Jordi Vengohechea, Linda Woltjes, Germaine Escames, Vincent E de Meijer, Amelia J Hessheimer, Constantino Fondevila
Ex situ normothermic machine perfusion (NMP) of the liver offers considerable promise for both transplant and non-transplant purposes, including repair, regenerative conditioning, therapeutic testing, disease modeling, and diverse bioengineering applications. While some functions of the liver may be maintained during NMP for periods lasting from days to weeks, a fundamental "blind spot" in prolonged liver NMP protocols remains their near universal failure to reproduce the temporal variability in liver inputs and physical conditions normally directed by circadian rhythms in the in vivo environment. In this narrative review article, we examine key aspects of hepatic circadian rhythmicity and describe how circadian regulation sustains liver health and homeostasis. We consider current liver NMP protocols and explore potential consequences of chronodisruption - the failure to reproduce or meaningfully mimic normal chronobiological conditions - during these procedures. Ultimately, we aim to establish a conceptual framework for understanding how temporal synchronization may influence the success of liver NMP and highlight potential strategies for incorporating temporal cues into future NMP applications.