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.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Orthopedics and Musculoskeletal Study Section (ORTH)
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Panagis, James S
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Mayo Clinic, Rochester
United States
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Rezaie, E S; Visser, N J; Friedrich, P F et al. (2017) Intra-luminal gene therapy in the porcine artery using a recombinant adeno-associated virus 9. Gene 618:24-27
Willems, Wouter F; Larsen, Mikko; Friedrich, Patricia F et al. (2015) Vascularized bone transplant chimerism mediated by vascular endothelial growth factor. Microsurgery 35:45-51
Willems, Wouter F; Larsen, Mikko; Friedrich, Patricia F et al. (2014) Cell lineage in vascularized bone transplantation. Microsurgery 34:37-43
Larsen, Mikko; Willems, Wouter F; Pelzer, Michael et al. (2014) Fibroblast growth factor-2 and vascular endothelial growth factor mediated augmentation of angiogenesis and bone formation in vascularized bone allotransplants. Microsurgery 34:301-7
Mattar, Tiago; Friedrich, Patricia F; Bishop, Allen T (2013) Effect of rhBMP-2 and VEGF in a vascularized bone allotransplant experimental model based on surgical neoangiogenesis. J Orthop Res 31:561-6
Kremer, Thomas; Giessler, Goetz A; Friedrich, Patricia F et al. (2013) Surgical angiogenesis with short-term immunosuppression maintains bone viability in rabbit allogenic knee joint transplantation. Plast Reconstr Surg 131:148e-157e
Kremer, Thomas; Giusti, Guilherme; Friedrich, Patricia F et al. (2012) Knee joint transplantation combined with surgical angiogenesis in rabbits--a new experimental model. Microsurgery 32:118-27
Larsen, Mikko; Pelzer, Michael; Friedrich, Patricia F et al. (2011) Living bone allotransplants survive by surgical angiogenesis alone: development of a novel method of composite tissue allotransplantation. J Bone Joint Surg Am 93:261-73
Larsen, Mikko; Willems, Wouter F; Pelzer, Michael et al. (2010) 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. J Orthop Res 28:1015-21
Larsen, Mikko; Friedrich, Patricia F; Bishop, Allen T (2010) A modified vascularized whole knee joint allotransplantation model in the rat. Microsurgery 30:557-64

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