Measuring direct current trans-epithelial electrical resistance in organ-on-a-chip microsystems

Abstract

Trans-epithelial electrical resistance (TEER) measurements are widely used as real-time, non-destructive, and label-free measurements of epithelial and endothelial barrier function. TEER measurements are ideal for characterizing tissue barrier function in organs-on-chip studies for drug testing and investigation of human disease models; however, published reports using this technique have reported highly conflicting results even with identical cell lines and experimental setups. The differences are even more dramatic when comparing measurements in conventional Transwell systems with those obtained in microfluidic systems. Our goal in this work was therefore to enhance the fidelity of TEER measurements in microfluidic organs-on-chips, specifically using direct current (DC) measurements of TEER, as this is the most widely used method reported in the literature. Here we present a mathematical model that accounts for differences measured in TEER between microfluidic chips and Transwell systems, which arise from differences in device geometry. The model is validated by comparing TEER measurements obtained in a microfluidic gut-on-a-chip device versus in a Transwell culture system. Moreover, we show that even small gaps in cell coverage (e.g., 0.4%) are sufficient to cause a significant (~80%) drop in TEER. Importantly, these findings demonstrate that TEER measurements obtained in microfluidic systems, such as organs-on-chips, require special consideration, specifically when results are to be compared with measurements obtained from Transwell systems.

Organs-on-chips with integrated electrodes for trans-epithelial electrical resistance (TEER) measurements of human epithelial barrier function

“…As a result, the results of TEER studies with cells cultured in Organ Chips presented to date very often suffer from large measurement variability, low sensitivity and they can be highly affected by non uniform cell cultures. Electrode location also can significantly alter TEER readouts in these cultures, although mathematical models have been proposed that can help reduce these variations [5, 17, 18]. Thus, successful fabrication of a robust on-chip TEER sensing capability would allow performing simple electrochemical measurements to reliably study barrier function.…”

Tissue chips to aid drug development and modeling for rare diseases

“…Other systems incorporate ‘reporter’ cells that have been transfected with viral vectors which fluoresce when products of apoptosis or excessive hydrogen peroxide are present 42 , giving real-time readouts on cell health or distress. The technology in this field is fast-paced, and reporting mechanisms for these systems are improving rapidly; for example, detectors embedded in the PDMS structure of the chip may in the future be able to measure trans-epithelial electric resistance (TEER) more accurately than the currently standard, yet variable, Ag/AgCl electrodes 49 .…”

Early Detection of NephrotoxicityIn VitroUsing a Transparent Conducting Polymer Device

“…This method has multiple advantages, including being highly sensitive, and allowing continuous label-free monitoring. [30][31][32][33] EIS was first demonstrated for monitoring cell attachment and spreading on electrodes in the 1980s, and is explained as changes in impedance caused by the presence of cells on or near the electrodes. [34][35][36] EIS can be used to monitor a variety of parameters, including distance from substrate, 37 cell growth, proliferation, differentiation [35][36][37][38][39][40] and even micromotion.…”