Microfluidic biochip for the perifusion of precision‐cut rat liver slices for metabolism and toxicology studies

Abstract

Early detection of kinetic, metabolic, and toxicity (ADME-Tox) profiles for new drug candidates is of crucial importance during drug development. This article describes a novel in vitro system for the incubation of precision-cut liver slices (PCLS) under flow conditions, based on a poly(dimethylsiloxane) (PDMS) device containing 25-microL microchambers for integration of the slices. The microdevice is coupled to a perifusion system, which enables a constant delivery of nutrients and oxygen and a continuous removal of waste products. Both a highly controlled incubation environment and high metabolite detection sensitivity could be achieved using microfluidics. Liver slices were viable for at least 24 h in the microdevice. The compound, 7-ethoxycoumarin (7-EC), was chosen to test metabolism, since its metabolism includes both phase I and phase II metabolism and when tested in the conventional well plate system, correlates well with the in vivo situation (De Kanter et al. 2004. Xenobiotica 34(3): 229-241.). The metabolic rate of 7-EC was found to be 214 +/- 5 pmol/min/mg protein in the microdevice, comparable to well plates, and was constant over time for at least 3 h. This perifusion system better mimics the in vivo situation, and has the potential to significantly contribute to drug metabolism and toxicology studies of novel chemical entities.

Polymer-Based Microfluidic Devices for Pharmacy, Biology and Tissue Engineering

“…To overcome this adsorption problem, a number of PDMS surface treatments have been developed. Due to the porous structure of PDMS, coatings with a hydrophilic compound can be performed [383,385]. However, the coatings might influence cell responses [386].…”

Chip-based liver equivalents for toxicity testing – organotypicalness versus cost-efficient high throughput

“…The precision cut liver slice (100 mm thick, 4 mm diameter) was perfused by a 10 ml min 21 media flow in an incubator chamber with constant pH and dissolved oxygen. 71 In a human setting, the tissue used here would correspond to approximately two liver lobules (around 2 6 10 5 liver cells). Biotransformation activity was shown to be equal in control slices in static culture over three hours.…”

Application of Precision-Cut Rat Liver Slice to Study the Influence of Monocrotaline, <i>Tussilago farfara</i> Alkaloids on the Expression of Cytochrome P450 Enzymes

“…Since precision-cut liver slice was reported in the early 1980s [6], it has became more and more mature and perfect along with the improvement of culture method [1] [7] [8]. Precision-cut liver slice has been successfully used in the study of drug toxicity mechanism and prediction, the discovery of early toxicity markers and drug metabolism and transformation.…”