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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

基本信息

批准号：
9440959
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
项目类别：
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/9440959
关键词：
Allogenic Allografting Animal Model Animals Area Autologous Autologous Transplantation Biomechanics Blood Blood Circulation Blood Vessels Blood capillaries Blood flow Bone remodeling Chimerism Defect Excision Failure Family suidae Fracture Generations Goals Growth Factor Gene 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 primary bone cancer public health relevance reconstruction therapeutic angiogenesis tumor

项目摘要

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例肢体保留手术，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缺损。目前的保肢重建选择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，以及后期应力骨折，感染和骨移植不愈合。需要更好地解决这个难题。移植活体同种异体骨的能力，或者使形状与缺失骨形态紧密匹配的冷冻保存骨同种异体移植物（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。其结果可能是相同的愈合和重建潜力的自体活骨。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的重要重塑。这可以在骨血管化复合同种异体移植物（VCA）中完成，而不需要长期的免疫调节。相反，仅使用2周的药物免疫抑制，足以允许新血管生成循环的产生。在相同的大鼠和兔模型中，相同的过程可以使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地转化为临床应用，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，原位重建节段性胫骨缺损与同种异体骨。我们将测试当用植入的自体血管进行手术血运重建时，骨VCA和CBA节段是否会表现出增强的骨循环和重塑潜力。我们将探讨血管生成和全身免疫反应的相互作用，并询问它们如何影响同种异体骨节段性再生，骨重建和生物力学。我们将进一步询问通过血管内皮细胞的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骨同种异体移植物（CBA）和骨VCA重建的结果。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Repopulation of vascularized bone allotransplants with recipient-derived cells: detection by laser capture microdissection and real-time PCR.

DOI：
10.1002/jor.20915
发表时间：
2009-11
期刊：
JOURNAL OF ORTHOPAEDIC RESEARCH
影响因子：
2.8
作者：
Pelzer, Michael;Larsen, Mikko;Friedrich, Patricia F.;Aleff, Ross A.;Bishop, Allen T.
通讯作者：
Bishop, Allen T.

Fibroblast growth factor-2 and vascular endothelial growth factor mediated augmentation of angiogenesis and bone formation in vascularized bone allotransplants.

成纤维细胞生长因子-2 和血管内皮生长因子介导血管化同种异体骨移植中血管生成和骨形成的增强。

DOI：
10.1002/micr.22221
发表时间：
2014
期刊：
Microsurgery
影响因子：
2.1
作者：
Larsen,Mikko;Willems,WouterF;Pelzer,Michael;Friedrich,PatriciaF;Dadsetan,Mahrokh;Bishop,AllenT
通讯作者：
Bishop,AllenT

Augmentation of surgical angiogenesis in vascularized bone allotransplants with host-derived a/v bundle implantation, fibroblast growth factor-2, and vascular endothelial growth factor administration.

DOI：
10.1002/jor.21098
发表时间：
2010-08
期刊：
JOURNAL OF ORTHOPAEDIC RESEARCH
影响因子：
2.8
作者：
Larsen, Mikko;Willems, Wouter F.;Pelzer, Michael;Friedrich, Patricia F.;Yaszemski, Michael J.;Bishop, Allen T.
通讯作者：
Bishop, Allen T.

Vascularized bone transplant chimerism mediated by vascular endothelial growth factor.

由血管内皮生长因子介导的血管化骨移植嵌合体。