BACKGROUND: Vascularized composite tissue allotransplantation has demonstrated clinical success with standard immunosuppression in hand and upper extremity transplantation. The authors developed a fibular vascularized composite tissue allotransplantation model in nonhuman primates to investigate healing and rejection patterns of bone and associated tissues. METHODS: Five fibular vascularized composite tissue allotransplantations were performed between mismatched cynomolgus macaques (Macaca fascicularis). Vascularized fibular segments with associated muscle and skin were transplanted to recipient forearm radius defects. Recipients were treated with either tacrolimus monotherapy or tacrolimus plus co-stimulatory blockade with a novel anti-CD28 antibody. Animals were followed for 6 months with serial radiographs, blood sample collection, and biopsies. At the study endpoint, angiographic, biomechanical, histologic, and immunologic assays were performed. RESULTS: All animals survived to the experimental endpoint of 180 days. Rapid or immediate skin loss was evident secondary to vascular compromise (n = 3) or rejection (n = 1) in four animals. Despite loss of nonbony segments and the development of transplant arteriopathy consistent with chronic rejection in two animals, serial radiologic imaging and histology demonstrated bone healing and donor-recipient bony union by 10 weeks in all animals. Histology confirmed the presence of viable cortical and marrow elements. Biomechanical analysis supported donor-recipient bony union. Short-tandem repeated genotypic analysis revealed that donor marrow had been completely replaced by recipient marrow. CONCLUSIONS: In contrast to successes in extremity vascularized composite tissue allotransplantation, the authors' nonhuman primate fibular vascularized composite tissue allotransplantation model showed early skin loss, replacement of donor bone marrow, and chronic rejection. Donor-recipient bone union did occur and supports the potential for reconstruction of bony continuity defects using isolated vascularized bone allotransplants.
BACKGROUND: Vascularized composite tissue allotransplantation has demonstrated clinical success with standard immunosuppression in hand and upper extremity transplantation. The authors developed a fibular vascularized composite tissue allotransplantation model in nonhuman primates to investigate healing and rejection patterns of bone and associated tissues. METHODS: Five fibular vascularized composite tissue allotransplantations were performed between mismatched cynomolgus macaques (Macaca fascicularis). Vascularized fibular segments with associated muscle and skin were transplanted to recipient forearm radius defects. Recipients were treated with either tacrolimus monotherapy or tacrolimus plus co-stimulatory blockade with a novel anti-CD28 antibody. Animals were followed for 6 months with serial radiographs, blood sample collection, and biopsies. At the study endpoint, angiographic, biomechanical, histologic, and immunologic assays were performed. RESULTS: All animals survived to the experimental endpoint of 180 days. Rapid or immediate skin loss was evident secondary to vascular compromise (n = 3) or rejection (n = 1) in four animals. Despite loss of nonbony segments and the development of transplant arteriopathy consistent with chronic rejection in two animals, serial radiologic imaging and histology demonstrated bone healing and donor-recipient bony union by 10 weeks in all animals. Histology confirmed the presence of viable cortical and marrow elements. Biomechanical analysis supported donor-recipient bony union. Short-tandem repeated genotypic analysis revealed that donor marrow had been completely replaced by recipient marrow. CONCLUSIONS: In contrast to successes in extremity vascularized composite tissue allotransplantation, the authors' nonhuman primate fibular vascularized composite tissue allotransplantation model showed early skin loss, replacement of donor bone marrow, and chronic rejection. Donor-recipient bone union did occur and supports the potential for reconstruction of bony continuity defects using isolated vascularized bone allotransplants.
Authors: Flemming Puscz; Mehran Dadras; Alexander Dermietzel; Frank Jacobsen; Marcus Lehnhardt; Björn Behr; Tobias Hirsch; Maximilian Kueckelhaus Journal: PLoS One Date: 2020-06-26 Impact factor: 3.240
Authors: Abraham J Matar; Rebecca L Crepeau; Gerhard S Mundinger; Curtis L Cetrulo; Radbeh Torabi Journal: Front Immunol Date: 2021-06-30 Impact factor: 7.561