Background: The restoration of complex tissue deficits with vascularized composite allotransplantation is a paradigm shift in reconstructive surgery. Clinical adoption of vascularized composite allotransplantation is limited by the need for systemic immunosuppression, with associated morbidity and mortality. Small-animal models lack the biological fidelity and preclinical relevance to enable translation of immunologic insights to humans. Large-animal models have been described; however, limitations persist, including the inability of heterotopic models to evaluate functional nerve regeneration, and the sensitivity of primates to toxicity of immunosuppressive drugs. The authors' novel orthotopic porcine limb transplant model has broad applicability and translational relevance to both immunologic and functional outcomes after vascularized composite allotransplantation.
Methods: Recipients underwent amputation at a level corresponding to the mid forearm. Replantation or transplantation of grafts was performed by plate fixation of the radio-ulna, microsurgical repair of brachial artery and median nerve, and extensor and flexor tendon repairs. Viability of replants was monitored clinically and radiologically. Transplants were monitored for clinicopathologic signs of rejection. Animals mobilized freely postoperatively.
Results: Replantations remained viable until the endpoint of 14 days. Transplants developed Banff grade 4 acute rejection by postoperative day 7. Doppler sonography and angiography confirmed vascular patency. Serial biopsy specimens of skin and histopathology of replants at endpoint confirmed tissue viability and bone healing.
Conclusions: An orthotopic load-bearing porcine forelimb vascularized composite allotransplantation model was successfully established. Technical, procedural, and logistic considerations were optimized to allow model use for immunologic, bone healing, functional nerve regeneration, and other translational studies.