Structural Graft Healing: Angiogenesis and Osteogenesis

结构性移植物愈合：血管生成和成骨

• 批准号: 6811882
• 负责人: XINPING ZHANG
• 金额: $ 27.12万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-16 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6811882
• 关键词: X ray; angiogenesis; bioengineering /biomedical engineering; biotechnology; bone disorder; bone marrow; bone morphogenetic proteins; bone regeneration; bone transplantation; cell transplantation; combination therapy; computed axial tomography; connective tissue cells; femur; gene therapy; genetically modified animals; homologous transplantation; laboratory mouse; morphometry; orthopedics; osteogenesis; stem cells; tissue engineering; tissue support frame; vascular endothelial growth factors

DESCRIPTION (provided by applicant): Repair of large structural bone defects remains a major problem in orthopaedic reconstruction surgery due to the limited supply of cortical bone autograft and the poor long-term outcomes obtained with structural allografts. While there is no substitute for structural allografts, based on their biomechanical and biocompatible properties, their lack of osteogenic and osteoinductive potential, combined with the host's inability to remodel processed cortical bone, results in a high percentage of fractures. Towards elucidating the cellular and molecular mechanisms that regulate structural bone graft healing, we have developed a murine femoral segmental allograft model. Using this model we were able to demonstrate that autograft healing is superior to that observed with allografts due to the angiogenic and osteogenic activity from live periosteal cells. We have also developed novel approaches to engraft cells and/or recombinant adeno-associated viruses (rAAV) on the cortical surface of the femoral allografts. Based on this, we hypothesize that: 1) allograft healing and later repair is limited by the absence of angiogenic and osteogenic cells. 2) Revitalization of lifeless allograft using a cell based tissue engineering approach and/or AAV based gene therapy will confer angiogenic, osteogenic and remodeling properties on processed cortical bone leading to enhanced bone allograft healing. In our first Specific Aim, we will utilize our murine femoral bone graft model to perform transplantation of live isografts from C57B/6 Rosa 26A male mice to formally demonstrate the contributions of periosteal donor cells in structural bone graft revascularization, osteogenesis and remodeling, in our second Specific Aim, we will seed bone marrow stromal cells onto processed allograft to examine their efficacy on bone healing and remodeling of frozen allograft. In our third aim, we will combine stem cell engraftment and rAAV gene therapy to complement processed structural allograft with live cells and angiogenic-osteogenic signals, and compare its healing with autograft and allograft.

描述（由申请人提供）：由于自体皮质骨的供应有限以及结构性同种异体移植物的长期效果不佳，大结构性骨缺损的修复仍然是骨科重建手术中的一个主要问题。虽然结构性同种异体移植物无可替代，但基于其生物力学和生物相容性特性，它们缺乏成骨和骨诱导潜力，加上宿主无法重塑加工后的皮质骨，导致骨折比例很高。为了阐明调节结构性骨移植愈合的细胞和分子机制，我们开发了小鼠股骨节段同种异体移植模型。使用该模型，我们能够证明，由于活骨膜细胞的血管生成和成骨活性，自体移植愈合优于同种异体移植观察到的愈合。我们还开发了将细胞和/或重组腺相关病毒（rAAV）移植到同种异体股骨皮质表面的新方法。基于此，我们假设：1）同种异体移植愈合和后期修复受到血管生成和成骨细胞缺乏的限制。 2) 使用基于细胞的组织工程方法和/或基于 AAV 的基因治疗使无生命的同种异体移植物恢复活力，将赋予加工后的皮质骨血管生成、成骨和重塑特性，从而增强骨同种异体移植物的愈合。在我们的第一个具体目标中，我们将利用我们的鼠股骨移植模型对 C57B/6 Rosa 26A 雄性小鼠进行活同种移植，以正式证明骨膜供体细胞在结构性骨移植血运重建、成骨和重塑中的贡献，在我们的研究中第二个具体目标，我们将骨髓基质细胞接种到加工后的同种异体移植物上，以检查它们对冷冻同种异体移植物的骨愈合和重塑的功效。在我们的第三个目标中，我们将结合干细胞移植和rAAV基因治疗，用活细胞和血管生成-成骨信号来补充加工后的同种异体结构移植物，并将其愈合与自体移植物和同种异体移植物进行比较。