Metabolomics-on-a-Chip
and Predictive Systems Toxicology in Microfluidic
Bioartificial Organs
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Abstract
The world faces complex challenges for chemical hazard
assessment.
Microfluidic bioartificial organs enable the spatial and temporal
control of cell growth and biochemistry, critical for organ-specific
metabolic functions and particularly relevant to testing the metabolic
dose–response signatures associated with both pharmaceutical
and environmental toxicity. Here we present an approach combining
a microfluidic system with <sup>1</sup>H NMR-based metabolomic footprinting,
as a high-throughput small-molecule screening approach. We characterized
the toxicity of several molecules: ammonia (NH<sub>3</sub>), an environmental
pollutant leading to metabolic acidosis and liver and kidney toxicity;
dimethylsulfoxide (DMSO), a free radical-scavenging solvent; and <i>N</i>-acetyl-para-aminophenol (APAP, or paracetamol), a hepatotoxic
analgesic drug. We report organ-specific NH<sub>3</sub> dose-dependent
metabolic responses in several microfluidic bioartificial organs (liver,
kidney, and cocultures), as well as predictive (99% accuracy for NH<sub>3</sub> and 94% for APAP) compound-specific signatures. Our integration
of microtechnology, cell culture in microfluidic biochips, and metabolic
profiling opens the development of so-called “metabolomics-on-a-chip”
assays in pharmaceutical and environmental toxicology