Bioinspired Synthetic Grafts for Bone Regeneration

描述（由申请人提供）：在激活内源性细胞形成功能性骨组织的同时提供结构支持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，自体移植物和同种异体移植物是移植物的主要选择，但两者都存在各种缺陷，如供体部位发病率、稀缺性、免疫排斥或疾病传播。相比之下，具有内在成骨性和成骨性的人工骨移植物可以为治疗骨缺损/骨衰竭提供一种易于制造、成本效益高且广泛应用的治疗策略。在本研究中，我们将研究在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功效。本文描述的仿生骨移植物是利用生物矿化原理开发的，它导致合成骨样细胞外基质的形成，该基质概括了原生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。利用这种移植物，我们将：(1)确定来自基质和矿物环境的各种物理化学线索对体外干细胞成骨分化的作用；(2)阐明生物矿化移植物表现出成骨性和成骨性的机制；(3)通过后侧融合蛋白作为模型系统，移植物在体内形成骨的能力。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。这种方法涉及合成移植物缺乏任何生长因子也将限制骨形成

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.