Toxicokinetics for organ-on-chip devices

Abstract

Organ-on-chip (OOC) devices are an emerging New Approach Method in both pharmacology and toxicology. Such devices use heterotypic combinations of human cells in a micro-fabricated device to mimic in vivo conditions and better predict organ-specific toxicological responses in humans. One drawback of these devices is that they are typically made from polydimethylsiloxane (PDMS), a polymer known to interact with hydrophobic chemicals. Due to this interaction, the actual dose experienced by cells inside OOC devices can differ strongly from the nominal dose. To account for these effects, we have developed a comprehensive toxicokinetic approach to measure and model chemical-PDMS interactions, including partitioning into and diffusion through PDMS. We use these methods to characterize PDMS interactions for ten chemicals, ranging from fluorescent dyes to persistent organic pollutants to organophosphate pesticides. We further show that these methods return physical interaction parameters that can be used to accurately predict time-dependent doses under continuous-flow conditions, as would be present in an OOC device. These results demonstrate the validity of the methods and model across geometries and flow rates.