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）：这项研究的长期目标是研究骨向内生物降解的骨降解骨诱导支架，以重建颅面缺陷。由于骨形态发生蛋白（BMP）信号受到高度调节，因此移植物必须加载4-5个数量级（不良副作用）的剂量高于内源性量的量。一个有吸引力的替代方法是基于BMP的活性结构域使用肽来启动骨化的级联。该策略涉及将骨诱导的“ BMP肽”的共价依赖，对应于重组人骨形态发生蛋白2（RHBMP-2）的氨基酸残基73-92，与新型生物可吸收型多乳酸 - 乳糖 - 果糖果皮纤维化（Plgflgflgflgflgfflgfffffflgffffffffffffffflgfffffffffffflgffffffflgfffffffffffffff cack）（ PLGF中短的乳酸基 - 糖链链赋予宏观物，而富马酸酯单元则提供了交联的位点，以实现结构支持。我们假设交联的支架为再生区域提供了结构支撑，并通过迁移的骨髓基质（BMS）细胞与移植的BMP肽的相互作用来诱导骨气。此外，脚手架将与矿化基质的产生同时降解以增加骨骼体积。该建议的目的是确定骨诱导率和BMP肽接枝PLGF支架的骨形成程度。在AIM 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。 AIM 1.1的结果是最好的乳酸：PLGF的甘油比和脚手架的最佳孔隙率。在AIM 1的第二部分中，BMP肽接枝PLGF对BMS细胞分化和矿化的影响将在体外确定。 AIM 1.2的结果是由最高矿物质含量来判断的BMP肽的最佳密度。在AIM 2中，我们将确定BMP肽接枝支架对临界大鼠颅内颅骨缺损的骨形成的影响。实验组将包括用突变体BMP肽（阴性对照），BMP肽（实验组）和带有RHBMP-2蛋白（阳性对照）的支架的支架。成功将通过在脚手架和骨矿物质密度上连续桥接新骨的桥接来判断成功。 公共卫生相关性：美国超过两千万人完全厌倦，全世界大约有50万儿童每年出生先天性颅面畸形。占用空间的可降解生物材料具有保护缺陷免受软组织崩溃的一致性，并与形成新的细胞外基质的降解相同，从而增加了骨骼体积的潜力，从而有可能在不断变化的颅面防水裂缝中发展出突破性的潜力。