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

一种模拟自然骨的机械强度、吸收能力和成分的合成生物材料 羟基磷灰石(HAP)和胶原蛋白目前还不可用。折衷性能的合成接枝 对于修复临界尺寸的缺陷来说，介于初始强度和可再吸收之间并不理想。因此，大骨 目前的合成材料没有很好地解决缺陷，导致生物的显著损伤 功能、外观和患者的生活质量。该项目计划开发一种刚性的、受生物启发的材料。 利用1)明胶分子中羟基磷灰石纳米晶的自组织和2)pH诱导钙离子交换的原理. 配体交联剂的灵感来自贻贝的粘附性蛋白质-多巴胺。 强大的试点数据支持所有拟议的目标。我们的聚多巴胺修饰羟基磷灰石-明胶纳米复合材料 (PDHG)的压缩和抗拉强度分别接近皮质骨的90%和60%，以及 在体外可降解。我们相信，加入多巴胺接枝的长链聚合物可以进一步 提高长链增强型PDHG(LcPDHG)多孔支架的抗拉强度及应用前景 用于CSD维修。从支架中释放的多巴胺对成骨也有积极的作用。这个 这个团队的长期目标是设计LcPDHG，以满足最初的生物力学要求，并成为 最终被吸收，并被内源性骨取代。此特定应用程序目标是识别 长链聚合物的加入如何影响物理性能(例如，拉伸强度， LcPDHG的降解)，以及天然骨骼和干细胞如何对从 LcPDHG. 中心假设是LcPDHG是一种具有足够机械强度的生物活性材料， 骨传导性和骨吸收潜能作为颅面及其他CSD的负重移植物 骨骼区域。为了验证这一假说，提出了三个具体的目标：(1)阐明 LcPDHG提高了PDHG的力学性能，使其接近天然骨，并提高了其体外力学性能 (2)确定多巴胺促进骨再生的细胞机制。 LcPDHG支架；以及(3)评估LcPDHG支架中的骨形成和移植材料的替代。 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良好的相互作用 和多巴胺刺激，并提示通过多巴胺受体的新信号促进干细胞为基础的 心理治疗。 这项拟议的研究具有重要意义，因为它将促进和扩大对 多巴胺可用于骨组织工程，提供第一个“羟基磷灰石和胶原蛋白”。 人工骨TE支架修复大块骨缺损。有了这种类型的嫁接材料，应该可以 避免多次手术，简化临界大小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.