Mesoscale maladaptation in disease organoids.

In chronic diseases, multiple tissue components at a shared interface often deteriorate concurrently, and disease progression may depend on interactions among these failures rather than on any single defect. Multi-tissue organoid models can mimic disease-relevant pathology in vitro, but the field lacks a simple framework for comprehensive interrogation. Here, we propose mesoscale maladaptation as an operational concept for multi-tissue disease modelling, defined as a synergistic decline in interdependent functions that can occur between two or more tissue elements. To detect maladaptation, we introduce a stepwise workflow that identifies the failing tissue elements, defines directionality of potential interdependence between these elements and compares combined perturbations with single perturbations to evaluate synergistic decline. We apply this framework to intestinal neuromuscular, hepatic sinusoidal, blood-brain barrier and tumour-neural interfaces, but it can be extrapolated to other organs and systems. This framework will illuminate future directions for in vitro complex disease modelling by enriching biological insights to disentangle progressive pathology, shifting the focus from localised biological failures to concurrent multi-tissue failures that produce synergistic pathology.