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Biodegradable Self-Inductive Scaffold for Cranial Regeneration

用于颅骨再生的可生物降解自感应支架

基本信息

批准号：
7790647
负责人：
Esmaiel Jabbari
金额：
$ 10.69万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
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/7790647
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

项目摘要

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的可生物降解的骨诱导支架，以重建颅面缺损。由于骨形态发生蛋白 (BMP) 信号传导受到高度调控，因此移植物必须装载比内源剂量高 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 活性结构域的肽来启动成骨级联。该策略涉及将骨诱导性叠氮化物功能化的“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）支架上。 PLGF 中的短丙交酯-乙交酯链赋予大分子单体可降解性，而富马酸酯单元则为结构支撑提供交联位点。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 (BMS) 细胞与移植的 BMP 肽的相互作用诱导成骨。此外，支架将在矿化基质产生的同时降解，以增加骨体积。本提案的目的是确定体外和体内 BMP 肽移植 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 成分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。在目标 1 的第二部分中，将在体外测定 BMP 肽接枝 PLGF 对 BMS 细胞分化和矿化的影响。目标 1.2 的结果是接枝到 PLGF 支架上的 BMP 肽的最佳密度，根据最高矿物质含量来判断。在目标 2 中，我们将确定 BMP 肽移植支架对体内临界尺寸大鼠颅骨缺损骨形成的影响。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）和带有rhBMP-2蛋白的支架（阳性对照）。成功的判断标准是新骨在支架上的持续桥接以及骨矿物质密度。公共健康相关性：美国有超过 2000 万人完全无牙颌，全世界每年约有 50 万儿童出生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、具有保护缺损免于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，因此有可能在开发适应不断变化的颅面缺损的适应性支架方面取得突破。