A Human Stem Cell-Derived Brain-Liver Chip for Assessing Blood-Brain-Barrier Permeation of Pharmaceutical Drugs
Leopold Koenig, Anja Patricia Ramme, Daniel Faust, Manuela Mayer, Tobias Flötke, Anna Gerhartl, Andreas Brachner, Winfried Neuhaus, Antje Appelt‐Menzel, Marco Metzger, Uwe Marx, Eva‐Maria Dehne
Abstract
Significant advancements in the field of preclinical in vitro blood-brain barrier (BBB) models have been achieved in recent years, by developing monolayer-based culture systems towards complex multi-cellular assays. The coupling of those models with other relevant organoid systems to integrate the investigation of blood-brain barrier permeation in the larger picture of drug distribution and metabolization is still missing. Here, we report for the first time the combination of a human induced pluripotent stem cell (hiPSC)-derived blood-brain barrier model with a cortical brain and a liver spheroid model from the same donor in a closed microfluidic system (MPS). The two model compounds atenolol and propranolol were used to measure permeation at the blood-brain barrier and to assess metabolization. Both substances showed an in vivo-like permeation behavior and were metabolized in vitro. Therefore, the novel multi-organ system enabled not only the measurement of parent compound concentrations but also of metabolite distribution at the blood-brain barrier.