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: 9012688
• 负责人: Ching-Chang Ko
• 金额: $ 43.52万
• 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/9012688
• 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; Engineering; Extracellular Matrix; Formulation; 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; 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; knock-down; meetings; mineralization; nanocomposite; nanocrystal; novel; physical property; receptor; repaired; scaffold; self organization; skeletal

DESCRIPTION (provided by applicant): 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 thi type, it should be possible to eliminate multiple surgeries and simplify the treatment of critical-size cranial and facial bone defects.

描述（由申请人提供）：目前还没有模仿天然骨羟基磷灰石（HAP）和胶原蛋白的机械强度、可吸收性和成分的合成生物材料。合成移植物会损害初始强度和可吸收性之间的性能，对于修复临界尺寸的缺陷并不理想。因此，目前的合成材料不能很好地解决大骨缺损问题，导致生物功能、外观和患者生活质量显着受损。该项目计划利用以下原理开发一种刚性仿生材料：1) 明胶分子中 HAP 纳米晶体的自组织，2) 受贻贝粘附蛋白 - 多巴胺启发，pH 诱导的钙配体交联。 强大的试点数据支持所有拟议目标。我们的聚多巴胺掺入的 HAP-明胶纳米复合材料 (PDHG) 的压缩强度和拉伸强度分别约为皮质骨的 90% 和 60%，并且在体外可降解。我们相信，加入多巴胺接枝的长链聚合物可以进一步提高拉伸强度，并预示着适用于 CSD 修复的长链增强 PDHG (LcPDHG) 多孔支架。从支架释放的多巴胺也对成骨产生积极影响。该团队的长期目标是设计 LcPDHG 以满足最初的生物力学要求，并最终被内源性骨吸收和取代。该特定应用的目的是确定长链聚合物的掺入如何影响 LcPDHG 的物理特性（例如拉伸强度、降解），以及天然骨和干细胞如何响应 LcPDHG 释放的游离多巴胺。中心假设是 LcPDHG 是一种生物活性材料，具有足够的机械强度、骨传导性和吸收潜力，可用作颅面和其他骨骼区域 CSD 的承重移植物。为了检验这一假设，提出了三个具体目标：（1）阐明LcPDHG增强PDHG机械性能以接近天然骨并增加其体外降解的机制； (2)确定多巴胺促进LcPDHG支架骨再生的细胞机制； (3) 在大鼠颅骨临界尺寸缺损模型中评估 LcPDHG 支架中的骨形成和移植材料的替代。初步数据预测成骨细胞和多巴胺刺激之间有希望的相互作用，并表明通过多巴胺受体的新信号传导可促进基于干细胞的治疗。 拟议的研究意义重大，因为它将推进和扩大对多巴胺如何用于骨组织工程（TE）的理解，并提供第一个“羟基磷灰石和胶原蛋白”人造骨TE支架来修复大骨缺损。使用这种类型的移植材料，应该可以消除多次手术并简化临界尺寸颅骨和面部骨缺损的治疗。