Advances in Machine Perfusion for Liver Transplantation: Mechanisms, Clinical Evidence, and Future Directions

Abstract

Liver transplantation is the definitive treatment for end-stage liver disease, acute liver failure, and selected hepatic malignancies, but its success is limited by a persistent shortage of suitable donor organs. This has driven increased use of extended criteria donors (ECDs), including steatotic and donation after circulatory death (DCD) grafts, which are more susceptible to preservation injury and often inadequately supported by traditional static cold storage (SCS). Machine perfusion (MP) has emerged as a transformative strategy that enables organ preservation, viability assessment, therapeutic intervention, and graft optimization. This narrative review searched PubMed, MEDLINE, and the Cochrane Library up to June 2026, including randomized controlled trials, cohort studies, meta-analyses, registry analyses, and translational studies in English, to evaluate MP modalities-hypothermic oxygenated perfusion (HOPE), normothermic machine perfusion (NMP), normothermic regional perfusion (NRP), and sequential approaches-integrating mechanistic insights into ischemia-reperfusion injury (IRI) with clinical evidence and critically appraising the limitations and heterogeneity of the supporting data throughout. MP mitigates IRI through improved oxygenation, modulation of mitochondrial function, and reduction of oxidative stress. HOPE reduces biliary complications and graft dysfunction, particularly in DCD grafts, while NMP maintains physiological metabolism, allows real-time functional assessment, and lowers graft discard rates, improving utilization of marginal organs. NRP reverses warm ischemic injury in situ with outcomes comparable to brain-death donors, and sequential strategies further enhance graft recovery. Emerging biomarkers, including flavin mononucleotide and syndecan-1, improve viability assessment, while MP also enables therapeutic interventions such as graft defatting and extends preservation time. Overall, MP has transformed liver transplantation into a controlled, data-driven process that expands the donor pool, improves outcomes, and introduces objective viability assessment. However, study heterogeneity, variable viability criteria, and high implementation costs remain as significant challenges. Ongoing advances in multi-omics, regenerative therapies, and artificial intelligence are expected to further refine this approach, address those challenges and establish it as standard care.