Refinement of Methodology in Ex-Situ Lung Perfusion

Abstract

Lung transplantation is the gold-standard treatment for eligible patients with end-stage lung disease; however, there is an inadequate supply of high-quality donor lungs for transplant, resulting in a wait-list mortality of 15-30%. Ex-situ Lung Perfusion (ESLP) has become an established means of increasing the donor pool over the last twenty years. Significant progress has been made to extend ESLP preservation from 4-hours to 12-hours in the pre-clinical realm. Unfortunately, clinically approved ESLP preservation is still limited to 4-6 hours, but this will continue to expand along with clinical familiarity. A few preclinical ESLP protocols, including our own, have managed to achieve 24-hours of continuous preservation with porcine lungs, although only one platform has managed to achieve adequate reliability for successful in-vivo transplantation assessment. Xenogeneic cross-circulation ESLP and cyclic ESLP (prolonged cold static preservation [CSP] with brief intermittent periods of ESLP) have successfully achieved total preservation durations of 36-72 hours; however, these approaches deviate from the core tenets of ESLP: 1) isolation of the lungs from other organ systems with vulnerable physiology, and 2) continuous physiologic assessment. For ESLP to reach its full potential and optimize the pool of donor lungs, we believe that ultra-prolonged continuous and isolated preservation that allows for increased dwell time of advanced therapeutics is essential (i.e., without cyclic CSP interruption or vulnerable host dependent cross-circulation). A preservation window of 36- to 48 -hours could eliminate global geographic barriers to transplant and organ sharing, allow for optimized donor-recipient matching with more thorough assessment, and enable the expansion of the donor pool by treating and improving poor quality lungs with advanced pathologies. Our lab has previously established that our unique Negative Pressure Ventilation (NPV)-ESLP device produces less lung injury and inflammation compared to a standard Positive Pressure Ventilation (PPV)-ESLP strategy. Therefore, NPV-ESLP is well-positioned to be the ideal platform for ultra-prolonged ESLP. Hence, the objectives of this thesis are to: 1) Develop a clinically relevant large animal lung transplant model to validate ESLP physiology via in-vivo assessment; 2) Systematically investigate key aspects of our current ESLP protocol, including temperature, flow rate, blood-gas management, and perfusate management, for further optimization as demonstrated through improved acute transplant outcomes; 3) Apply our refined protocol to achieve a reliable 24-hour NPV-ESLP transplant model, and push the envelope to achieve 36-hours of continuous, isolated ESLP preservation, which would represent a milestone achievement.