Microengineering vascularized and innervated bone-like scaffolds as an alternative to autologous bone grafts

项目总结 许多骨骼疾病需要辅助性骨修复，包括创伤、癌症切除和骨骼。 用于口腔种植治疗的增强术。目前治疗这些疾病的方法依赖于程序来收获 以及植入自体骨移植，这是昂贵的，有创的，很难扩大规模。其他替代方案包括 人工骨替代材料失败率高，无法模拟天然骨结构， 成分和成骨特性。基于干细胞的组织工程长期以来一直被认为是一种 很有希望成为修复骨缺损的替代方法。然而，治疗巨大的骨性结构仍然是个问题。 人们普遍认为，与天然骨特征相近的支架材料 代表用于骨再生的改良材料。然而，体外仿生支架的研究进展 低至纳米级的高度血管化、神经化和矿化的富含细胞的骨基质仍然存在 到目前为止还难以捉摸。在这里，我们将开发一种新的骨支架生物制造工艺，其中骨祖细胞 三维植入受控的纳米矿化、预血管和神经支配的骨样 可注射微凝胶，从而模拟矿化的纳米结构、细胞和细胞外微环境 天然的骨头。(目标1)我们将确定使hMSCs分化的机制特征 转化为受骨样微环境影响的成骨表型，并工程细胞矿化 接近自体骨移植再生潜力的可注射微凝胶。然后我们将适应 这种设计(目标2)周细胞支持的血管毛细血管和(目标3)神经元网络的策略，是 嵌入在纳米级矿化水凝胶中，以确定使血管生成和 神经支配促进体外成骨和体内再生。我们认为这是多管齐下的 战略将使高度创新的骨支架材料和体外骨模型系统的工程成为可能 这将与天然骨骼在纳米结构和物理上有很大的相似之处。最终，这将导致 在临床上接近自体骨再生潜力的生物材料。

PROJECT SUMMARY A wide range of skeletal conditions require assisted bone repair, including trauma, cancer resections, and bone augmentation for oral implant therapy. Current methods to treat these conditions rely on procedures to harvest and implant bone autografts, which are costly, invasive and difficult to scale up. The other alternatives are synthetic bone replacement materials, which show high failure rates and fail to mimic the native bone structure, composition and osteogenic properties. Stem cell-based tissue engineering has long been proposed as a promising alternative for the repair of bone defects. However, treating large bony structures remains problematic. It is generally believed that scaffold materials that closely approximate the characteristics of native bone represent improved materials for bone regeneration. However, the development of in-vitro scaffolds mimicking the highly vascularized, innervated, and mineralized cell-rich bone matrix down to the nanoscale has remained elusive to date. Here, we will develop a new bone scaffold biomanufacturing process where osteoprogenitor cells are three-dimensionally embedded in controlled nano-mineralized, pre-vascularized and innervated bone-like injectable microgels, thus mimicking the mineralized nanostructure, cellular and extracellular microenvironment of native bone. (aim 1) We will determine the mechanistic characteristics enabling the differentiation of hMSCs into osteogenic phenotypes as influenced by bone-like microenvironments, and engineer cell-laden mineralized injectable microgels that approximate the regenerative potential of autologous bone grafts. We will then adapt this strategy to engineer (aim 2) pericyte-supported vascular capillaries and (aim 3) neuronal networks, that are embedded in nanoscale mineralized hydrogels, to determine the mechanisms that enable vasculature and innervation enhancement of osteogenesis in-vitro and regeneration in-vivo. We argue that this multi-pronged strategy will enable the engineering of highly innovative bone scaffold materials and in-vitro bone model systems that will share great nanostructural and physical similarities to native bone. Ultimately, this will lead to biomaterials that closely approximate the regenerative potential of autologous bone in the clinic.