Engineering structural bone allografts for enhanced repair and reconstruction

工程结构同种异体骨移植以增强修复和重建

• 批准号: 9978190
• 负责人: Jingwei Xie
• 金额: $ 16.86万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-17 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978190
• 关键词: Allografting; Autologous Transplantation; Biocompatible Materials; Biological Assay; Bone Growth; Bone Marrow Stem Cell; Bone Regeneration; Bone Surface; Bone Tissue; Bone Transplantation; Bone callus; Bone structure; Cadaver; Cell Line; Cell Transplantation; Cells; Chondrocytes; Clinical; Collaborations; Data; Defect; Dependovirus; Deposition; Dose; Engineering; Engraftment; Failure; Fibroblasts; Fibrosis; Formulation; Fracture; Histology; Hydrogels; Immunohistochemistry; Impairment; Implant; Infection; Literature; Luciferases; Mechanics; Mediating; Medical Device; Membrane; Methodology; Methods; Modeling; Modification; Mus; Organ Transplantation; Osseointegration; Osteoblasts; Osteogenesis; Pathway interactions; Peptides; Performance; Pharmaceutical Preparations; Polymers; Process; Production; Property; Regulation; Reporter; Reporting; Research; Role; Safety; Signal Pathway; Signal Transduction; Structure; Surface; TGF Beta Signaling Pathway; Testing; Tissues; Torsion; Transforming Growth Factor alpha; Transforming Growth Factor beta; Transplantation; United States; Vascularization; Viral Vector; Virus; allogenic bone transplantation; base; bone; bone engineering; bone healing; bone morphogenetic protein 2; bone morphogenic protein; bone xenograft; combat; controlled release; healing; immunoreaction; improved; in vivo; in vivo evaluation; inhibitor/antagonist; insight; macrophage; microCT; muscle regeneration; nanofiber; novel; novel strategies; operation; osteoblast differentiation; osteogenic; reconstruction; repaired; response; scaffold; success; surface coating; tissue regeneration; vector

PROJECT SUMMARY Bone grafting procedures number over 500,000 annually in the United States, with allograft tissues used for 33% of the bone grafting operations. Although bone allografts from cadavers and donors have been utilized extensively to repair bone defects, bone allografts have not achieved the similar level of efficacy as compared with bone autografts. Furthermore, bone allografts for treatment of critical-sized bone defects show extremely slow engraftment and ≈ 60% long-term failure rates due to fibrotic nonunions, poor vascularization, poor osteointegration, infections, and microcrack propagation. To improve the healing and integration, strategies have been developed to modify bone allografts to enhance their osteogenic and angiogenic properties. These strategies include coating with polymers with and without incorporation of different drugs, coating with adeno-associated virus – bone morphogenetic protein 2 (AAV-BMP2) vectors, coating with hydrogels containing bone marrow stem cells (BMSCs), wrapping with BMSCs-seeded nanofiber membranes. However, these strategies are associated with many problems including i) fibrosis tissue formation, ii) involvement of living cells, iii) uneven callus formation, and iv) safety of virus vectors. Therefore, there is an urgent need to engineer off-the-shelf bone allografts to improve their efficacy and performance in repair of the critical-sized bone defects. The primary objective of this study is to engineer bone allografts with a novel coating capable of releasing anti-fibrotic agents and bone growth regulating factors in either simultaneous or sequential fashion to improve the healing and osteointegration. To test the hypothesis and accomplish the primary objective, our strategy includes: i) Establish a method of engineering bone allograft with incorporation of BMP-2 peptides and a TGF-β signaling inhibitor to the coatings; and ii) Assess the anti-fibrotic efficacy, new bone formation, and osseointegration of engineered bone allografts in a murine femoral defect model; and 3) Examine the antagonism between TGF-β and BMP-2 signaling during bone allograft repair. We expect to identify the role of anti-fibrotic agents and bone growth regulatory factors on the healing of a critical bone defect through surface engineered bone allografts. The proposed strategy could also be useful in various applications aimed at promoting tissue regeneration.

项目概要 美国每年进行的同种异体骨移植手术数量超过 500,000 例 33% 的骨移植手术使用的组织。虽然来自尸体的同种异体骨移植物 供体已被广泛用于修复骨缺损，但同种异体骨移植尚未 与自体骨移植相比，达到了相似水平的功效。此外，骨 用于治疗临界尺寸骨缺损的同种异体移植物显示植入速度极慢且 ≈ 60% 的长期失败率归因于纤维化骨不连、血管化不良、不良 骨整合、感染和微裂纹传播。为了改善愈合和 整合，已经制定了策略来修改同种异体骨移植物以增强其 成骨和血管生成特性。这些策略包括用聚合物涂覆和 不掺入不同药物，涂有腺相关病毒-骨 形态发生蛋白 2 (AAV-BMP2) 载体，涂有含有骨髓的水凝胶 干细胞（BMSC），用 BMSC 种子纳米纤维膜包裹。然而，这些 策略与许多问题相关，包括 i) 纤维化组织形成，ii) 活细胞的参与，iii) 愈伤组织形成不均匀，以及 iv) 病毒载体的安全性。所以， 迫切需要设计现成的同种异体骨移植物以提高其功效和 修复临界尺寸骨缺损的性能。本研究的主要目的是 设计具有能够释放抗纤维化剂和骨的新型涂层的同种异体骨移植物 以同时或顺序的方式生长调节因子，以改善愈合和 骨整合。为了检验假设并实现主要目标，我们的策略 包括： i) 建立掺入 BMP-2 的同种异体骨移植工程方法 涂层上的肽和 TGF-β 信号抑制剂； ii) 评估抗纤维化功效， 小鼠股骨中工程骨同种异体移植物的新骨形成和骨整合 缺陷模型； 3) 检查 TGF-β 和 BMP-2 信号传导过程中的拮抗作用 同种异体骨移植修复。我们希望确定抗纤维化药物和骨骼生长的作用 通过表面工程骨修复关键骨缺损的调节因素 同种异体移植物。所提出的策略也可用于旨在实现以下目标的各种应用： 促进组织再生。