Biodegradable Self-Inductive Scaffold for Cranial Regeneration

用于颅骨再生的可生物降解自感应支架

• 批准号: 7649711
• 负责人: Esmaiel Jabbari
• 金额: $ 10.8万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7649711
• 关键词: Address; Adhesions; Adhesives; Adverse effects; Amino Acid Sequence; Amino Acids; Antibiotics; Autologous Transplantation; Azides; Biocompatible Materials; Bone Density; Bone Marrow; Bone Morphogenetic Proteins; Calvaria; Cells; Cephalic; Characteristics; Chemotaxis; Child; Cytoskeleton; Defect; Deformity; Development; Differentiation Inducer; Diffusion; Dose; Edentulous Mouth; Extracellular Matrix; Fumarates; Glycolic-Lactic Acid Polyester; Goals; In Vitro; Integrin Binding; Irrigation; Light; Mechanics; Minerals; Natural regeneration; Operative Surgical Procedures; Osteogenesis; Outcome; Peptide Antibiotics; Peptides; Porosity; Production; Proteins; Public Health; RGD (sequence); Rattus; Research; Shapes; Signal Transduction; Site; Stromal Cells; Surface; Testing; Tissue Engineering; allogenic bone transplantation; base; bone; bone healing; copolymer; craniofacial; crosslink; density; fumaryl chloride; in vivo; mineralization; mutant; novel; osteogenic; pi bond; prevent; protein aminoacid sequence; public health relevance; recombinant human bone morphogenetic protein-2; reconstruction; scaffold; skeletal; soft tissue; success; wound

DESCRIPTION (provided by applicant): The long-term objective of this research is to study bone ingrowth into synthetic biodegradable osteoinductive scaffolds for reconstruction of craniofacial defects. Since bone morphogenetic proteins (BMPs) signaling is highly regulated, the graft has to be loaded with doses of 4-5 orders of magnitude (with adverse side effects) higher than the amount found endogenously. An attractive alternative is to use peptides, based on the active domains of BMPs to initiate the cascade of osteogenesis. The strategy involves covalent attachment of an osteoinductive azide-functionalized "BMP peptide", corresponding to amino acid residues 73-92 of the recombinant human bone morphogenetic protein-2 (rhBMP-2), to a novel bioresorbable poly(lactide-co-glycolide fumarate) (PLGF) scaffold. The short lactide-co-glycolide chains in PLGF impart degradability to the macromer while the fumarate units provide sites for crosslinking for structural support. We hypothesized that the crosslinked scaffold provides structural support to the regenerating region and induces osteogenesis by the interaction of migrating bone marrow stromal (BMS) cells with the grafted BMP peptide. Moreover, the scaffold will degrade concurrent with the production of mineralized matrix to increase bone volume. The aim of this proposal is to determine osteoinductivity and the extent of bone formation of BMP peptide grafted PLGF scaffold in-vitro and in-vivo. In the first part of Aim 1, the effect of PLGF composition and scaffold porosity on degradation characteristics and mechanical strength will be determined. The outcome of Aim 1.1 is the best lactide: glycolide ratio of PLGF and best porosity of the scaffold. In the second part of Aim 1, effect of BMP peptide grafted PLGF on differentiation and mineralization of BMS cells will be determined in-vitro. The outcome of Aim 1.2, is the best density of BMP peptide grafted to PLGF scaffold, as judged by the highest mineral content. In Aim 2, we will determine the effect of BMP peptide grafted scaffold on bone formation in critical-size rat cranial defect in-vivo. Experimental groups will include scaffolds grafted with mutant BMP peptide (negative control), BMP peptide (experimental group), and scaffolds with rhBMP-2 protein (positive control). Success will be judged by the continuous bridging of new bone across the scaffold and by bone mineral density. PUBLIC HEALTH RELEVANCE: Over twenty million people in USA are totally edentulous and about half a million children worldwide are born annually with congenital craniofacial deformities. Degradable biomaterials that are space occupying, osteoinductive, have the consistency to protect the defect from soft tissue collapse, and degrade concurrent with the formation of new extra-cellular matrix to increase bone volume have the potential for breakthroughs in the development of adaptable scaffolds to the changing craniofacial defect.

描述（由申请人提供）：本研究的长期目标是研究骨长入合成生物可降解骨诱导支架，用于重建颅面缺损。由于骨形态发生蛋白（BMP）信号传导受到高度调节，因此移植物必须负载比内源性发现的量高4-5个数量级的剂量（具有不良副作用）。一种有吸引力的替代方案是使用基于BMP的活性结构域的肽来启动成骨级联。该策略涉及将骨诱导叠氮化物官能化的“BMP肽”（对应于重组人骨形态发生蛋白-2（rhBMP-2）的氨基酸残基73-92）共价连接到新型生物可吸收聚（丙交酯-共-乙交酯富马酸酯）（PLGF）支架。PLGF中的短丙交酯-共-乙交酯链赋予大分子单体可降解性，而富马酸酯单元提供用于结构支撑的交联位点。我们假设交联支架为再生区域提供结构支持，并通过迁移的骨髓基质细胞（BMS）与移植的BMP肽的相互作用诱导成骨。此外，支架将在产生矿化基质的同时降解以增加骨体积。本研究的目的是在体外和体内测定BMP肽接枝PLGF支架的骨诱导性和骨形成程度。在目标1的第一部分中，将确定PLGF组成和支架孔隙率对降解特性和机械强度的影响。目标1.1的结果是PLGF的最佳丙交酯：乙交酯比例和支架的最佳孔隙率。目的1的第二部分，将在体外确定BMP肽接枝PLGF对BMS细胞分化和矿化的影响。目标1.2的结果是通过最高矿物质含量判断的移植到PLGF支架上的BMP肽的最佳密度。目的2：研究BMP肽移植支架对大鼠颅骨缺损成骨的影响。实验组将包括移植有突变BMP肽的支架（阴性对照）、BMP肽（实验组）和移植有rhBMP-2蛋白的支架（阳性对照）。通过新骨在支架上的连续桥接和骨矿物质密度来判断成功。 公共卫生相关性：在美国有超过两千万的人是完全无牙的，全世界每年大约有50万儿童出生时患有先天性颅面畸形。可降解生物材料具有占位性、骨诱导性、具有保护缺损免受软组织塌陷的一致性，并且在降解的同时形成新的细胞外基质以增加骨体积，这在开发适应性支架以适应不断变化的颅面缺损方面具有突破性的潜力。