Sepsis modelling: current approaches and organ-on-chip perspectives

Sepsis is a complex life-threatening condition involving immune dysregulation, endothelial dysfunction, and multi-organ failure. To investigate molecular and systemic processes driving disease progression, in vitro, in vivo, and ex vivo experimental methods have been developed. While these systems have advanced understanding of immune activation, cytokine signalling, and organ injury, differences in complexity, reproducibility, and alignment with human pathophysiology have limited the translation of many promising preclinical findings into clinical success. This review examines current literature on sepsis systems, evaluating them in terms of biological complexity, reproducibility, ethical constraints, and clinical applicability. In parallel, it discusses the potential use of microfluidic technology, particularly organ-on-chip, in replicating human physiology and capturing key features of sepsis. By comparing conventional and advanced systems, this review outlines challenges in sepsis research and identifies key directions for a more integrated approach to sepsis modelling, aiming to improve translational outcomes and therapeutic discovery. We aim to provide a structured basis for comparing models when selecting approaches for a given question or candidate therapy.