From Preservation to Repair: A Systematic Review of Therapeutic Organ Rehabilitation During Normothermic Ex Vivo Machine Perfusion

Background. Normothermic ex vivo machine perfusion (NMP) enables active organ rehabilitation rather than passive preservation. While lung perfusion represents the most mature therapeutic paradigm, kidney, liver, and heart applications are emerging. This review examines therapeutic interventions during NMP across these organs to identify shared mechanisms and translational gaps. Methods. Following PROSPERO registration (CRD420251134637), a PRISMA-compliant search of PubMed, Web of Science, and Embase identified 3336 records. After screening, 155 articles underwent full-text review for inclusion of therapeutic delivery during NMP. Data extraction captured intervention characteristics, perfusion parameters, and outcomes across predefined domains. Results. Twenty-one studies met inclusion criteria: kidney (n = 12, 57%), liver (n = 8, 38%), and heart (n = 1, 5%). Models were predominantly human (n = 13, 62%) or porcine (n = 6, 29%). Interventions included pharmacologic agents (n = 12, 57%), cellular/subcellular therapies (n = 6, 29%), defatting protocols (n = 2, 10%), and circuit modifications (n = 1, 5%). Three mechanistic themes emerged: (1) mitochondrial resuscitation via agents such as AP39 preserved ATP and reduced oxidative stress; (2) immune modulation through CD47 blockade or cytokine hemoadsorption attenuated inflammation; and (3) regenerative approaches using mesenchymal stromal cells to repair structural injuries. Molecular improvements were reported in 95% of studies, but functional improvement in only 38%, revealing an outcome translation gap. Only 19% of studies included posttransplant validation. Conclusions. NMP has enabled effective metabolic and inflammatory reprogramming in kidney and liver perfusion, while cardiac applications lag behind. Standardized reporting, organ-specific functional endpoints, and transplant-linked validation are needed to convert currently rejected organs into viable grafts and expand the effective donor pool.