A transport-only null model for apparent heterogeneity in diffusively dosed organoid arrays

Abstract

Spatial transport can create apparent biological heterogeneity even when organoids are intrinsically identical. We develop a transport-to-phenotype null model for diffusively dosed liver-cancer organoid arrays. The model couples bulk diffusion and clearance to partially accessible adsorption, reversible surface residence, productive internalization, and intracellular state dynamics. Matched asymptotics reduce the perforated-domain problem to a Green-function system, while renewal resolvents describe desorption, re-adsorption, and residence-time effects. Across $2000$ random ten-organoid arrays with localized dosing, the predicted transport-only maturation coefficient of variation has median $0.623$; one-factor design changes move this median between $0.27$ and $0.86$. After matching array-mean exposure, distributed dosing reduces the baseline spread approximately fivefold. The analysis also shows that, in a conservative reflecting chamber, desorption changes uptake timing and allocation but not total eventual uptake; reductions in total uptake require a competing loss channel. Residence laws with equal means can nevertheless produce different transient phenotypes. The spatial reduction is verified against finite-element solutions of the full PDE, and the time reconstruction against numerical Laplace inversion. Finally, a large-batch theorem shows that increasing batch size averages independent process variation but not shared line or batch effects. The framework provides a geometry-specific null against which measured organoid heterogeneity can be assessed.