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: 7056814
• 负责人: ALLEN T BISHOP
• 金额: $ 24.61万
• 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/7056814
• 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，用微骨转移的生活同种异体移植物替代节段性的骨骼和关节，而无需长期免疫抑制或耐受性。当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，以及晚期应力骨折，非工会或不可行同种异体移植的感染是常见的。血管化自体的大小和形状不足，不提供关节功能。与缺陷相匹配的血管化同种异体移植物的显微外科转移应通过提供稳定的重建以及有利的愈合和应激适应特性来改善临床结果。当前同种异体的生存力取决于长期免疫抑制，并有可能严重的并发症。他们的常规使用需要一种在没有长期免疫抑制而无需长期免疫抑制的方法。在这些实验中，在微外科生物同种异体植入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。我们将测试来自宿主血管束的新血管生成是否会在戒断FK-506免疫抑制后将骨血流动到血管化骨移植。免疫抑制，动脉束植入和存活时间对血管生成，血管通畅和骨血流动的影响。我们将询问使用组织形态计量分析，在手术血管生成和免疫抑制后的血管化同种异体移植物中是否保持骨重塑。我们将询问观察到从移植细胞中观察到的重塑结果，还是嵌合置换骨的作用，在性不匹配的同种异体移植后使用原位杂交用于Y染色体特异性标记。我们将证明，宿主衍生的内皮细胞置换和供体特异性耐受性的移植适应不影响移植物的生存。内皮细胞谱系及其与通畅的关系将评估移植物的适应性，并从相同的近交大鼠供体中获得第二个同种异体皮肤移植物的存活率将测试供体特异性耐受性的发生。在临床上采用的类似方法将提供能够用相似的大小和形状的活组织替代缺失的骨骼的能力，同时保持生命骨骼的优质愈合和重塑能力。最重要的是，免疫抑制仅维持足够长的时间来消除长期免疫调节的发病率和潜在死亡率，以使宿主衍生的血管血管生成发生。可以想象，可以使用类似方法（包括部分或整个联合同种植物甚至异种移植植物）对其他肌肉骨骼组织进行移植。