Angiogenesis and Long-term Bone and Joint Allotransplant Survival

血管生成和长期骨和关节同种异体移植存活

• 批准号: 9207420
• 负责人: ALLEN T BISHOP
• 金额: $ 44.08万
• 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 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9207420
• 关键词: Allogenic; Allografting; Animal Model; Animals; Area; Autologous; Autologous Transplantation; Biomechanics; Blood; Blood Circulation; Blood Vessels; Blood capillaries; Blood flow; Bone neoplasms; Bone remodeling; Chimerism; Defect; Excision; Failure; Family suidae; Fracture; Generations; Genes; Goals; HLA Antigens; Haplotypes; Immune response; Immunosuppression; Implant; Infection; Joints; Knowledge; Life; Limb Salvage; Limb structure; Measures; Mechanics; Mediating; Methods; Miniature Swine; Modeling; Morbidity - disease rate; Morphology; Natural regeneration; Necrosis; Neoplasms; Operative Surgical Procedures; Oryctolagus cuniculus; Osteocytes; Osteogenesis; Pharmaceutical Preparations; Pharmacotherapy; Problem Solving; Process; Prosthesis; Rattus; Research; Shapes; Stress Fractures; Testing; Therapeutic Effect; Time; Tissue Viability; Transduction Gene; Translating; Transplantation; Trauma; United States; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vascular Endothelium; Vascular blood supply; Vascular remodeling; Viral; allogenic bone transplantation; allotransplant; angiogenesis; bone; bone circulation; bone healing; bone loss; bone strength; clinical application; congenital anomaly; density; gene therapy; healing; immunoregulation; implantation; improved; novel; peripheral blood; public health relevance; reconstruction; therapeutic angiogenesis; tumor

 DESCRIPTION (provided by applicant): More than 3000 limb-sparing surgeries are performed annually in the United States to reconstruct segmental loss of bone resulting from treatment of neoplasm, infection, trauma or congenital anomaly. Current limb salvage reconstructive options have significant morbidity and frequent complications including prosthetic loosening and mechanical failures, as well as late stress fracture, infection and nonunion of bone allografts. A better solution to this difficult problem is required. The ability to transplant living allogeneic one, or alternatively, to revitalize cryopreserved bone allografts (CBAs) whose shape closely matches missing bone morphology potentially provides both the immediate stability needed for limb function as well as the vascularity needed to maintain or restore osteocyte viability. The result may be the same healing and remodeling potential as autogenous living bone. We have demonstrated the use of angiogenesis from autogenous vessels to provide a neoangiogenic circulation and promote vital, remodeling of bone. This may be accomplished in bone vascularized composite allotransplants (VCA) without need for long-term immune modulation. Instead, only 2 weeks of drug immunosuppression is used, sufficient to permit generation of the neoangiogenic circulation. The same process may revitalize cryopreserved bone allografts in the same rat and rabbit models. The important next steps require the use of a large animal model if our decade of small animal study is to be successfully translated into clinical applications. We propose to use Yucatan miniature swine for this purpose, orthotopically reconstructing segmental tibial defects with allogeneic bone. We will test if bone VCA and CBA segments will demonstrate enhanced bone circulation and remodeling potential, when surgically revascularized with implanted autogenous vessels. We will investigate the interplay of angiogenesis and systemic immune responses, and ask how they influence allograft segmental revitalization, bone remodeling and biomechanics. We will further ask if vascular endothelial growth factor (VEGF) delivery provided by VEGF gene transduction of vascular endothelial cells may further improve the results in both cryopreserved bone allografts (CBA) and bone VCA reconstruction.

 描述（由申请人提供）：美国每年进行超过 3000 例保肢手术，以重建因治疗肿瘤、感染、创伤或先天性异常而导致的节段性骨质流失。目前的保肢重建方案具有显着的发病率和频繁的并发症，包括假体松动和机械故障，以及晚期应力性骨折、感染和同种异体骨移植不愈合。需要更好的解决这个难题。移植活体同种异体骨的能力，或者使形状与缺失骨形态密切匹配的冷冻保存同种异体骨移植物 (CBA) 恢复活力的能力，可能提供肢体功能所需的即时稳定性以及维持或恢复骨细胞活力所需的血管供应。结果可能具有与自体活骨相同的愈合和重塑潜力。我们已经证明了利用自体血管的血管生成来提供新血管生成循环并促进骨骼的重要重塑。这可以通过骨血管化复合同种异体移植（VCA）来实现，而不需要长期的免疫调节。相反，仅使用两周的药物免疫抑制，足以产生新血管生成循环。相同的过程可以使相同的大鼠和兔子模型中冷冻保存的同种异体骨移植物恢复活力。如果我们十年的小动物研究要成功转化为临床应用，接下来的重要步骤需要使用大型动物模型。我们建议使用尤卡坦小型猪来实现此目的，用同种异体骨原位重建节段性胫骨缺损。我们将测试当通过手术植入自体血管进行血运重建时，骨 VCA 和 CBA 段是否会表现出增强的骨循环和重塑潜力。我们将研究血管生成和全身免疫反应的相互作用，并探讨它们如何影响同种异体移植节段再生、骨重塑和生物力学。我们将进一步询问血管内皮细胞的 VEGF 基因转导提供的血管内皮生长因子 (VEGF) 递送是否可以进一步改善冷冻保存的同种异体骨移植 (CBA) 和骨 VCA 重建的结果。