Cell-Based and Cell-Derived Therapies Delivered During Ex Vivo Machine Perfusion for Solid Organ Reconditioning Prior to Transplantation: A Systematic Review

Background/Objectives: Organ shortage is a major barrier to transplantation, leading to the emergence of marginal donor organs and extended criteria donor grafts and, alongside these, machine perfusion as a platform for reconditioning grafts to meet transplantation standards. Despite functioning as a reconditioning platform in its own right, machine perfusion also allows for the delivery of therapeutic agents directly to grafts prior to transplant. Cell-based and cell-derived therapies have been increasingly explored for delivery during this window, although evidence is fragmented across individual organ systems, and whether ex vivo benefit is confirmed post-transplant remains unclear. This systematic review aimed to synthesise the evidence from both perfusion-phase findings and post-transplant findings across solid organ machine perfusion, evaluating the concordance between the two. Methods: This review was prospectively registered on PROSPERO and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance. Included studies delivered cell-based or cell-derived therapies during ex vivo machine perfusion of a solid organ. The SYRCLE tool was used across all studies to assess risk of bias, and given substantial heterogeneity in cell type, protocol, and organ models, findings were synthesised narratively, with a sensitivity analysis restricted to the subset of studies incorporating a transplantation phase. Results: Thirty-one studies met inclusion criteria, spanning kidney (n = 10), liver (n = 11), lung (n = 9), and heart (n = 1). Mechanisms converged largely on immunomodulatory and metabolic pathways, most consistently reported across organs, alongside a less consistent but notable cross-organ parallel in regenerative progenitor activation between liver and kidney. Benefit was reported more consistently at the molecular and histological levels rather than the physiological level. Eight of the studies proceeded to transplantation, of which half showed a beneficial post-transplant result, and half showed mixed results. Conclusions: Cell-based and cell-derived therapies are best understood as adjuncts to the existing reconditioning capacity of machine perfusion. Molecular and mechanistic benefit was consistently reported; however, confirmation beyond the perfusion phase remained incomplete across organ systems. Mechanisms supported by direct interventional evidence represent priority candidates for further preclinical validation and independent replication.