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: 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
• 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

 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.



项目成果

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。

• DOI: 10.1002/micr.22300
• 发表时间: 2015
• 期刊: Microsurgery
• 影响因子: 2.1
• 作者: Willems,WouterF;Larsen,Mikko;Friedrich,PatriciaF;Bishop,AllenT
• 通讯作者: Bishop,AllenT

Knee joint transplantation combined with surgical angiogenesis in rabbits--a new experimental model.

• DOI: 10.1002/micr.20946
• 发表时间: 2012-02
• 期刊: MICROSURGERY
• 影响因子: 2.1
• 作者: Kremer, Thomas;Giusti, Guilherme;Friedrich, Patricia F.;Willems, Wouter;Bishop, Allen T.;Giessler, Goetz A.
• 通讯作者: Giessler, Goetz A.