Primary hepatocytes display a precipitous decline in phenotypic functions when cultured in a sandwich of extracellular matrix proteins (i.e. collagen, Matrigel). This severely limits the ability of these model systems to accurately predict clinical outcomes. Here, we describe a human liver model with precise microscale cyto-architecture and optimal stromal interactions (HepatoPac®) that displays high levels of liver-specific functions for several weeks in vitro and has been shown to improve the predictions of clinical outcomes as compared to traditional approaches. This document also describes the various applications where HepatoPac has been applied.