Bioengineering hepatic organoids: Development of an alternative model for liver toxicity

Abstract

The liver is the major organ involved in the biotransformation of drugs and other chemicals. Disturbance of this process can lead to accumulation of toxic compounds and is therefore a key determinant in liver toxicity. Currently drug safety evaluations are mainly based on animal testing, however differences in drug metabolism between species hamper accurate prediction of the human situation. A shift towards human-based cell models to screen for drug-induced liver toxicity is ongoing. This thesis is focused on the use of intrahepatic cholangiocyte organoids (liver organoids) in the development of a human-based in vitro models for liver toxicity. These organoids can be applied in disease modeling and regenerative medicine approaches. We have shown the biotransformation capacity of liver organoids and their sensitivity to well-known drugs, which showed their potential as novel model for liver toxicity although a further improvement of the hepatic functionality is desired to accurately predict drug-induced liver toxicity. The addition of microphysiological relevant features, e.g., co-culture and/or flow, in in vitro systems is known to improve hepatic functionality of (stem cell-derived) hepatic cells. We added such features using bioprinting techniques combined with media perfusion in a tailor-made bioreactor. The techniques described in this these provide tools to aid in creating more complex in vivo-like models with increased cellular functionality. Bioengineered microphysiologically relevant tissue analogs can help to decrease the gap between animal models and simplistic in vitro models, which leads to a safer and more effective drug development.