Engineering novel bio-inspired materials for stem-cell mediated bone regeneration

模拟天然骨的机械强度、可吸收性和组成的合成生物材料 羟基磷灰石（HAP）和胶原蛋白目前不可用。合成移植物损害性能 初始强度和可再吸收性之间的差对于修复临界尺寸的缺陷并不理想。因此，大骨 目前的合成材料不能很好地解决缺陷， 功能、外观和患者生活质量。该项目提出开发一种刚性的生物启发材料 利用1）明胶分子中HAP纳米晶体的自组织和2）pH诱导的钙离子的原理， 配体交联的灵感来自贻贝粘附蛋白-多巴胺。 强有力的试点数据支持所有拟议目标。我们的聚多巴胺掺杂的HAP-明胶纳米复合材料 （PDHG）的抗压强度和抗拉强度分别约为皮质骨的90%和60%， 在体外可降解。我们相信，引入多巴胺接枝的长链聚合物可以进一步 提高拉伸强度，预示长链增强PDHG（LcPDHG）多孔支架的适用性 用于CSD修复。从支架释放的多巴胺也对骨生成产生积极影响。的 该团队的长期目标是设计LcPDHG以满足初始生物力学要求， 最终被吸收并被内源性骨取代。本申请的目的是确定 长链聚合物的引入如何影响物理性能（例如，抗拉强度， LcPDHG的降解），以及天然骨和干细胞如何响应从LcPDHG释放的游离多巴胺。 LcPDHG。 中心假设是LcPDHG是具有足够机械强度的生物活性材料， 骨传导性和再吸收潜力，作为颅面和其他 骨骼区域。为了验证这一假设，提出了三个具体的目标：（1）阐明机制， LcPDHG增强了PDHG的力学性能，使其接近天然骨， （2）确定多巴胺促进骨再生的细胞机制， LcPDHG支架;和（3）评估骨形成和LcPDHG支架中移植材料的替代， 大鼠颅骨临界大小缺损模型。初步数据预测成骨细胞之间有希望的相互作用 和多巴胺刺激，并提出新的信号通过多巴胺受体，以促进干细胞为基础的 疗法 拟议的研究是重要的，因为它将推进和扩大了解如何 多巴胺可用于骨组织工程（TE），并提供第一个“羟基磷灰石和胶原”， 人工骨TE支架修复大面积骨缺损。使用这种类型的移植材料，应该可以 消除多次手术，简化关键尺寸颅骨和面部骨缺损的治疗。

A synthetic biomaterial that mimics the mechanical strength, resorbability, and composition of natural bone hydroxyapatite (HAP) and collagen is not currently available. Synthetic grafts compromising properties between initial strength and resorbability are not ideal for repairing critical sized defects. Thus, large bone defects are not well addressed with current synthetic materials leading to significant impairments of biological function, appearance, and patient quality of life. This project proposes to develop a rigid, bio-inspired material using principles of 1) self-organization of HAP nanocrystals in gelatin molecule and 2) pH-induced calcium- ligand cross-links inspired from the mussel adhesive protein - dopamine. Strong pilot data support all of the proposed aims. Our polydopamine laced HAP-gelatin nanocomposite (PDHG) has compressive and tensile strength approximating 90% and 60% of cortical bone, respectively, and is degradable in vitro. We believe that incorporation of a dopamine-grafted long chain polymer can further improve tensile strength and portends the Long Chain enhanced PDHG (LcPDHG) porous scaffold applicable for CSD repair. The dopamine released from the scaffold also produces positive effects on osteogenesis. The long-term goal of this team is to engineer LcPDHG to fulfill the initial biomechanical requirements and to be eventually resorbed and replaced by endogenous bone. The objective in this particular application is to identify how the incorporation of long chain polymers affects the physical properties (e.g., tensile strength, degradation) of LcPDHG, and how the natural bone and stem cells respond to free dopamine released from LcPDHG. The central hypothesis is that the LcPDHG is a bioactive material with adequate mechanical strength, osteoconductivity and resorption potential to serve as a load bearing graft in CSDs in craniofacial and other skeletal areas. To test this hypothesis three specific aims are proposed: (1) Elucidate the mechanism by which LcPDHG enhances mechanical properties of PDHG to approximate natural bone, and increases its in vitro degradation; (2) Determine cellular mechanisms by which dopamine promotes bone regeneration in the LcPDHG scaffold; and (3) Assess bone formation and replacement of graft materials in LcPDHG scaffolds in a rat calvarial critical sized defect model. Preliminary data predict promising interactions between osteoblasts and dopamine stimuli, and suggest novel signaling via dopamine receptors to promote stem cell-based therapy. The proposed research is significant because it will advance and expand the understanding of how dopamine can be used in bone tissue engineering (TE) and provide the first "hydroxyapatite and collagenous" artificial bone TE scaffold to repair large bone defects. With a graft material of this type, it should be possible to eliminate multiple surgeries and simplify the treatment of critical-size cranial and facial bone defects.