Can patient-derived in vitro models improve clinical translation in critical care research when used before animal...

Translational failure remains a major barrier in critical illness research, with preclinical findings from animal models often failing to replicate in human trials.

we hypothesize that the integration of advanced in vitro models derived from human cells-particularly those from ICU patients-prior to animal studies will enhance clinical translation in critical care research.

These emerging human-relevant platforms-such as organ-on-chip microfluidic systems-recapitulate key aspects of human physiology and pathology that animal models often cannot, thereby avoiding interspecies differences, capturing patient-specific variability, and enabling the study of disease phenotypes and endotypes. We propose that advanced in vitro models should be used first to gain mechanistic insights and assess efficacy in a human-relevant setting, while subsequent animal studies would then serve to evaluate systemic effects and safety before translation to patients. By leveraging such complementary strengths, an integrated in vitro-in vivo pipeline could better bridge the bench-to-bedside gap. This approach aligns with 3Rs principles by refining and reducing animal use (screening therapeutics in human models to focus subsequent animal experiments), and potentially replacing certain animal tests pending rigorous validation and regulatory acceptance. Implementation will require regulatory support, as well as training and funding to overcome technical barriers. This hypothesis is testable through analyses of past translational failures to determine whether human in vitro models could have predicted outcomes, and through prospective studies comparing drug development pipelines with and without an in vitro prescreening step to assess improvements in clinical success rates.

By harnessing the strengths of both model systems, this two-step strategy could help bridge the translational gap in critical care, improve therapeutic development, and accelerate precision medicine in sepsis and other critical illnesses.