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.

一种模拟天然骨机械强度、可吸收性和成分的合成生物材料 目前还没有羟基磷灰石（HAP）和胶原蛋白。合成移植物会损害性能 初始强度和可吸收性之间的差异对于修复临界尺寸的缺陷并不理想。因此，大骨 当前合成材料的缺陷没有得到很好的解决，导致生物功能的严重损害 功能、外观和患者的生活质量。该项目建议开发一种刚性的仿生材料 利用 1) 明胶分子中 HAP 纳米晶体的自组织和 2) pH 诱导的钙- 配体交联的灵感来自于贻贝粘附蛋白——多巴胺。 强大的试点数据支持所有拟议目标。我们的聚多巴胺掺入 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长链增强PDHG（LcPDHG）多孔支架的适用 用于 CSD 修复。从支架释放的多巴胺也对成骨产生积极影响。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成为 最终被内源性骨吸收并取代。该特定应用的目标是确定 长链聚合物的掺入如何影响物理性能（例如拉伸强度、 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 是一种具有足够机械强度的生物活性材料， 骨传导性和吸收潜力，可作为颅面和其他 CSD 的承重移植物 骨骼区域。为了检验这一假设，提出了三个具体目标：（1）阐明其机制 LcPDHG 增强 PDHG 的机械性能以接近天然骨，并提高其体外 降解; (2) 确定多巴胺促进骨再生的细胞机制 LcPDHG支架； (3) 评估 LcPDHG 支架中的骨形成和移植材料的替代 大鼠颅骨临界尺寸缺损模型。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，并提出通过多巴胺受体的新信号传导来促进基于干细胞的 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“羟基磷灰石和胶原蛋白” 人工骨TE支架修复大骨缺损。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。