New tools for intracellular electrophysiology that push the limits of spatiotemporal resolution while reducing invasiveness could provide a deeper understanding of electrogenic cells and their networks in tissues, and push progress towards human–machine interfaces. Although significant advances have been made in developing nanodevices for intracellular probes, current approaches exhibit a trade-off between device scalability and recording amplitude. We address this challenge by combining deterministic shape-controlled nanowire transfer with spatially defined semiconductor-to-metal transformation to realize scalable nanowire field-effect transistor probe arrays with controllable tip geometry and sensor size, which enable recording of up to 100 mV intracellular action potentials from primary neurons. Systematic studies on neurons and cardiomyocytes show that controlling device curvature and sensor size is critical for achieving high-amplitude intracellular recordings. In addition, this device design allows for multiplexed recording from single cells and cell networks and could enable future investigations of dynamics in the brain and other tissues.
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The data that support the findings of this study are available from the corresponding author upon reasonable request.
The authors declare no competing interests.
Journal peer review information: Nature Nanotechnology thanks Bozhi Tian, Bruce Wheeler and other anonymous reviewer(s) for their contribution to the peer review of this work.
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Chen, R., Canales, A. & Anikeeva, P. Neural recording and modulation technologies. Nat. Rev. Mater. 2, 16093 (2017).
Spira, M. E. & Hai, A. Multi-electrode array technologies for neuroscience and cardiology. Nat. Nanotechnol. 8, 83–94 (2013).
Kruskal, P. B., Jiang, Z., Gao, T. & Lieber, C. M. Beyond the patch clamp: nanotechnologies for intracellular recording. Neuron 86, 21–24 (2015).
Savtchenko, L. P., Poo, M. M. & Rusakov, D. A. Electrodiffusion phenomena in neuroscience: a neglected companion. Nat. Rev. Neurosci. 18, 598 (2017).
Hamill, O. P., Marty, A., Neher, E., Sakmann, B. & Sigworth, F. J. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 391, 85–100 (1981).
Martina, M. & Taverna, S. Patch-clamp Methods and Protocols, 2nd edn (Humana Press, 2014).
Jiang, Y. W. et al. Rational design of silicon structures for optically controlled multiscale biointerfaces. Nat. Biomed. Eng. 2, 508–521 (2018).
Parameswaran, R. et al. Photoelectrochemical modulation of neuronal activity with free-standing coaxial silicon nanowires. Nat. Nanotechnol. 13, 260–266 (2018).
Abbott, J., Ye, T. Y., Ham, D. & Park, H. Optimizing nanoelectrode arrays for scalable intracellular electrophysiology. Acc. Chem. Res. 51, 600–608 (2018).
McGuire, A. F., Santoro, F. & Cui, B. X. Interfacing cells with vertical nanoscale devices: applications and characterization. Annu. Rev. Anal. Chem. 11, 101–126 (2018).
Spira, M. E., Shmoel, N., Huang, S. H. M. & Erez, H. Multisite attenuated intracellular recordings by extracellular multielectrode arrays, a perspective. Front. Neurosci. 12, 212 (2018).
Abbott, J. et al. CMOS nanoelectrode array for all-electrical intracellular electrophysiological imaging. Nat. Nanotechnol. 12, 460–466 (2017).
Dipalo, M. et al. Intracellular and extracellular recording of spontaneous action potentials in mammalian neurons and cardiac cells with 3D plasmonic nanoelectrodes. Nano Lett. 17, 3932–3939 (2017).
Dipalo, M. et al. Plasmonic meta-electrodes allow intracellular recordings at network level on high-density CMOS-multi-electrode arrays. Nat. Nanotechnol. 13, 965–972 (2018).
Tian, B. Z. et al. Three-dimensional, flexible nanoscale field-effect transistors as localized bioprobes. Science 329, 830–834 (2010).
Qing, Q. et al. Free-standing kinked nanowire transistor probes for targeted intracellular recording in three dimensions. Nat. Nanotechnol. 9, 142–147 (2014).
Lou, H. Y., Zhao, W. T., Zeng, Y. P. & Cui, B. X. The role of membrane curvature in nanoscale topography-induced intracellular signaling. Acc. Chem. Res. 51, 1046–1053 (2018).
Zhao, W. T. et al. Nanoscale manipulation of membrane curvature for probing endocytosis in live cells. Nat. Nanotechnol. 12, 750–756 (2017).
Iversen, L., Mathiasen, S., Larsen, J. B. & Stamou, D. Membrane curvature bends the laws of physics and chemistry. Nat. Chem. Biol. 11, 822–825 (2015).
Kaksonen, M. & Roux, A. Mechanisms of clathrin-mediated endocytosis. Nat. Rev. Mol. Cell Biol. 19, 313–326 (2018).
Zhao, Y. et al. Shape-controlled deterministic assembly of nanowires. Nano Lett. 16, 2644–2650 (2016).
Wu, Y., Xiang, J., Yang, C., Lu, W. & Lieber, C. M. Single-crystal metallic nanowires and metal/semiconductor nanowire heterostructures. Nature 430, 61–65 (2004).
Study, R. E. & Kral, M. G. Spontaneous action potential activity in isolated dorsal root ganglion neurons from rats with a painful neuropathy. Pain 65, 235–242 (1996).
Delmas, P., Hao, J. & Rodat-Despoix, L. Molecular mechanisms of mechanotransduction in mammalian sensory neurons. Nat. Rev. Neurosci. 12, 139–153 (2011).
Aalipour, A., Xu, A. M., Leal-Ortiz, S., Garner, C. C. & Melosh, N. A. Plasma membrane and actin cytoskeleton as synergistic barriers to nanowire cell penetration. Langmuir 30, 12362–12367 (2014).
Cossell, L. et al. Functional organization of excitatory synaptic strength in primary visual cortex. Nature 518, 399–403 (2015).
Burridge, P. W. et al. Chemically defined generation of human cardiomyocytes. Nat. Methods 11, 855–860 (2014).
Sanders, K. M., Ward, S. M. & Hennig, G. W. Problems with extracellular recording of electrical activity in gastrointestinal muscle. Nat. Rev. Gastroenterol. Hepatol. 13, 731–741 (2016).
Dipalo, M. et al. Cells adhering to 3D vertical nanostructures: cell membrane reshaping without stable internalization. Nano Lett. 18, 6100–6105 (2018).
Dietschy, J. M. & Turley, S. D. Thematic review series: brain lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J. Lipid Res. 45, 1375–1397 (2004).
Zhu, H. Q. et al. Two dimensional electrophysiological characterization of human pluripotent stem cell-derived cardiomyocyte system. Sci. Rep. 7, 43210 (2017).
Woodcock, E. A. & Matkovich, S. J. Cardiomyocytes structure, function and associated pathologies. Int. J. Biochem. Cell Biol. 37, 1746–1751 (2005).
Gold, C., Henze, D. A., Koch, C. & Buzsáki, G. On the origin of the extracellular action potential waveform: a modeling study. J. Neurophysiol. 95, 3113–3128 (2006).
Luo, Z. et al. Atomic gold—enabled three-dimensional lithography for silicon mesostructures. Science 348, 1451–1455 (2015).
Lee, J. H., Zhang, A. Q., You, S. S. & Lieber, C. M. Spontaneous internalization of cell penetrating peptide-modified nanowires into primary neurons. Nano Lett. 16, 1509–1513 (2016).
Fu, T. M. et al. Stable long-term chronic brain mapping at the single-neuron level. Nat. Methods 13, 875–882 (2016).
Hong, G. S. et al. A method for single-neuron chronic recording from the retina in awake mice. Science 360, 1447–1451 (2018).
Patolsky, F., Zheng, G. & Lieber, C. M. Fabrication of silicon nanowire devices for ultrasensitive, label-free, real-time detection of biological and chemical species. Nat. Protoc. 1, 1711–1724 (2006).
Kittel, C. Introduction to Solid State Physics 8th edn (Wiley, 2005).
Minteer, S. D. Microfluidic Techniques: Reviews and Protocols (Humana Press, 2006).
Cardiomyocytes User Manual (NCardia, 2018); https://ncardia.com/files/documents/manuals/PluricyteCardiomyocyte_Manual_v2.pdf.
Shmoel, N. et al. Multisite electrophysiological recordings by self-assembled loose-patch-like junctions between cultured hippocampal neurons and mushroom-shaped microelectrodes. Sci. Rep. 6, 27110 (2016).
Xie, C., Lin, Z., Hanson, L., Cui, Y. & Cui, B. Intracellular recording of action potentials by nanopillar electroporation. Nat. Nanotechnol. 7, 185–190 (2012).
C.M.L. acknowledges support from the Air Force Office of Scientific Research (FA9550-14-1-0136). S.S.Y. acknowledges an NSF Graduate Research Fellowship. This work was performed in part at the Center for Nanoscale Systems (CNS) of Harvard University.
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Nature Nanotechnology (2019)