Angiogenesis and Long-Term Bone Allograft Survival

血管生成和同种异体骨移植的长期存活

• 批准号: 6847852
• 负责人: ALLEN T BISHOP
• 金额: $ 27.45万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6847852
• 关键词: angiogenesis; blood flow measurement; bone transplantation; femur; fluorescent in situ hybridization; graft versus host disease; homologous transplantation; immunocytochemistry; immunosuppression; in situ hybridization; laboratory rat; limb transplantation; microangiography; musculoskeletal circulation; physiologic bone resorption; radioactive microsphere technique; transplant rejection; transplantation immunology

DESCRIPTION (provided by applicant): This research Aims to develop a method to replace segmental defects of bone and joint with microsurgically transferred living allografts, without need for long-term immunosuppression or induction of tolerance. Current reconstructive methods do not adequately replicate the size, strength, and function of the original bone. Prosthetic loosening or fracture, and late stress fracture, non-union or infection of non-viable allografts are common. Vascularized autografts are inadequate in size and shape, and do not provide for joint function. Microsurgical transfer of vascularized allografts matched to the defect should improve clinical outcomes, by providing a stable reconstruction combined with favorable healing and stress adaptation properties. Allograft viability currently depends upon long-term immunosuppression, with potentially serious complications. Their routine use requires a method that maintains graft viability without long-term immunosuppression. In these experiments, angiogenesis from host vessels, implanted at the time of microsurgical living bone allotransplantation, will be used to develop a host-derived neoangiogenic bone circulation using an inbred rat model. We will test whether neoangiogenesis from the host vascular bundle will maintain bone blood flow to a vascularized bone allograft after withdrawal of FK-506 immunosuppression. The effects of immunosuppression, arteriovenous bundle implantation and survival time on angiogenesis, vessel patency and bone blood flow will be determined. We will ask whether bone remodeling is maintained in vascularized bone allografts after surgical angiogenesis and withdrawal of immunosuppression using histomorphometric analysis. We will ask whether observed remodeling results from graft-derived cells, or is the effect of chimeric replacement of bone, using in situ hybridization for a Y chromosome-specific marker following sex-mismatched allotransplantation. We will demonstrate that graft adaptation by host-derived endothelial cell replacement and donor specific tolerance do not contribute to graft survival. Endothelial cell lineage, and its relationship to patency will evaluate graft adaptation, and survival of a second allogeneic skin graft from identical inbred rat donors will test the occurrence of donor-specific tolerance. Similar methods applied clinically would provide the ability to replace missing bone with living tissue of similar size and shape, while maintaining the superior healing and remodeling abilities of living bone. Most importantly, the morbidity and potential mortality of long-term immune modulation are obviated by immunosuppression maintained only long enough for host-derived vessel angiogenesis to occur. It is conceivable that other musculoskeletal tissues could be transplanted using similar methods, including partial or whole joint allo- or even xenotransplants.

描述（由申请人提供）：本研究旨在开发一种方法，用显微手术转移的活体同种异体移植物替代骨和关节的节段性缺损，而无需长期免疫抑制或诱导耐受。目前的重建方法不能充分复制原始骨的大小、强度和功能。假体松动或断裂、晚期应力性骨折、骨不连或无活性同种异体移植物感染是常见的。带血管的自体移植物在尺寸和形状上都不合适，并且不能提供关节功能。显微外科转移吻合血管的同种异体移植物与缺损相匹配，通过提供稳定的重建结合良好的愈合和应力适应特性，可以改善临床结局。同种异体移植物的存活目前依赖于长期的免疫抑制，具有潜在的严重并发症。它们的常规使用需要一种方法来维持移植物的活力，而无需长期的免疫抑制。在这些实验中，来自在显微外科活骨同种异体移植时植入的宿主血管的血管生成将用于使用近交系大鼠模型开发宿主衍生的新血管生成骨循环。我们将测试在撤除FK-506免疫抑制后，来自宿主血管束的新血管生成是否会维持骨血流到血管化骨同种异体移植物。将确定免疫抑制、动静脉束植入和存活时间对血管生成、血管通畅性和骨血流的影响。我们将通过组织形态计量学分析探讨在手术血管生成和免疫抑制剂撤除后，血管化骨移植物中骨重建是否得以维持。我们将询问所观察到的重塑是否来自移植物来源的细胞，或者是嵌合体替代骨的效果，使用原位杂交的Y染色体特异性标记后，性别不匹配的同种异体移植。我们将证明宿主来源的内皮细胞替代和供体特异性耐受的移植物适应性并不有助于移植物存活。内皮细胞谱系及其与通畅性的关系将评价移植物适应性，来自相同近交系大鼠供体的第二次同种异体皮肤移植物的存活将测试供体特异性耐受的发生。临床上应用的类似方法将提供用类似尺寸和形状的活组织替换缺失骨的能力，同时保持活骨的上级愈合和重塑能力。最重要的是，长期免疫调节的发病率和潜在死亡率通过仅维持足够长的时间以使宿主来源的血管生成发生的免疫抑制来避免。可以想象，其他肌肉骨骼组织可以使用类似的方法进行移植，包括部分或整个关节同种异体甚至异种移植。