Attenuation of Ischemia-Reperfusion Injury in Limb Auto- and Allografts

Brigham And Women'S Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): Tissue injury results in decreased delivery of oxygen, which is needed to perform basic cell metabolic functions. Tissues exposed to prolonged oxygen deprivation, or ischemia, followed by restoration of bloodflow demonstrate ischemia-reperfusion injury (IRI), a well-described autoimmune-mediated cause of tissue damage and organ failure in a wide range of tissues. During periods of ischemia, injury antigens are displayed on cell surfaces; these antigens are bound by IgM, which initiates an autoimmune cascade that leads to tissue death. Transplantation and replantation surgeries involve the most extreme ischemia and reperfusion imaginable - complete disconnection from cardiopulmonary circulation, whether by surgical or traumatic means, followed by a period of ischemia and a subsequent return to physiologic bloodflow. Thus, the potential for tissue death due to IRI in transplanted and replanted tissues is enormous. Traumatic amputation (TA) is the 2nd leading cause of limb loss in the U.S., with nearly 70% of TAs involving the upper extremity (UE); UE loss also occurs due to cancer and congenital disease and has consequences including lifelong disability, decreased quality of life, and long-term costs. Despite advances in UE prostheses, the resulting sensorimotor function is severely limited; thus, surgical replantation is the preferrd method of treatment. Today, with the global rise in clinical experience with composite tissue allotransplantation, UE transplantation is gaining support as a treatment option for victims of UE loss. However ischemia time correlates directly with extent of IRI, which in turn correlates with risk of tissue rejection. As a result, the 4-hour window of ischemia time that allows survival of transplanted or replanted limbs presents limits the clinical practice of UE replantation and transplantation. TA often occurs in locations far from centers capable of replantation, and suitable limb donors are often located long distances from potential transplant recipients. Often, the 4-hour time limit prohibits surgical limb salvage. Extracorporeal membrane oxygenation (ECMO) was developed to support patients incapable of adequate oxygen delivery, and has been adapted into portable devices used to help support patients in cardiopulmonary failure and to perfuse donor organs in transit to recipient sites. We aim to use portable ECMO technology to artificially perfuse amputated porcine limbs for 8-12 hours with acellular perfusate. Tissue biopsies will be performed throughout perfusion to measure histological and chemical markers of injury for comparison with control limbs preserved on ice - the current standard. Past study has shown that peptides that bind damaging IgM auto-antibodies can attenuate IRI. Limbs treated with these peptides will be transplanted into recipients, and the tissues will subsequently be monitored for signs of IRI. We expect that these trials will show that (a) portable ECMO is capable of extending allowable limb ischemia time, and (b) treatment with IgM-inhibiting peptides decreases IRI in transplanted limbs. If successful, this study will promote access to limb salvage for victims of UE loss and provide support for the development of agents that promote limb viability after salvage.