Advantages, considerations and challenges in using Electrochemical Impedance Spectroscopy to monitor tissue integrity...

Over the past few decades, the scientific community has become increasingly aware of the limitations of extrapolating animal models to humans. Consequently, microphysiological systems (MPS), such as spheroids, organoids, and organ-on-chip (OOC) technologies, have been suggested as pertinent alternatives. By combining cell biology, microfluidics, tissue engineering and materials science, these technologies reconstruct the 3D properties of biological cells and tissues in-vitro to provide physiological relevant models for drug screening, disease modelling and personalized medicine. However, transitioning MPS into straightforward tools for clinical investigations requires integrating sensors for non-invasive, continuous, and live monitoring. Electrochemical Impedance Spectroscopy (EIS) addresses this by taking advantage of the electrical properties of biological tissues that provide biophysical information associated with tissue integrity, cell viability and differentiation. This review addresses EIS in the context of MPS from a biological, an electrochemical, and an electrical point of view, with a fundamental emphasis on the selection of electrode materials and the complex electrode-electrolyte interface. We provide an in-depth evaluation of how electrode material properties impact the sensitivity of the interrogation system and discuss technical approaches to tackle these challenges. Furthermore, we challenge the incoherent use of the generic term "TEER" within the community, prompting us to introduce the distinct notions of TEER_sqrw, TEER_sine, and TEER_eqm to better account for the nature of the measurements and enable refined data analysis and comparability. By bridging these perspectives, this review aims to provide a comprehensive overview of current systems and to serve as a strategic guide for future experimental designs.