Induced hepatic (iHep) cells generated by direct reprogramming have been proposed as cell sources for drug screening and regenerative medicine. However, the practical use of a 3D hepatic tissue culture comprised of iHep cells for drug screening and toxicology testing has not been demonstrated. In this study, a 3D vascularized liver organoid composed of iHep cells and a decellularized liver extracellular matrix (LEM) cultured in a microfluidic system is demonstrated. iHep cells are generated by transfection with polymer nanoparticles and plasmids expressing hepatic transcription factors. The iHep cells are cocultured with endothelial cells in the 3D LEM hydrogel in a microfluidic‐based cell culture device with a continuous dynamic flow of media. The resultant 3D vascularized liver organoids maintained under this physiologically relevant culture microenvironment exhibit improved hepatic functionalities, metabolic activity, biosynthetic activity, and drug responses. Finally, the feasibility of using the iHep‐based 3D liver organoid as a high‐throughput drug screening platform, as well as its use in a multiorgan model comprised of multiple internal organoids is confirmed. The study suggests that a combined strategy of direct reprogramming, matrix engineering, and microfluidics can be used to develop a highly functional, standardized, drug screening, and toxicological analysis platform.
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