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Scalable ultrasmall three-dimensional nanowire transistor probes for intracellular recording

Abstract

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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Fig. 1: Ultrasmall U-NWFET probe as a new approach for electrophysiology.
Fig. 2: Fabrication and characterization of U-NWFET probes.
Fig. 3: Intracellular recording of DRG neurons by the ultrasmall U-NWFET probe.
Fig. 4: Effect of size and geometry of U-NWFET probes on electrophysiological recordings.
Fig. 5: Multiplexed electrophysiological recording by U-NWFET probes.

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The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Chen, R., Canales, A. & Anikeeva, P. Neural recording and modulation technologies. Nat. Rev. Mater. 2, 16093 (2017).

    Article  CAS  Google Scholar 

  2. Spira, M. E. & Hai, A. Multi-electrode array technologies for neuroscience and cardiology. Nat. Nanotechnol. 8, 83–94 (2013).

    Article  CAS  Google Scholar 

  3. Kruskal, P. B., Jiang, Z., Gao, T. & Lieber, C. M. Beyond the patch clamp: nanotechnologies for intracellular recording. Neuron 86, 21–24 (2015).

    Article  CAS  Google Scholar 

  4. Savtchenko, L. P., Poo, M. M. & Rusakov, D. A. Electrodiffusion phenomena in neuroscience: a neglected companion. Nat. Rev. Neurosci. 18, 598 (2017).

    Article  CAS  Google Scholar 

  5. 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).

    Article  CAS  Google Scholar 

  6. Martina, M. & Taverna, S. Patch-clamp Methods and Protocols, 2nd edn (Humana Press, 2014).

  7. Jiang, Y. W. et al. Rational design of silicon structures for optically controlled multiscale biointerfaces. Nat. Biomed. Eng. 2, 508–521 (2018).

    Article  CAS  Google Scholar 

  8. Parameswaran, R. et al. Photoelectrochemical modulation of neuronal activity with free-standing coaxial silicon nanowires. Nat. Nanotechnol. 13, 260–266 (2018).

    Article  CAS  Google Scholar 

  9. Abbott, J., Ye, T. Y., Ham, D. & Park, H. Optimizing nanoelectrode arrays for scalable intracellular electrophysiology. Acc. Chem. Res. 51, 600–608 (2018).

    Article  CAS  Google Scholar 

  10. 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).

    Article  Google Scholar 

  11. 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).

    Article  Google Scholar 

  12. Abbott, J. et al. CMOS nanoelectrode array for all-electrical intracellular electrophysiological imaging. Nat. Nanotechnol. 12, 460–466 (2017).

    Article  CAS  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

  14. 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).

    Article  CAS  Google Scholar 

  15. Tian, B. Z. et al. Three-dimensional, flexible nanoscale field-effect transistors as localized bioprobes. Science 329, 830–834 (2010).

    Article  CAS  Google Scholar 

  16. Qing, Q. et al. Free-standing kinked nanowire transistor probes for targeted intracellular recording in three dimensions. Nat. Nanotechnol. 9, 142–147 (2014).

    Article  CAS  Google Scholar 

  17. 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).

    Article  CAS  Google Scholar 

  18. Zhao, W. T. et al. Nanoscale manipulation of membrane curvature for probing endocytosis in live cells. Nat. Nanotechnol. 12, 750–756 (2017).

    Article  CAS  Google Scholar 

  19. 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).

    Article  CAS  Google Scholar 

  20. Kaksonen, M. & Roux, A. Mechanisms of clathrin-mediated endocytosis. Nat. Rev. Mol. Cell Biol. 19, 313–326 (2018).

    Article  CAS  Google Scholar 

  21. Zhao, Y. et al. Shape-controlled deterministic assembly of nanowires. Nano Lett. 16, 2644–2650 (2016).

    Article  CAS  Google Scholar 

  22. 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).

    Article  CAS  Google Scholar 

  23. 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).

    Article  CAS  Google Scholar 

  24. Delmas, P., Hao, J. & Rodat-Despoix, L. Molecular mechanisms of mechanotransduction in mammalian sensory neurons. Nat. Rev. Neurosci. 12, 139–153 (2011).

    Article  CAS  Google Scholar 

  25. 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).

    Article  CAS  Google Scholar 

  26. Cossell, L. et al. Functional organization of excitatory synaptic strength in primary visual cortex. Nature 518, 399–403 (2015).

    Article  CAS  Google Scholar 

  27. Burridge, P. W. et al. Chemically defined generation of human cardiomyocytes. Nat. Methods 11, 855–860 (2014).

    Article  CAS  Google Scholar 

  28. 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).

    Article  CAS  Google Scholar 

  29. Dipalo, M. et al. Cells adhering to 3D vertical nanostructures: cell membrane reshaping without stable internalization. Nano Lett. 18, 6100–6105 (2018).

    Article  CAS  Google Scholar 

  30. 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).

    Article  CAS  Google Scholar 

  31. Zhu, H. Q. et al. Two dimensional electrophysiological characterization of human pluripotent stem cell-derived cardiomyocyte system. Sci. Rep. 7, 43210 (2017).

    Article  Google Scholar 

  32. Woodcock, E. A. & Matkovich, S. J. Cardiomyocytes structure, function and associated pathologies. Int. J. Biochem. Cell Biol. 37, 1746–1751 (2005).

    Article  CAS  Google Scholar 

  33. 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).

    Article  CAS  Google Scholar 

  34. Luo, Z. et al. Atomic gold—enabled three-dimensional lithography for silicon mesostructures. Science 348, 1451–1455 (2015).

    Article  CAS  Google Scholar 

  35. 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).

    Article  CAS  Google Scholar 

  36. Fu, T. M. et al. Stable long-term chronic brain mapping at the single-neuron level. Nat. Methods 13, 875–882 (2016).

    Article  CAS  Google Scholar 

  37. Hong, G. S. et al. A method for single-neuron chronic recording from the retina in awake mice. Science 360, 1447–1451 (2018).

    Article  CAS  Google Scholar 

  38. 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).

    Article  CAS  Google Scholar 

  39. Kittel, C. Introduction to Solid State Physics 8th edn (Wiley, 2005).

  40. Minteer, S. D. Microfluidic Techniques: Reviews and Protocols (Humana Press, 2006).

  41. Cardiomyocytes User Manual (NCardia, 2018); https://ncardia.com/files/documents/manuals/PluricyteCardiomyocyte_Manual_v2.pdf.

  42. 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).

    Article  CAS  Google Scholar 

  43. Xie, C., Lin, Z., Hanson, L., Cui, Y. & Cui, B. Intracellular recording of action potentials by nanopillar electroporation. Nat. Nanotechnol. 7, 185–190 (2012).

    Article  CAS  Google Scholar 

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Acknowledgements

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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Authors and Affiliations

Authors

Contributions

Y.Z., S.S.Y. and C.M.L. conceived and designed the experiments. Y.Z., S.S.Y. and A.Z. performed the experiments and analysed the data. Y.Z., S.S.Y., A.Z. and C.M.L. co-wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Charles M. Lieber.

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The authors declare no competing interests.

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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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Zhao, Y., You, S.S., Zhang, A. et al. Scalable ultrasmall three-dimensional nanowire transistor probes for intracellular recording. Nat. Nanotechnol. 14, 783–790 (2019). https://doi.org/10.1038/s41565-019-0478-y

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