Development of a hollow fiber membrane microfluidic system to predict human pharmacokinetics in vitro

Abstract

Drug efficacy and side effects are significantly impacted by the first-pass metabolism, a sequence of events that occurs in the stomach and the liver after oral ingestion. Accurate prediction of this mechanism is crucial for a faster and more cost-efficient drug development process. Replicating the first-pass metabolism in vitro using standard cell culture techniques is challenging due to its complexity involving simultaneous transport and organ-organ interactions in both the gut and liver tissue. A more precise in vitro to in vivo translation of drug distribution, efficacy, and toxicity may be provided by organ-on-a-chip (OoC) models, thereby creating the ability to partially replace currently-used animal models. More specifically, gut-liver-on-a-chip models can aid with in vitro predictions of oral drug administration and the first-pass metabolism. Therefore, the aim of this thesis was to develop an OoC system that could accommodate both intestinal and hepatic cell sources. A hollow fiber membrane (HFM) as a cell scaffold was a critical component of the chip design in order to more accurately reproduce the three-dimensional native environment of the cells. Additionally, the system would need to exhibit the ability to be interconnected quickly and easily, thereby creating the possibility to develop a MOoC system in a plug-and-play manner in a later stage of development, enabling the ultimate realization of organ-organ interactions.