Decellularized liver scaffolds for constructing drug-metabolically functional ex vivo human liver models

The creation of ex vivo human liver models has long been a critical objective in academic, clinical, and pharmaceutical research, particularly for drug development, where accurate evaluation of hepatic metabolic dynamics is crucial. We have developed a bioengineered, perfused, organ-level human liver model that accurately replicates key liver functions, including metabolic activities, and protein synthesis, thus addressing some of the limitations associated with traditional liver monolayers, organoids, and matrix-embedded liver cells. Our approach utilizes liver-specific biomatrix scaffolds, prepared using an innovative protocol and fortified with matrix components that facilitate cellular interactions. These scaffolds, when seeded with human fetal liver cells or co-seeded with liver parenchymal and endothelial cell lines, enable the formation of three-dimensional (3D) human livers with enhanced cellular organization. The “recellularized tissue-engineered livers” (RCLs) have undergone various analyses, demonstrating the capability for establishing liver microenvironments ex vivo. Within 7–14 days, the RCLs exhibit evidence of liver differentiation and metabolic capabilities, underscoring the potential for use in drug metabolism and toxicity studies. Although our study represents a significant step forward, we acknowledge the need for direct comparisons with existing models and further research to fully elucidate the spectrum of regenerative responses. The high drug-metabolizing enzyme activity of RCLs, as demonstrated in our study, provides a promising avenue for investigating drug-induced liver injury mechanisms, contributing to a more detailed understanding of early drug discovery processes. [Display omitted] •Novel RCLs used fetal liver cells in biomatrix for liver-specific function and regeneration.•Co-seed hepatic and endothelial cells in RCLs for enhanced utility.•RCLs maintain metabolism, enzyme activity, simulate liver injury, aiding drug discovery.•Biomatrix scaffolds in RCLs enable the study of liver-specific metabolic traits and differentiation.•RCLs offer precise hepatic response predictions, boosting early drug development.