Hence, we report our effort to develop a 3D hepatocyte model based on a composite nanofibrous scaffold that mimics both the microstructures of the native liver ECM and its biochemical composition. Instead of using primary human hepatocytes, which have limited availability and are difficult to trace (e.g., donor health/medical history), or hepatocyte-like cells derived from pluripotent stem cells, which are expensive and challenging to maintain , we used HepaRG hepatocytes in our model . HepaRG is an immortalized cell line that can be differentiated into human hepatocyte cells in one simple step . Numerous pieces of evidence have demonstrated the cells preserve liverspecific genes, protein expression, and functions . We found that HepaRG progenitor cells were successfully seeded and differentiated on the scaffold and exhibited typical hepatic functions. More importantly, by treating the differentiated hepatocytes with well-documented drugs that need to be metabolized before excretion, we discovered that hepatocytes on our model reproduced in vivo drug clearance rates, while cells in conventional well plates (2D culture) showed significantly slower drug clearance and reduced clearing capacities. Also, to make the model more translational-after all, end users tend to implement the simplest models, we developed modular 3D-printed holders and batch-produced scaffold inserts, which can be assembled in seconds and housed in standard well plates. The ease of use of the fibrous scaffold and its ability to modulate in vivo-like functions of HepaRG hepatocytes represents a novel and significant improvement in preclinical modeling.