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Accurate and low-cost analysis of biomolecules is important for many applications. This work seeks to further improve the measurement bandwidths achievable with solid-state nanopores, which have emerged as an important platform for this analysis. We report single-stranded DNA translocation recordings at a bandwidth of 10 MHz copolymers of 80 (C(20)A(20)C(20)A(20)), 90 (C(30)A(30)C(30)), and 200 (C(50)A(50)C(50)A(50)) nucleotides through Si nanopores with effective diameters of 1.4–2.1 nm and effective membrane thickness 0.5 – 8.9 nm. By optimizing glass chips with thin nanopores and by integrating them with custom-designed amplifiers based on complementary metal-oxide-semiconductor (CMOS) technology, this work demonstrates detection of translocation events as brief as 100 ns with a signal-to-noise ratio exceeding seven at a measurement bandwidth of 10 MHz. We also report data robustness and variability across 13 pores of similar size and thickness yielding a current blockade between 30 and 60 % with a mean ionic current blockade (ΔI) of ~ 3 to 9 nA and a characteristic dwell time of ~ 2 to 21 ns per nucleotide. These measurements show that characteristic translocation rates are at least ten times faster than previously recorded. We detect transient intra-event fluctuations, multiple current levels within translocation events, and variability of DNA-translocation-event signatures and durations.

Recent work has pushed the noise-limited bandwidths of solid-state nanopore conductance recordings to more than 5 MHz and of ion channel conductance recordings to more than 500 kHz through the use of integrated complementary metal-oxide-semiconductor (CMOS) integrated circuits. Despite the spectral spread of the pulse-like signals that characterize these recordings when a sinusoidal basis is employed, Bessel filters are commonly used to denoise these signals to acceptable signal-to-noise ratios (SNRs) at the cost of losing many of the faster temporal features. Here, we report improvements to the SNR that can be achieved using wavelet denoising instead of Bessel filtering. When combined with state-of-the-art high-bandwidth CMOS recording instrumentation, we can reduce baseline noise levels by over a factor of four compared to a 2.5-MHz Bessel filter while retaining transient properties in the signal comparable to this filter bandwidth. Similarly, for ion channel recordings, we achieve a temporal response better than a 100-kHz Bessel filter with a noise level comparable to that achievable with a 25-kHz Bessel filter. Improvements in SNR can be used to achieve robust statistical analyses of these recordings, which may provide important insights into nanopore translocation dynamics and mechanisms of ion channel function.

Intracellular electrophysiology is a foundational method in neuroscience and uses electrolyte-filled glass electrodes and benchtop amplifiers to measure and control transmembrane voltages and currents. Commercial amplifiers perform such recordings with high signal-to-noise ratios (SNRs) but are often expensive, bulky, and not easily scalable to many channels due to reliance on board-level integration of discrete components. Here, we present a monolithic complementary-metal-oxide-semiconductor (CMOS) multi-clamp amplifier integrated circuit capable of recording both voltages and currents with performance exceeding that of commercial benchtop instrumentation. Miniaturization enables high-bandwidth current mirroring, facilitating the synthesis of large-valued active resistors with lower noise than their passive equivalents. This enables the realization of compensation modules that can account for a wide range of electrode impedances. We validate the amplifier's operation electrically, in primary neuronal cultures, and in acute slices, using both high-impedance sharp and patch electrodes. This work provides a solution for low-cost, high-performance and scalable multi-clamp amplifiers.

In this letter, we present a CMOS-integrated low noise junction field-effect transistor (JFET) developed in a standard 0.18 $\mu \text{m}$ CMOS process. These JFETs reduce input referred flicker noise power by more than a factor of 10 when compared with equally sized n-channel MOS devices by eliminating oxide interfaces in contact with the channel. We show that this improvement in device performance translates into a factor-of-10 reduction in the input-referred noise of integrated CMOS operational amplifiers when JFET devices are used at the input, significant for many applications in bioelectronics.

Transport processes through ion-channel proteins, protein pores, or solid-state nanopores are traditionally recorded with commercial patch-clamp amplifiers. The bandwidth of these systems is typically limited to 10 kHz by signal-to-noise-ratio (SNR) considerations associated with these measurement platforms. At high bandwidth, the input-referred current noise in these systems dominates, determined by the input-referred voltage noise of the transimpedance amplifier applied across the capacitance at the input of the amplifier. This capacitance arises from several sources: the parasitic capacitance of the amplifier itself; the capacitance of the lipid bilayer harboring the ion channel protein (or the membrane used to form the solid-state nanopore); and the capacitance from the interconnections between the electronics and the membrane. Here, we review state-of-the-art applications of high-bandwidth conductance recordings of both ion channels and solid-state nanopores. These approaches involve tightly integrating measurement electronics fabricated in complementary metal-oxide semiconductors (CMOS) technology with lipid bilayer or solid-state membranes. SNR improvements associated with this tight integration push the limits of measurement bandwidths, in some cases in excess of 10 MHz. Recent case studies demonstrate the utility of these approaches for DNA sequencing and ion-channel recordings. In the latter case, studies with extended bandwidth have shown the potential for providing new insights into structure-function relations of these ion-channel proteins as the temporal resolutions of functional recordings matches time scales achievable with state-of-the-art molecular dynamics simulations.

Despite the potential for nanopores to be a platform for high-bandwidth study of single-molecule systems, ionic current measurements through nanopores have been limited in their temporal resolution by noise arising from poorly optimized measurement electronics and large parasitic capacitances in the nanopore membranes. Here, we present a complementary metal-oxide-semiconductor (CMOS) nanopore (CNP) amplifier capable of low noise recordings at an unprecedented 10 MHz bandwidth. When integrated with state-of-the-art solid-state nanopores in silicon nitride membranes, we achieve an SNR of greater than 10 for ssDNA translocations at a measurement bandwidth of 5 MHz, which represents the fastest ion current recordings through nanopores reported to date. We observe transient features in ssDNA translocation events that are as short as 200 ns, which are hidden even at bandwidths as high as 1 MHz. These features offer further insights into the translocation kinetics of molecules entering and exiting the pore. This platform highlights the advantages of high-bandwidth translocation measurements made possible by integrating nanopores and custom-designed electronics.

Single-channel recordings are widely used to explore functional properties of ion channels. Typically, such recordings are performed at bandwidths of less than 10 kHz because of signal-to-noise considerations, limiting the temporal resolution available for studying fast gating dynamics to greater than 100 µs. Here we present experimental methods that directly integrate suspended lipid bilayers with high-bandwidth, low-noise transimpedance amplifiers based on complementary metal-oxide-semiconductor (CMOS) integrated circuits (IC) technology to achieve bandwidths in excess of 500 kHz and microsecond temporal resolution. We use this CMOS-integrated bilayer system to study the type 1 ryanodine receptor (RyR1), a Ca2+-activated intracellular Ca2+-release channel located on the sarcoplasmic reticulum. We are able to distinguish multiple closed states not evident with lower bandwidth recordings, suggesting the presence of an additional Ca2+ binding site, distinct from the site responsible for activation. An extended beta distribution analysis of our high-bandwidth data can be used to infer closed state flicker events as fast as 35 ns. These events are in the range of single-file ion translocations.

Solid-state nanopores are being pursued for a number of applications including, most notably, DNA sequencing. One of the challenges that nanopores present is the fast rate at which molecules translocate. Significant improvements in the measurement bandwidth can be obtained through the optimization of detection electronics and reduction in nanopore membrane capacitance. We present a low-noise, custom-designed complementary metal-oxide-semiconductor (CMOS) amplifier chip capable of recording translocation dynamics in nanopores at bandwidths up to 10 MHz. We integrate state-of-the-art silicon nitride nanopores with this amplifier to achieve signal to noise ratios (SNRs) of better than 10 at 5 MHz bandwidth in ssDNA translocation experiments. We observe transient features with durations as short as 200 ns in some translocation events, features that would have been hidden at lower recording bandwidths. We also use our platform to record ssDNA translocation through glass-passivated silicon-nitride nanopores with membrane capacitances of less than 1 pF, further extending the achievable recording bandwidth. At these speeds, the potential exists to realize free-running DNA sequencing using solid-state nanopores.

Conventional electronics typically limit the available temporal resolution for single ion-channel measurements, making fast channel gating events (