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

工程新型仿生材料用于干细胞介导的骨再生

• 批准号: 8632328
• 负责人: Ching-Chang Ko
• 金额: $ 45.71万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-14 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632328
• 关键词: Address; Affect; Animal Model; Appearance; Area; Autologous Transplantation; Behavior; Binding; Biochemical; Biocompatible Materials; Biological; Biological Assay; Biological Process; Biomechanics; Bone Marrow Stem Cell; Bone Regeneration; Bone Surface; Bone Tissue; Bone Transplantation; Bromodeoxyuridine; Calcium; Calvaria; Carbonates; Catecholamines; Cell Culture Techniques; Cell Proliferation; Cell Therapy; Cephalic; Ceramics; Collagen; Compressive Strength; Data; Defect; Deformity; Dental; Development; Dopamine; Dopamine Receptor; Dose; Drug Formulations; Engineering; Extracellular Matrix; Gelatin; Gene Expression; Goals; Growth; Healed; Health; High Pressure Liquid Chromatography; Hydroxyapatites; Impairment; In Vitro; Inherited; Kinetics; Ligands; Materials Testing; Measurement; Mechanics; Mediating; Mesenchymal Stem Cells; Minerals; Mission; Modeling; Molds; Molecular Structure; Natural regeneration; Operative Surgical Procedures; Oral; Osseointegration; Osteoblasts; Osteogenesis; Pathway interactions; Patients; Performance; Phosphate Buffer; Polymers; Production; Property; Public Health; Quality of life; Rattus; Research; Side; Signal Transduction; Silanes; Siloxanes; Small Interfering RNA; Solutions; Staining method; Stains; Stem cells; Stimulus; Stress; TdT-Mediated dUTP Nick End Labeling Assay; Tensile Strength; Testing; Time; Tissue Engineering; Transplanted tissue; Trauma; Weight-Bearing state; adhesive protein (mussel); biodegradable polymer; bone; bone cell; bone healing; copolymer; craniofacial; crosslink; dentofacial; design; dopamine graft; face bone structure; healing; improved; in vivo; interfacial; meetings; mineralization; nanocomposite; nanocrystal; novel; physical property; public health relevance; receptor; repaired; scaffold; self organization; silane; skeletal

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.

一种合成生物材料，模仿天然骨的机械强度，可吸收性和组成 目前尚不可用羟基磷灰石（HAP）和胶原蛋白。合成移植物损害特性 初始强度和可吸收性之间并不是修复关键尺寸缺陷的理想选择。因此，大骨头 当前合成材料无法很好地解决缺陷，从而导致生物学的重大损害 功能，外观和患者生活质量。该项目建议开发一种僵化的生物启发材料 使用1）明胶分子中HAP纳米晶体的自组织和2）pH诱导的钙 - 贻贝粘合剂蛋白 - 多巴胺启发的配体交联。 强大的飞行员数据支持所有拟议的目标。我们的多巴胺系带HAP明星蛋白纳米复合材料 （PDHG）分别具有约90％和60％皮质骨的压缩和拉伸强度，并且 在体外可降解。我们认为，掺入多巴胺的长链聚合物可以进一步 提高拉伸强度并预示长链增强PDHG（LCPDHG）的多孔脚手架 用于CSD维修。从支架释放的多巴胺也会对成骨作用产生积极影响。这 该团队的长期目标是设计LCPDHG，以满足最初的生物力学要求，并将 最终被内源性骨头吸收并取代。该特定应用程序的目的是确定 长链聚合物的掺入如何影响物理特性（例如，拉伸强度， LCPDHG的降解），以及天然骨骼和干细胞如何反应自由的多巴胺从 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， 在颅面和其他的CSD中充当CSD的载荷移植物的破骨接球率和吸收潜力 骨骼区域。为了检验该假设，提出了三个具体目标：（1）阐明该机制 LCPDHG增强了PDHG的机械性能近似于天然骨骼，并增加了其体外 降解; （2）确定多巴胺促进骨再生的细胞机制 lcpdhg脚手架； （3）评估在A中的LCPDHG支架中的骨形成和替代移植物材料 大鼠颅关临界大小缺陷模型。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，并通过多巴胺受体提出新的信号传导，以促进基于干细胞 治疗。 拟议的研究很重要，因为它将提高和扩大对如何的理解 多巴胺可用于骨组织工程（TE），并提供第一个“羟基磷灰石和胶原蛋白” 人造骨支架可修复大骨缺损。使用这种类型的移植物材料，应该有可能 消除多次手术，并简化临界大小的颅骨和面部骨缺损的处理。