Prevention of Ischemia-Reperfusion Injury and Chronic Rejection in a Porcine Vascularized Composite Allotransplantation Model

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Abstract

Aim

Modern body armor, rapid evacuation, and advanced combat casualty care have improved survival after catastrophic extremity and maxillofacial trauma. Restoration using vascularized composite allotransplantation (VCA) is superior to conventional reconstruction in such injuries but requires immunosuppression and long-term outcomes suffer due to chronic rejection (CR). An approach that can improve the functional outcome, reduce immunosuppression load and minimize or eliminate CR would have a substantial impact on VCA and increase the number of war fighters who benefit. To mitigate obligate reperfusion injury and subsequently CR in VCA, we evaluate the efficacy of ex vivo tissue preservation using a novel machine preservation/hemoglobin oxygen carrier (MP/HBOC) for 17 hours.

Methods

A proven porcine myocutaneous heterotopic transplant flap model was performed. Control flaps (n=24) underwent CSP at 4°C with University of Wisconsin (UW) solution for 5 hours prior to transplant. Experimental group (n=24) flaps were perfused with MP/HBOC for 17 hours at a subnormothermic temperature of 21°C. Flaps were monitored daily for clinical evidence of viability and biopsied per protocol with an end-point of either 17 hours for ex vivo only, 14 days for autotransplants and 60 days for allotransplants. The allotransplanted animals were placed on systemic triple immune suppression and maintained at therapeutic levels for the duration of the study. Histologic analysis was blinded and reviewed by an expert veterinarian pathologist at the conclusion of the study.

Results

Twenty-four porcine myocutaneous flaps are designated to experimental groups, and 24 to the control group. We anticipate results will be similar to previous porcine myocutaneous flaps exposed to 14 hours of CSP (n=4) or MP/HBOC (n=4). Results that indicated significantly attenuated markers of IRI, significant apoptosis on TUNEL staining, and endothelial damage in the CSP group when compared to subnormothermic MP/HBOC treated tissue.

Conclusion

If VCA can be preserved for 17 hours or more and be protected from ischemic damage and CR following allotransplantation in the porcine model, then this achievement will have a profound clinical application in VCA as well as solid organ transplantation. Based on the promising preliminary data, we believe efficient tissue oxygenation promoted by subnormothermic (21°C) MP/HBOC in VCA could (1) extend graft preservation times and improve donor access across geographic spans, (2) enable increased efficacy of ex-vivo targeted graft manipulation and (3) ensure graft quality and tissue viability prior to VCA transplantation.

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