A hollow fiber membrane-based liver organoid-on-a-chip model for examining drug metabolism and transport

Liver-on-a-chip models predictive for both metabolism and transport of drug candidates in humans are lacking. Here, we have established an advanced, bioengineered and animal-free hepatocyte-like millifluidic system based on 3D hollow fiber membranes (HFMs), recombinant human laminin 332 and adult human stem cell-derived organoids. Organoid cells formed polarized and tight monolayers on HFMs, which displayed improved hepatocyte-like maturation over standard organoid cultures in Matrigel from matched donors. mRNA sequencing and immunofluorescence revealed that HFM cultures exhibited the expression of broad panel of phase I and II drug metabolizing enzymes, and of drug transporters. Functionally, in both static conditions and under flow circulation, HFM monolayers metabolized a cocktail of drugs that are targets for most important phase I and II enzymes. In addition, we were able to study disposition of those parental compounds and their metabolites in the basal circulation and apical compartment of the chip. Moreover, we demonstrated that our system can be used to study drug disposition in a modular setting with other PK/ADME-relevant organ systems. In conclusion, we have generated a proof-of-concept liver organoid-on-a-chip model for examining both metabolism and transport of drugs, which can be further developed towards prediction of PK/ADME profiles in humans.