Engineering Organoid Morphology and Tissue Interaction Models for Drug Discovery Applications

Abstract

Organoid technology has attracted considerable attention as a next-generation alternative to animal models for drug discovery and disease modeling. However, conventional organoids are typically formed through self-organization under spatially uniform culture conditions, resulting in spherical tissues lacking defined polarity, lumen connectivity, and physiological transport pathways. Consequently, they cannot adequately reproduce in vivo pharmacokinetics such as absorption, distribution, metabolism, and excretion (ADME). In contrast, Organ-on-a-Chip (OoC) technologies enable precise fluidic control and tissue–tissue interactions, but most systems rely on two-dimensional cell cultures and fail to reproduce the three-dimensional architecture of native tissues. Therefore, integration of organoids with OoC systems is essential for constructing physiologically relevant in vitro models. Here, we present a modular engineering platform for controlling organoid morphology and integrating tissue modules into microfluidic devices. By spatially regulating cell positioning, extracellular matrix localization, and morphogen gradients, engineered organoids can be connected to fluidic networks for drug transport analysis. As a proof of concept, we constructed a blood–brain barrier (BBB)–brain tumor interconnected model and demonstrated enhanced vincristine transport and anti-tumor effects following P-glycoprotein inhibition. This approach provides a promising platform for evaluating brain-targeting therapeutics and drug delivery systems (DDS).