Bioinspired Synthetic Grafts for Bone Regeneration

描述（由申请人提供）：在激活内源性细胞以形成功能性骨组织的同时提供结构支撑的合成系统被认为是治疗严重骨缺损的最佳治疗策略。目前，自体移植物和异体移植物是植入物的主要选择，但两者都存在各种缺点，例如供体部位发病率、稀缺性、免疫排斥或疾病传播。相比之下，具有内在骨诱导性和成骨性的合成骨移植物可以提供一种易于制造、具有成本效益且广泛可用的治疗骨缺损/失败的治疗策略。在拟议的研究中，我们将研究我们实验室开发的全合成骨移植物在体外和体内形成骨组织的有效性。本文描述的仿生骨移植物是通过使用生物矿化原理开发的，其导致合成骨样细胞外基质的形成，所述合成骨样细胞外基质概括天然组织的各种静态和动态物理化学线索，包括矿物相的动态溶解/形成。使用这种移植，我们将：（1）确定来自基质和矿物质环境的各种物理化学因素在体外干细胞成骨分化中的作用，（2）阐明生物矿化移植物表现成骨性和骨诱导性的机制，（3）通过使用后外侧融合蛋白作为模型系统，观察移植物的体内骨形成能力。移植物旨在提供骨移植所需的结构和机械完整性，同时激活内源性细胞以促进骨形成。再生医学中的这种内源性细胞驱动策略有可能规避与成本，空间和时间相关的现有方法的限制。这种涉及没有任何生长因子的合成移植物的方法也将骨形成限制在骨形成区域。 并克服与含生长因子移植物相关的主要副作用。虽然拟议的研究重点是骨组织的形成和修复，但仿生方法可以应用于研究其他细胞/系统，从而产生深远的影响。

DESCRIPTION (provided by applicant): Synthetic systems that provide structural support while activating endogenous cells to form functional bone tissues have been considered as an optimal therapeutic strategy for treating critical bone defects. Currently, autografts and allografs are the primary choice of implants, but both suffer from various drawbacks such as donor site morbidity, scarcity, immunorejection, or disease transmission. In contrast, synthetic bone grafts with intrinsic osteoinductivity and osteogenicity could provide an easy-to-manufacture, cost-effective, and widely available therapeutic strategy for treating bone defects/failures. In the proposed study, we will investigate the efficacy of a fully synthetic bone grafts being developed in our laboratory to form in vitro and in vivo bone tissues. The biomimetic bone graft described here is developed by using principles of biomineralization, which leads to formation of a synthetic bone-like extracellular matrix that recapitulates various static and dynamic physicochemical cues of the native tissue including the dynamic dissolution/formation of mineral phase. Using this graft, we will: (1) determine the role of various physicochemical cues from the matrix and the mineral environment on osteogenic differentiation of stem cells in vitro, (2) elucidate the mechanism by which the biomineralized grafts exhibits osteogenicity and osteoinductivity, and (3) in vivo bone formation ability of the grafts by using posterolateral fusin as a model system. The grafts are designed to provide the structural and mechanical integrity required for bone grafting, while activating endogenous cells to promote bone formation. Such an endogenous cell-driven strategy in regenerative medicine has the potential to circumvent the limitations of existing approaches associated with cost, space, and time. Such an approach involving synthetic grafts devoid of any growth factors will also confine the bone formation to the implant site and overcome major side effects associated with growth factor-containing grafts. Though the proposed study is focused on bone tissue formation and repair, the biomimetic approach can be applied to study other cells/systems, thus having a far-reaching impact.