Establishment\nof an Idiosyncratic Drug-Induced Liver\nInjury Model on a Stacked Array Chip for Identification of CCL5-Mediated\nParacrine Dynamics

Idiosyncratic\ndrug-induced liver injury (iDILI) poses significant\nchallenges in both drug development and clinical practice due to its\nunpredictable nature and poorly understood mechanism. The current <i>in vitro</i> iDILI models are limited in their ability to replicate\ndynamic paracrine signaling in the inflammatory microenvironment.\nHere, we develop an iDILI model on a stacked array chip, allowing\nease of assembly and disassembly for precise temporal manipulation\nof 3D liver microtissue and macrophages. First, the iDILI model is\nconstructed and optimized on the chip to effectively distinguish drugs\ninducing idiosyncratic versus intrinsic liver injuries. Next, the\niDILI mechanism is investigated using nimesulide (NIM) as a case study.\nOur organ-on-a-chip model successfully recapitulates iDILI, offering\na platform to distinguish drugs between intrinsic and idiosyncratic\nliver injury. Our findings revealed that NIM-induced iDILI triggered\ninflammation-induced injury in the liver microtissues through activating\nthe TNF pathways. Moreover, NIM-induced iDILI promotes the M1 polarization\nof macrophages through CCL5-mediated paracrine dynamics, influenced\nby the interactions between hepatocytes and macrophages. Leveraging\nthe flexibility of the chip, we observe a dynamic equilibrium between\npreactivation of inflammation and the pretreatment of NIM during iDILI\nprocess. Therefore, our developed iDILI model on a stacked array chip\nprovides a valuable tool for identifying iDILI drugs and understanding\nthe importance of temporal specificity in intercellular signaling\nin iDILI.