Optimizing Perfusates for Ex Vivo Lung Perfusion: A Pharmaceutic Perspective on Formulations, Functions, and Future Innovations.

Abstract

Ex vivo lung perfusion (EVLP) is now an established normothermic machine-perfusion strategy in lung transplantation, primarily enabling structured donor lung assessment, short-term preservation, and selective rehabilitation outside the recipient. Because the supply of transplantable lungs remains limited, clinically implemented EVLP protocols have increased donor-lung utilization by allowing transplant teams to evaluate marginal grafts under near-physiological ventilation and perfusion rather than relying exclusively on static cold storage. The perfusate is central to this process because it stabilizes colloid osmotic pressure, electrolytes, buffering capacity, metabolic substrates, and oxygen transport according to protocol requirements. This review critically summarizes the development of EVLP perfusates and separates clinically validated roles from experimental repair strategies. We first distinguish EVLP perfusates from cold preservation solutions and compare acellular, red blood cell-containing, and whole-blood approaches with attention to their physiological rationale, logistical constraints, and level of evidence. We then discuss protocol-specific additives, including anti-inflammatory agents, antioxidants, antimicrobials, anticoagulants, hormones, nutritional substrates, and cellular or gene-based therapies. Emerging interventions such as polymerized hemoglobin, cytokine adsorption, mesenchymal stromal cell-derived products, CRISPR-Cas-mediated interleukin-10 modulation, and prolonged or intermittent EVLP illustrate the expanding therapeutic potential of the platform. However, most of these strategies remain preclinical or early translational. Future perfusate development should therefore prioritize standardized outcome measures, evidence-based component selection, and careful separation of organ preservation, organ assessment, and organ rehabilitation.