架，完成了支架的生物学性能评价。钙磷基复合支架用于犬下颌骨大段缺损（长23mm，直径 14mm）的修复，具有优异的力学性能，支架3个月新生骨体积为70%，诱导下颌下缘骨形成效果显著。另外，将复合支架用于兔骨质疏松性桡骨缺损修复，术后3个月支架诱导的新骨生成体积和致密程度是对照组的170%，能抑制骨质流失，形成完整闭合的环形骨结构，这些可为临床提供指导。