Angiogenesis & Osteogenesis in Structural Graft Healing

血管生成

• 批准号: 7106424
• 负责人: XINPING ZHANG
• 金额: $ 25.24万
• 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/7106424
• 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）：由于皮质骨自体移植物的供应有限，并且使用结构同种异体移植物获得的长期较差的长期结局，对大结构骨缺损的修复仍然是骨科重建手术中的一个主要问题。尽管基于其生物力学和生物相容性的特性，虽然无法替代结构性同种异体移植物，但它们缺乏成骨和骨诱导的潜力，加上宿主无法重塑经过的皮质骨，导致骨折的比例很高。为了阐明调节结构骨移植愈合的细胞和分子机制，我们开发了一种鼠股股分段同种异体移植模型。使用该模型，我们能够证明自体移植愈合优于通过活骨膜细胞的血管生成和成骨活性引起的同种异体移植物所观察到的。我们还开发了新的方法来植入股骨同种异体移植的皮质表面上的细胞和/或重组腺相关病毒（RAAV）。基于此，我们假设：1）同种异体移植愈合和后来的修复受到缺乏血管生成和成骨细胞的限制。 2）使用基于细胞的组织工程方法和/或基于AAV的基因疗法对无生命的同种异体移植进行振兴，将赋予加工皮质骨的血管生成，成骨和重塑特性，从而增强同种异体移植疗法。 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重塑冷冻同种异体移植物。在我们的第三个目标中，我们将结合干细胞的植入和RAAV基因治疗，以将处理的结构同种异体移植物与活细胞和血管生成性稳态信号相辅相成，并将其与自体移植和同种异体移植物进行比较。