Multi-parametric functional imaging of cell cultures and tissues with a CMOS microelectrode array

• Published in: Lab on a chip Vol. 22; no. 7; pp. 1286 - 1296
• Main Authors: Abbott, Jeffrey, Mukherjee, Avik, Wu, Wenxuan, Ye, Tianyang, Jung, Han Sae, Cheung, Kevin M, Gertner, Rona S, Basan, Markus, Ham, Donhee, Park, Hongkun
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 29.03.2022; The Royal Society of Chemistry
• Subjects: Arrays; Biology; Cell adhesion; Cell Culture Techniques; Chemistry; CMOS; Electrodes; Electrophysiological Phenomena; Electrophysiology; Impedance; Mapping; Metabolism; Microelectrodes; Oxides; Population statistics; Semiconductors; Spatial resolution; Temporal resolution; Wound healing
• ISSN: 1473-0197; 1473-0189; 1473-0189
• DOI: 10.1039/d1lc00878a

Electrode-based impedance and electrochemical measurements can provide cell-biology information that is difficult to obtain using optical-microscopy techniques. Such electrical methods are non-invasive, label-free, and continuous, eliminating the need for fluorescence reporters and overcoming optical imaging's throughput/temporal resolution limitations. Nonetheless, electrode-based techniques have not been heavily employed because devices typically contain few electrodes per well, resulting in noisy aggregate readouts. Complementary metal-oxide-semiconductor (CMOS) microelectrode arrays (MEAs) have sometimes been used for electrophysiological measurements with thousands of electrodes per well at sub-cellular pitches, but only basic impedance mappings of cell attachment have been performed outside of electrophysiology. Here, we report on new field-based impedance mapping and electrochemical mapping/patterning techniques to expand CMOS-MEA cell-biology applications. The methods enable accurate measurement of cell attachment, growth/wound healing, cell-cell adhesion, metabolic state, and redox properties with single-cell spatial resolution (20 μm electrode pitch). These measurements allow the quantification of adhesion and metabolic differences of cells expressing oncogenes versus wild-type controls. The multi-parametric, cell-population statistics captured by the chip-scale integrated device opens up new avenues for fully electronic high-throughput live-cell assays for phenotypic screening and drug discovery applications. A CMOS-MEA device combined with new impedance and electrochemical techniques measures cell attachment, growth/wound healing, cell-cell adhesion, metabolic state, and redox properties with single-cell spatial resolution for cell-biology applications.