基于bio-MOF药物缓释体系的个性化Onlay人工骨块的构建及其修复牙槽骨缺损的机理研究

Alveolar bone defect is one of the most considerable problems in rehabilitation with dental implants. Onlay block grafting is currently the most reliable technique for alveolar bone augmentation. However, autologous onlay bone graft has disadvantages such as donor site morbidity, high resorption rate, and limited bone availability. Therefore, artificial bone onlay grafts are being developed to overcome the limitations of autografts. In this study, a novel customized onlay graft doping with bio-MOF based drug delivery system is to be fabricated for the restoration of alveolar bone defect via three dimensional printing technique. This customized onlay graft can accurately match the shape of defect site as well as facilitate the transportation of nutrients and the growth of both bone and vascular tissues through regulating the internal pore size and porosity. Additionally, bio-MOF has excellent biocompatibility, biodegradability and controlled drug-release effect, which can slowly release the zinc ions and angiogenic drugs, improving the osteogenesis, angiogenesis and antibacterial properties of the artificial onlay graft. In this study, the physicochemical properties, biological performance, and osteogenic mechanism of the customized onlay graft will be investigated systematically in vitro and in vivo, providing an important experimental basis for the restoration of alveolar bone defect.

牙槽骨量不足是牙种植治疗的难点，Onlay植骨是临床常用的牙槽骨增量技术，自体Onlay骨块存在来源有限、创伤大、难以精确塑形的弊端，亟需探索一种个性化人工骨来满足理想Onlay植骨的需求。本课题拟以PLGA、可降解骨替代材料DCPD和bio-MOF/DMOG载药体系为打印基质，采用3D打印制备一种新型的负载金属-有机骨架(bio-MOF)药物缓释系统的个性化Onlay人工骨块。该骨块能精确匹配缺损部位外形，能调控内部孔隙以促进营养物质运输、成骨细胞攀附及血管组织生长；bio-MOF载药体系具有优良的生物相容性、生物降解性及三级药物缓释特性，能缓释Zn2+和促血管生成药物DMOG，进一步优化人工骨块的抗菌性、成骨性及成血管性。本课题通过体外和体内动物模型，对此新型个性化人工骨块的理化特性、生物学性能、修复牙槽骨缺损的成骨机制进行探讨，为解决牙种植骨量不足临床难题提供重要的实验基础和理论指导

牙槽骨量不足是牙种植治疗的难点，Onlay植骨是临床常用的牙槽骨增量技术，自体Onlay骨块成骨效果良好，是目前修复牙槽骨缺损最佳选择，然而自体骨存在来源有限、创伤大、难以精确塑形的弊端，设计一种个性化人工Onlay骨块成为临床迫切需求。本课题以PCL、可降解骨替代材料DCPD以及ZIF-8/DMOG载药体系为打印基质，根据骨缺损区域CBCT数字信息，结合CAD技术与3D生物打印技术，成功制备了个性化Onlay人工骨块，该骨块可个性化设计，快速打印，并完美契合骨缺损的三维形态，达到个性化修复的目的。课题首先制备了ZIF-8/DMOG纳米药物载体，研究发现该纳米药物载体能缓释DMOG，并自我降解释放Zn2+，促进成骨细胞ALP和HIF-1α蛋白的分泌，并上调Vegf、ALP、Runx2和Ocn等相关基因的表达，促进细胞外基质矿化、细胞迁移和血管形成。其次，结合CAD设计和3D打印技术，构建了PCL/DCPD/nanoZIF-8多孔复合支架，采用分子生物学、生物力学、影像学、组织学等多手段检测方式对支架的理化性能、降解性能以及体内外生物学性能进行检测，实验结果显示我们构建的3D生物打印PCL/DCPD/nanoZIF-8多孔复合支架孔隙率及降解速度可控，机械性能良好，体外细胞学实验以及体内动物学实验证明该支架具有良好的体内外生物相容性及成骨成血管活性。最后，在前面研究的基础上，课题组制备了新西兰兔颅骨个性化缺损动物模型，分别设计并打印了标准形态的人工骨块和个性化形态人工骨块，其中个性化骨块形状与缺损形态完全匹配。实验结果显示，和对照组标准形态骨块相比，与骨缺损区形态更加契合的个性化骨块在植入家兔体内后具有更好的成骨成血管效果。综上，本课题3D打印个性化人工骨块的成功制备为骨缺损的个性化精准修复提供了理论和实验依据，为大尺寸和不规则牙槽骨缺损的修复提供了新的思路和策略。