ABSTRACT Developing predictive human in vitro drug screening platforms requires models that capture the spatial complexity, cellular diversity, and functional maturity of a native liver tissue. Here, we present a bioprinted multi‐cellular liver model that integrates induced pluripotent stem cells (iPSCs)‐derived hepatocytes and endothelial cells within a matrix metalloproteinase (MMP)‐degradable, YIGSR‐functionalized polyethylene glycol (PEG)—norbornene (NB) hydrogel. The multi‐cellular architecture recapitulates hepatic organization by spatially positioning endothelial and parenchymal compartments in physiologically relevant arrangements, enabling paracrine signaling, enhanced nutrient exchange, and stable cell–cell/matrix interactions. Integrated with a dynamic microfluidic perfusion system, the construct supports matrix remodeling, delivers physiological shear stress, and sustains a well‐oxygenated microenvironment. Compared to static culture, dynamic perfusion preserved long‐term albumin and urea secretion, enhanced cytochrome P450 activity, reduced oxidative stress, and maintained mitochondrial integrity over extended culture periods. Transcriptomic profiling confirmed significant enrichment of metabolic, junctional, and drug‐processing pathways. Functionally, the multi‐cellular platform demonstrated robust and inducible drug‐metabolizing capacity, enabling accurate identification of clinically relevant hepatotoxic compounds. Drug potency metrics—including IC 50 and benchmark dose values—closely matched reported human plasma concentration thresholds, underscoring the translational potential of the system. This reproducible, physiomimetic multi‐cellular liver platform provides a high‐content, human‐iPSC based liver tissue to conventional preclinical models, bridging the gap between early‐stage drug testing and clinical outcomes while offering new opportunities for predictive pharmacology and toxicity assessment.
Lu et al. (Mon,) studied this question.