Developing electrophysiological platforms to capture electrical activities of neurons and exert modulatory stimuli lays the foundation for many neuroscience-related disciplines, including the neuron-machine interface, neuroprosthesis, and mapping of brain circuitry. Intrinsically more advantageous than genetic and chemical neuronal probes, electrical interfaces directly target the fundamental driving force-transmembrane currents-behind the complicated and diverse neuronal signals, allowing for the discovery of neural computational mechanisms of the most accurate extent. Furthermore, establishing electrical access to neurons is so far the most promising solution to integrate large-scale, high-speed modern electronics with neurons that are highly dynamic and adaptive. Over the evolution of electrode-based electrophysiologies, there has long been a trade-off in terms of precision, invasiveness, and parallel access due to limitations in fabrication techniques and insufficient understanding of membrane-electrode interactions. On the one hand, intracellular platforms based on patch clamps and sharp electrodes suffer from acute cellular damage, fluid diffusion, and labor-intensive micromanipulation, with little room for parallel recordings. On the other hand, conventional extracellular microelectrode arrays cannot detect from subcellular compartments or capture subthreshold membrane potentials because of the large electrode size and poor seal resistance, making it impossible to depict a comprehensive picture of a neuron's electrical activities. Recently, the application of nanotechnology on neuronal electrophysiology has brought about a promising solution to mitigate these conflicts on a single chip. In particular, three dimensional nanostructures of 10-100 nm in diameter are naturally fit to achieve the purpose of precise and localized interrogations. Engineering them into vertical nanoprobes bound on planar substrates resulted in excellent membrane-electrode seals and high-density electrode distribution. There is no doubt that 3D vertical nanoelectrodes have achieved a fundamental milestone in terms of high precision, low invasiveness, and parallel recording at the neuron-electrode interface, albeit with there being substantial engineering issues that remain before the potential of nano neural interfaces can be fully exploited. Within this framework, we review the qualitative breakthroughs and opportunities brought about by 3D vertical nanoelectrodes, and discuss the major limitations of current electrode designs with respect to rational and seamless cell-on-chip systems.
