A Customizable Continuous and Near Real-time TEER Platform to Study Anti-cancer Drug Toxicity in Barrier Tissues

Abstract

Barrier tissues such as the endothelium are critical in the regulation of mass transfer throughout the body. Trans-endothelium/epithelium electrical resistance (TEER) is an important bioelectrical measurement technique to monitor barrier integrity. Although available on the market, TEER sensors are usually expensive and bulky and do not allow customization around experimental setups like specific microfluidic settings. We recently reported a customizable TEER sensor built on Arduino. In this paper, we significantly advanced a new generation of TEER sensors characterized by 1) a large dynamic range of 242 – 11,880 Ω·cm² with high accuracy (> 95%), which covers common needs for TEER studies, 2) a coupling 3D-printed microfluidic system enabling modular cell integration and flow-based barrier studies, 3) customizable on-off cycles to significantly reduce cell exposure to the current, and 4) automated continuous measurements with customizable intervals. With this sensor system, we investigated how doxorubicin could impair the endothelium layer’s permeability, at a 1-min interval for 24 h. Endothelium toxicity is a new research direction under cardiotoxicity, with many aspects unknown. We found that a clinically relevant dosage did not change the endothelium integrity significantly until approximately 16 h of treatment, after that, the TEER started to drop (showing higher permeability), followed by a slight restoration of its barrier integrity. With an excess dosage (2.5 μM), the TEER started to drop significantly after 5 h and did not show recovery afterward, indicating endothelium toxicity. Overall, we report a new TEER sensor that can monitor continuous drug toxicity on barrier tissues. The customizable features make it translational for various other studies, such as personalized dosage determination on stem cell-derived tissue barriers, and transient barrier permeability variations under diseased conditions.