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

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要在美国，骨移植程序每年有超过500,000，同种异体移植组织用于33％的骨移植手术。虽然来自尸体的骨骼合物并且捐赠者已广泛用于修复骨缺损，骨合金没有与骨自体移植相比，达到了相似的效率水平。此外，骨头治疗临界骨缺损的同种异体移植物显示出极慢的植入和≈ 由于纤维化不连续性，血管形成差，长期失败率60％稳定性，感染和微裂纹传播。改善康复和一体化，已经制定了修改骨外鼠的策略以增强其成骨和血管生成特性。这些策略包括与聚合物一起涂层和不掺入不同的药物，用腺相关病毒涂层 - 骨头形态发生蛋白2（AAV-BMP2）向量，用含有骨髓的水凝胶涂层干细胞（BMSC），用BMSCS种子纳米纤维膜包裹。但是，这些策略与许多问题有关，包括i）纤维化组织形成，ii）活细胞的参与，iii）不均匀的愈伤组织形成和IV）病毒载体的安全性。所以，迫切需要设计现成的骨合金以提高其效率和临界大小骨缺损的修复表现。这项研究的主要目的是工程师骨合金用新颖的涂层，能够释放抗纤维化剂和骨头以简单或顺序的方式进行的生长调节因素，以改善愈合和稳定性。为了检验假设并实现主要目标，我们的战略包括：i）通过BMP-2保险建立一种工程骨合金的方法肽和TGF-β信号抑制剂对涂料； ii）评估抗纤维化效率，新的骨形成和工程骨合金的骨整合股股合金缺陷模型； 3）检查TGF-β和BMP-2信号传导之间的拮抗作用同种异体移植修复。我们希望确定抗纤维化剂和骨骼生长的作用通过表面工程骨骼治愈临界骨缺损的调节因素同种异体移植。提出的策略在针对的各种应用中也可能有用促进组织再生。