Bioinspired Synthetic Grafts for Bone Regeneration

描述(申请人提供)：合成系统提供结构支持，同时激活内源性细胞形成功能性骨组织，已被认为是治疗严重骨缺损的最佳治疗策略。目前，自体移植和同种异体移植是植入物的主要选择，但两者都存在供体部位发病率、稀缺性、免疫排斥或疾病传播等缺点。相反，具有内在的骨诱导和成骨能力的人工骨移植可以提供一种易于制造、经济有效和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正在开发的一种完全合成的骨移植在体外和体内形成骨组织的效果。本文描述的仿生骨移植是利用生物矿化原理开发的，它导致形成一种合成的骨样细胞外基质，它概括了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。使用这种移植物，我们将：(1)确定基质和矿物环境中的各种物理化学信号在干细胞体外成骨分化中的作用；(2)阐明生物矿化移植物具有成骨和成骨活性的机制；(3)以后外侧融合蛋白为模型系统，研究移植物的体内成骨能力。这种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。在再生医学中，这种内源性细胞驱动的策略有可能绕过现有方法在成本、空间和时间方面的限制。这种方法涉及不含任何生长因子的合成移植物，也会将骨形成限制在 并克服与含有生长因子的移植物相关的主要副作用。虽然拟议的研究侧重于骨组织的形成和修复，但仿生方法可以应用于其他细胞/系统的研究，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.