Abstract
Current in vitro platforms are poor predictors of the in vivo safety, efficacy and pharmacokinetics of therapeutics,
owing to a significant difference in the test conditions compared to physiological conditions. Therefore, drug
toxicity testing is routinely performed using animal models. However, animal testing is expensive and time
consuming. In addition, ethical concerns about the use of animals are increasingly calling for
reduction/replacement of animal tests. To overcome these challenges, physiologically relevant organ-on-chip
assays have been developed. These assays mimic the dynamic interactions encountered during drug delivery
and recapitulates physiological flow rates, vascular architecture and the 3D nature of tissue (liver, lung, kidney,
etc.), thereby providing improved quantitative and predictive capabilities to guide the development of drugs via
accurate toxicity analysis. However, one of the critical components lacking from current organ-on-chip assays is
the real-time analysis of drug concentration at specified locations within the assay to determine drug toxicity at
defined tissue sites.
To address this need, we propose to integrate our microfluidics-based, organ-on-chip systems with on-chip mass
spectrometry analysis to measure drug concentrations across a vascularized liver construct. The Phase I effort
will focus on integration the microfluidic device with a novel mass spectrometry (MS) assay. This method enables
online temporal and spatial chemical characterization of chemical constituents within microfluidic devices by MS
for the first time. The ChemSitu approach enables the means to continuously sample and chemically characterize
small volumes of liquid directly from a microfluidic device at any point along the construct in near real-time and
without negatively altering the state of the microfluidic system. A multi-disciplinary team of scientists and
engineers with expertise in microfluidics-based cell assays and instrumentation development has been
assembled for successful completion of this project. By providing an accurate, quantitative and predictive model
of and quantitation of physiological interactions, the developed platform promises to establish a new paradigm
for in vitro assessment of the physiological response to therapeutics.
