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（申请人提供）：本研究旨在开发一种用显微外科移植活体同种异体移植物替代骨和关节节段性缺损的方法，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骼的大小、强度和功能。假体松动或断裂，以及晚期应力性骨折、不愈合或无活性同种异体移植物的感染是常见的。带血管的自体移植物的尺寸和形状不足，并且不能提供关节功能。与缺损相匹配的血管同种异体移植物的显微手术转移可以通过提供稳定的重建以及良好的愈合和应激适应特性来改善临床结果。目前，同种异体移植物的生存能力取决于长期的免疫抑制，可能存在严重的并发症。它们的常规使用需要一种无需长期免疫抑制即可维持移植物活力的方法。在这些实验中，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大鼠模型开发宿主衍生的新血管生成骨循环。我们将测试 FK-506 免疫抑制撤除后，来自宿主血管束的新生血管生成是否会维持流向血管化骨同种异体移植物的骨血流。将确定免疫抑制、动静脉束植入和存活时间对血管生成、血管通畅和骨血流的影响。我们将使用组织形态计量学分析来询问在手术血管生成和撤回免疫抑制后，血管化同种异体骨移植物中的骨重塑是否得以维持。我们将询问所观察到的重塑是否来自移植物衍生的细胞，或者是嵌合骨替代的效果，在性别不匹配的同种异体移植后使用 Y 染色体特异性标记的原位杂交。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不会有助于移植物存活。内皮细胞谱系及其与通畅的关系将评估移植物的适应性，并且来自相同近交系大鼠供体的第二个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能够用大小和形状相似的活体组织替换缺失的骨骼，同时保持活体骨骼卓越的愈合和重塑能力。最重要的是，长期免疫调节的发病率和潜在死亡率可以通过仅维持足以发生宿主衍生血管血管生成的时间的免疫抑制来避免。可以想象，其他肌肉骨骼组织也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。