无机-有机杂化纳米纤维素气凝胶组装硬骨素抗体及SDF-1搭载干细胞治疗大段骨缺损

The inorganic-organic hybrid aerogels composed of nano cellulose acetate, nano-hydroxyapatite and type I collagen produced by supercritical drying method belong to the fourth generation of new materials, which was characteristic with excellent Bioactivity, biomechanical properties, biocompatibility and drug loading capacity. This material can control the release of drugs and achieve a smooth release. Sclerostin antibody can activate the wnt pathway to promote osteoblastic differentiation of MBSCs, and stromal cell derived factor-1 (SDF-1) induces stem cells targeting homing. Vascular endothelial progenitor cells (EPCs) can induce the revascularization and promote osteogenic differentiation of BMSCs. In this study, the material is consist of Inorganic-organic hybrid nanocellulose aerogels combining BMSCs and EPCs is implanted into the bone defect area by in vitro and in vivo experiments, which can promote the homing of autologous BMSCs and EPCs and induce osteogenesis and revascularization in the area of bone defect. Our study will solve the problem that difficulties of osteogenesis and revascularization in the center of large bone defects. This material can provide the new idea and method to treat large segment of bone defects.

采用超临界干燥法制备的由纳米醋酸纤维素、纳米羟基磷灰石和I型胶原组成的无机-有机杂化气凝胶属于第四代新材料，具有良好的生物学活性、生物力学性能、生物相容性及强大的药物搭载能力和可控药物缓释性能，可实现药物的平稳释放。硬骨素（SOST）抗体激活经典wnt通路促进MBSCs成骨分化，基质细胞衍生因子（SDF-1）诱导干细胞靶向归巢。血管内皮祖细胞(EPCs)具有成血管能力，与BMSCs共培养可促进BMSCs成骨分化。本研究采用体外、体内实验相结合的方法，将组装硬骨素抗体及SDF-1的气凝胶支架搭载BMSCs和EPCs，植入骨缺损区，诱导自体BMSCs和EPCs向骨缺损区归巢，促进骨缺损区的成骨、成血管活动，解决大段骨缺损中心区域成骨及成血管困难这一难题，修复骨缺损。为大段骨缺损的治疗提供新材料、新思路和新方法。

骨缺损的临床治疗极为困难，自体骨和同种异体骨移植等常用方法均存在一定风险和不确定性，急需开发更安全的具有骨传导和骨诱导性能的人工骨支架修复骨缺损。本项目模拟天然骨组织的组成和结构特征，构建由胶原(COl)、纤维素（NCF）和纳米羟基磷灰石(NHA)组成的有机-无机复合气凝胶支架，引入具有诱导成骨活性的硬骨素抗体（SOST抗体）和促进干细胞归巢作用的SDF-1，研制具有血管诱导和骨诱导生物活性的可控降解的仿生骨支架材料用于骨缺损修复。本研究通过超声粉碎、混合交联和冷冻干燥相结合方式得到NCF-COL-NHA有机-无机气凝胶骨修复材料，并能通过调整NHA的含量调控材料的力学特性和降解速度。NHA:NCF-Col为1:1时制得的气凝胶支架具有最好的表征及力学性能。电镜下观察该气凝胶为多孔支架，孔隙率超过90%(96.4±1.6%)，平均孔径75um，弹性模量12.95±4.77 Mpa，抗压强度0.4067 ±0.084 Mpa，受压后可恢复95%的形变。体外研究结果证实，本研究研发的NCF-COL-NHA气凝胶支架具有良好的生物安全性和稳定的降解性。搭载SOST抗体和SDF-1后在药物可实现有效、稳定释放。体外实验和动物体内实验中搭载SOST抗体和SDF-1的NCF-COL-NHA气凝胶支架均表现出良好的促进新骨形成和促进新生血管形成的特性，在骨缺损造模手术后12周达到基本修复骨缺损，实现了研究的预期效果。搭载SOST抗体和SDF-1的NCF-COL-NHA气凝胶支架通过诱导自体BMSCs和EPCs向骨缺损区归巢，促进骨缺损区的成骨、成血管活动，解决骨缺损中心区域成骨及成血管困难这一难题。本研究为骨缺损的治疗提供新材料、新思路和新方法。

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