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CMOS nanoelectrode array for all-electrical intracellular electrophysiological imaging

Abstract

Developing a new tool capable of high-precision electrophysiological recording of a large network of electrogenic cells has long been an outstanding challenge in neurobiology and cardiology. Here, we combine nanoscale intracellular electrodes with complementary metal-oxide–semiconductor (CMOS) integrated circuits to realize a high-fidelity all-electrical electrophysiological imager for parallel intracellular recording at the network level. Our CMOS nanoelectrode array has 1,024 recording/stimulation ‘pixels’ equipped with vertical nanoelectrodes, and can simultaneously record intracellular membrane potentials from hundreds of connected in vitro neonatal rat ventricular cardiomyocytes. We demonstrate that this network-level intracellular recording capability can be used to examine the effect of pharmaceuticals on the delicate dynamics of a cardiomyocyte network, thus opening up new opportunities in tissue-based pharmacological screening for cardiac and neuronal diseases as well as fundamental studies of electrogenic cells and their networks.

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Figure 1: CMOS nanoelectrode array (CNEA).
Figure 2: CNEA pixel function and recording of a single rat neonatal ventricular cardiomyocyte.
Figure 3: Network-level intracellular recording of in vitro neonatal rat ventricular cardiomyocyte cultures.
Figure 4: CNEA study of effects of various drugs on in vitro neonatal rat ventricular cardiomyocyte cultures.

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Acknowledgements

The authors thank J. MacArthur, G. Zhong, D. Ha, B. Tinner and B. VanderElzen for scientific discussions and technical assistance. The CNEA post-fabrication and characterization were performed, in part, at the Center for Nanoscale Systems at Harvard University. The authors are grateful for the support of this research by Catalyst foundation, Valhalla, New York (J.A., D.H. and H.P.), the Army Research Office (W911NF-15-1-0565 to D.H.), the National Institutes of Health (1-U01-MH105960-01 to H.P.), the Gordon and Betty Moore Foundation (to H.P.), and the US Army Research Laboratory and the US Army Research Office (W911NF1510548 to H.P.).

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H.P., D.H., J.A., T.Y., L.Q. and M.J. conceived and designed the experiments. J.A. and L.Q. designed the CMOS IC, and T.Y. and M.J performed post-fabrication of nanoelectrodes. J.A., T.Y., M.J. and R.S.G. performed the experiments, and J.A., T.Y., D.H. and H.P. analysed the data. H.P. and D.H. supervised the project. J.A., T.Y., D.H. and H.P. wrote the manuscript, and all authors read and discussed it.

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Correspondence to Donhee Ham or Hongkun Park.

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The authors declare no competing financial interests.

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Abbott, J., Ye, T., Qin, L. et al. CMOS nanoelectrode array for all-electrical intracellular electrophysiological imaging. Nature Nanotech 12, 460–466 (2017). https://doi.org/10.1038/nnano.2017.3

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