Multimodal Multiorgan‐on‐a‐Chip Platform for Probing Liver‐Tumor Interactions and Advancing Prodrug Screening

ABSTRACT To advance the development of microphysiological systems with enhanced metabolic fidelity, there is a critical need to recapitulate native three‐dimensional multicellular architecture, enabling non‐invasive, multi‐parameter measurements. Here, we present a multimodal multi‐OoC platform designed to investigate liver‐tumor interactions and streamline prodrug screening. The platform features a sophisticated microfluidic circuit with pneumatically actuated valves for dynamic perfusion and strategically configured microwell arrays that support the formation and maturation of 3D hepatic constructs. By synergistically incorporating real‐time electrochemical sensing with automated solid‐phase microextraction coupled to mass spectrometry (SPME‐LC‐MS) for pharmaceutical kinetic analysis, the platform allows nonintrusive, longitudinal monitoring of prodrug metabolism. We further implemented an impedance‐based immunosensor for real‐time assessment of drug‐induced hepatotoxicity, quantifying secreted albumin across clinically relevant concentrations (1–80 µM). As proof of concept, we evaluated the metabolic activation and subsequent antineoplastic efficacy of two prodrugs, capecitabine and tamoxifen, highlighting the system's ability to elucidate hepatic metabolic activation pathways and resultant antineoplastic efficacy. By unifying 3D tissue models with complementary real‐time analytical modalities, this work provides a versatile and transformative approach for in vitro drug evaluation and mechanistic organ‐organ interaction studies. L. Z. conceived the study. D. W. performed the experiments, analyzed the data, and wrote the manuscript. L. Zhao. wrote and revised the manuscript. X. W., and G. G. helped on revising the manuscript. D. G., M. W., and Y. Z. helped to perform the mass spectrometry testing of the parent drug and its metabolites. T. C. assisted in completing all the work related to the proteomics section. Y. H. and S. B. assisted in the fabrication and characterization of the chip. L. Z. and X. W. supervised the research project. All authors read and approved the final manuscript.