Nanoprobes of Cell Potential: Direct electrical measurements of cell potentials usually face design compromises. Microelectrodes probe within the cytosol of cells but have a minimum size (hundreds of nanometers in width) for obtaining useful signals. Nanoscale field effect transistors (FETs) can have an active probe size of only tens of nanometers but generally allow only the outer cell potential to be measured. Tian et al. (p. 830 ) fabricated nanowires in which kinks could be introduced to create a sharp probe tip pointing away from the fabrication substrate. Coating the tip with a phospholipid bilayer allowed the probe to be inserted through the membranes of beating cardiac cells, where it could be used to follow temporal changes in cell potential.

The ability to make electrical measurements inside cells has led to many important advances in electrophysiology^1,2,3,4,5,6. The patch clamp technique, in which a glass micropipette filled with electrolyte is inserted into a cell, offers both high signal-to-noise ratio and temporal resolution^1,2. Ideally, the micropipette should be as small as possible to increase the spatial resolution and reduce the invasiveness of the measurement, but the overall performance of the technique depends on the impedance of the interface between the micropipette and the cell interior^1,2, which limits how small the micropipette can be. Techniques that involve inserting metal or carbon microelectrodes into cells are subject to similar constraints^4,7,8,9. Field-effect transistors (FETs) can also record electric potentials inside cells¹⁰, and because their performance does not depend on impedance^11,12, they can be made much smaller than micropipettes and microelectrodes. Moreover, FET arrays are better suited for multiplexed measurements. Previously, we have demonstrated FET-based intracellular recording with kinked nanowire structures¹⁰, but the kink configuration and device design places limits on the probe size and the potential for multiplexing. Here, we report a new approach in which a SiO₂ nanotube is synthetically integrated on top of a nanoscale FET. This nanotube penetrates the cell membrane, bringing the cell cytosol into contact with the FET, which is then able to record the intracellular transmembrane potential. Simulations show that the bandwidth of this branched intracellular nanotube FET (BIT-FET) is high enough for it to record fast action potentials even when the nanotube diameter is decreased to 3 nm, a length scale well below that accessible with other methods^1,2,4. Studies of cardiomyocyte cells demonstrate that when phospholipid-modified BIT-FETs are brought close to cells, the nanotubes can spontaneously penetrate the cell membrane to allow the full-amplitude intracellular action potential to be recorded, thus showing that a stable and tight seal forms between the nanotube and cell membrane. We also show that multiple BIT-FETs can record multiplexed intracellular signals from both single cells and networks of cells.

Nanopores could potentially be used to perform single-molecule DNA sequencing at low cost and with high throughput^1,2,3,4. Although single base resolution and differentiation have been demonstrated with nanopores using ionic current measurements^5,6,7, direct sequencing has not been achieved because of the difficulties in recording very small (∼pA) ionic currents at a bandwidth consistent with fast translocation speeds^1,2,3. Here, we show that solid-state nanopores can be combined with silicon nanowire field-effect transistors to create sensors in which detection is localized and self-aligned at the nanopore. Well-defined field-effect transistor signals associated with DNA translocation are recorded when an ionic strength gradient is imposed across the nanopores. Measurements and modelling show that field-effect transistor signals are generated by highly localized changes in the electrical potential during DNA translocation, and that nanowire–nanopore sensors could enable large-scale integration with a high intrinsic bandwidth.