Engineering an Oxygen-Carrying Perfusate for Normothermic Machine Lung Perfusion - PROJECT SUMMARY Lung transplantation is the only definitive and successful therapy for end-stage lung disease. However, while the waiting list of patients eligible for lung transplant grows, the number of suitable donor lungs falls far short of the demand, and people are dying while waiting for acceptable lungs. To attempt to address this shortfall, there has been an aggressive expansion of organ quality criteria for transplantation to meet this critical need. An evolving strategy to meet the critical unmet demand for viable lungs suitable for transplantation is donation after circulatory death (DCD) donation. Unfortunately, ischemia-reperfusion injury (IRI), which happens universally in transplantation, is especially pronounced in these DCD allografts and highly variable. Therefore, resulting in the use of marginal or extended criteria donor organs where there exists the increased potential for early allograft dysfunction or failure after transplantation. Normothermic ex-vivo lung perfusion (EVLP) is a technology that enables the assessment and, with sufficient metabolic support on the perfusion circuit, potential resuscitation of DCD donor lungs significant metabolic debt. In current clinical practice, EVLP uses either an acellular perfusion solution or perfusion solution containing red blood cells (RBCs), which are both unable to support the donor organ for extended duration perfusions. There are no commercially available or viable blood alternatives that are able to be used for EVLP. For RBC-based perfusates, there are limitations with respect to erythrocyte degradation, hemolysis, and antigen exposure over time while on the EVLP circuit. We have demonstrated that engineered hemoglobin-based oxygen carriers (HBOCs) can be tailored to mimic RBC oxygen delivery by mixing tense and relaxed quaternary state polymerized hemoglobin molecules. These molecules are stable at normothermia and can be the basis of an organ support solution or oxygen-carrying perfusate used to resuscitate donor lungs prior to transplantation. An engineered and tailored oxygen affinity HBOC that can effectively deliver oxygen over a broad range of physiologic conditions would be favorable, ensuring optimal lung viability. A novel, innovative HBOC-based perfusate with a prescriptive O2 affinity tailored to effectively deliver O2 over a broad range of physiologic conditions would favorably ensure lung viability, especially for lungs that have amassed different metabolic debts. This supports the rationale that a tailored HBOC-based perfusate with tunable O2 affinity can effectively support DCD lungs by meeting the enormous and variable metabolic O2 debt incurred during ischemia and can sustain organ viability through EVLP leading to successful transplantation. We will engineer a tailored oxygen affinity HBOC perfusate mixtures and define their biocompatibility and stability (Aim 1) and we will demonstrate the ability of the novel, tunable HBOC formulation to resuscitate DCD lungs during EVLP by meeting the metabolic demands of the lung to restore function and ensure successful transplantation (Aim 2).
