Revealing Toxicity Mechanisms by Real-Time Monitoring Drug Induction on a Liver-On-Chip

Metabolic processes are a principle component of cellular function and a sensitive indicator of cellular health. In contrast to gene and protein expression, metabolic fluxes change in seconds, thus real-time analysis of metabolic fluxes would permit detection of chemical toxicity before any other effects on cell or tissue viability can be observed. Here we present a sensor-integrated microfluidics platform that maintains human liver tissue under physiological conditions while permitting real-time monitoring of oxygen, glucose, lactate, and glutamine. Using this system we were able to measure human relevant time-to-onset effect of several marketed drugs with reported liver damage. Thapsigargin, an anticancer agent and the anticonvulsant valproate, showed both a very long time to onset, in the range of several hours, while amiodarone, an antiarrhythmic drug and the antidiabetic drug troglitazone, showed a much faster time to onset. Interestingly, the time to onset of all drugs showed a clear dose dependence.

The ability to monitor the dynamics of drug metabolism offers insight into the drugs mechanism of action. While direct damage would show a fast response, with the onset of damage appearing in minutes, secondary mechanisms such as fatty liver disease or cholestasis appear in hours due to the slow accumulation of toxic metabolites. In summary, the ability to monitor metabolic processes in real time enables a unique understanding of cellular response to stimuli, which is a critical advantage of organ-on-chip technology.