Jacob K. Rosenstein, Serge G. Lemay, Kenneth L. Shepard. Single-molecule bioelectronics, WIREs. 22 December 2014. DOI: 10.1002/wnan.1323
Experimental techniques that interface single biomolecules directly with microelectronic systems are increasingly being used in a wide range of powerful applications, from fundamental studies of biomolecules to ultra-sensitive assays. In this study, we review several technologies that can perform electronic measurements of single molecules in solution: ion channels, nanopore sensors, carbon nanotube field-effect transistors, electron tunneling gaps, and redox cycling. We discuss the shared features among these techniques that enable them to resolve individual molecules, and discuss their limitations. Recordings from each of these methods all rely on similar electronic instrumentation, and we discuss the relevant circuit implementations and potential for scaling these single-molecule bioelectronic interfaces to high-throughput arrayed sensing platforms.
Adrian Balan, Bartholomeus Machielse, David Niedzwiecki, Jianxun Lin, Peijie Ong, Rebecca Engelke, Kenneth L. Shepard, and Marija Drndić. Improving Signal-to-Noise Performance for DNA Translocation in Solid-State Nanopores at MHz Bandwidths, Nano Lett., 2014, 14 (12), pp 7215–7220. DOI:
DNA sequencing using solid-state nanopores is, in part, impeded by the relatively high noise and low bandwidth of the current state-of-the-art translocation measurements. In this Letter, we measure the ion current noise through sub 10 nm thick Si3N4 nanopores at bandwidths up to 1 MHz. At these bandwidths, the input-referred current noise is dominated by the amplifier’s voltage noise acting across the total capacitance at the amplifier input. By reducing the nanopore chip capacitance to the 1–5 pF range by adding thick insulating layers to the chip surface, we are able to transition to a regime in which input-referred current noise (∼117–150 pArms at 1 MHz in 1 M KCl solution) is dominated by the effects of the input capacitance of the amplifier itself. The signal-to-noise ratios (SNRs) reported here range from 15 to 20 at 1 MHz for dsDNA translocations through nanopores with diameters from 4 to 8 nm with applied voltages from 200 to 800 mV. Further advances in bandwidth and SNR will require new amplifier designs that reduce both input capacitance and input-referred amplifier noise.
Nicholas Petrone, Inanc Merici, Tarun Chari, Kenneth L. Shepard, and James Hone. Graphene Field-Effect Transistors for Radio-Frequency Flexible Electronics, Journal of the Electron Devices Society, 3:21. DOI: 10.1109/JEDS.2014.2363789
Flexible radio-frequency (RF) electronics require materials which possess both exceptional electronic properties and high-strain limits. While flexible graphene field-effect transistors (GFETs) have demonstrated significantly higher strain limits than FETs fabricated from thin films of Si and III-V semiconductors, to date RF performance has been comparatively worse, limited to the low GHz frequency range. However, flexible GFETs have only been fabricated with modestly scaled channel lengths. In this paper, we fabricate GFETs on flexible substrates with short channel lengths of 260 nm. These devices demonstrate extrinsic unity-power-gain frequencies, fmax, up to 7.6 GHz and strain limits of 2%, representing strain limits an order of magnitude higher than the flexible technology with next highest reported fmax.
Bellin, Daniel L.; Warren, Steven B.; Rosenstein, Jacob K.; Shepard, Kenneth L. Interfacing CMOS electronics to biological systems: from single molecules to cellular communities, Biomedical Circuits and Systems Conference (BioCAS), 2014 IEEE
Direct electronic interfaces between biological systems and solid-state devices offer considerable advantages over traditional optical interfaces by reducing system costs and affording increased signal levels. Integrating sensor transduction onto a complementary metal-oxide-semiconductor (CMOS) chip provides further advantages by enabling reduction of parasitics and improved sensor density. We present two sensing platforms that demonstrate the range of capabilities of CMOS-based bioelectronics. The first platform electrochemically images signaling molecules in multicellular communities, while the second focuses on single-molecule, high-bandwidth sensing using carbon nanotube field-effect transistors.
Jaebin Choi, Eyal Aklimi, Jared Roseman, David Tsai, Harish Krishnaswamy, Kenneth L. Shepard Matching the power density and potentials of biological systems: a 3.1-nW, 130-mV, 0.023-mm3 pulsed 33-GHz radio transmitter in 32-nm SOI CMOS, Custom Integrated Circuits Conference, 2014
A 3.1 nJ/bit pulsed millimeter-wave transmitter, 300μm by 300μm by 250μm in size, designed in 32-nm SOI CMOS, operates on an electric potential of 130mV and 3.1nW of dc power. These achieved power levels and potentials are comparable to those present across cellular and intracellular membranes. Far-field data transmission at 33 GHz is achieved by supply-switching an LC-oscillator with a duty cycle of 10-6. The time interval between pulses carries information on the amount of power harvested by the radio, supporting a data rate of ~1bps. The inductor of the oscillator also acts as an electrically small (~λ/30) on-chip antenna, enabling the extremely small form factor.
Haig Norian, Ryan M. Field, Ioannis Kymissis and Kenneth L. Shepard An integrated CMOS quantitative-polymerase-chain-reaction lab-on-chip for point-of-care diagnostics, Lab Chip, 2014, Advance Article.
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R.M. Field, S. Realov, and K.L. Shepard A 100-fps, Time-Correlated Single-Photon-Counting-Based Fluorescence-Lifetime Imager in 130-nm CMOS, IEEE Journal of Solid-State Circuite, vol.49, no.4 (2014) advanced online version.
A fully-integrated single-photon avalanche diode (SPAD) and time-to-digital converter (TDC) array for high-speed fluorescence lifetime imaging microscopy (FLIM) in standard 130-nm CMOS is presented. This imager is comprised of an array of 64-by-64 SPADs each with an independent TDC for performing time-correlated single-photon counting (TCSPC) at each pixel. The TDCs use a delay-locked-loop-based architecture and achieve a 62.5-ps resolution with up to a 64-ns range. A data-compression datapath is designed to transfer TDC data to off-chip buffers, which can support a data rate of up to 42 Gbps. These features, combined with a system implementation that leverages a x4 PCIe-cabled interface, allow for demonstrated FLIM imaging rates at up to 100 frames per second.
D.L. Bellin, H. Sakhtah, J.K. Rosenstein, P.M. Levine, J. Thimot, K. Emmet, L.E.P. Dietrich, and K.L. Shepard Integrated circuit-based electrochemical sensor for spatially resolved detection of redox-active metabolites in biofilms, Nature Communications 5:3256 (2014) doi:10.1038/ncomms4256
Despite advances in monitoring spatiotemporal expression patterns of genes and proteins with fluorescent probes, direct detection of metabolites and small molecules remains challenging. A technique for spatially resolved detection of small molecules would benefit the study of redox-active metabolites that are produced by microbial biofilms and can affect their development. Here we present an integrated circuit-based electrochemical sensing platform featuring an array of working electrodes and parallel potentiostat channels. ‘Images’ over a 3.250.9mm2 area can be captured with a diffusion-limited spatial resolution of 750 μm. We demonstrate that square wave voltammetry can be used to detect, identify and quantify (for concentrations as low as 2.6 μm) four distinct redox-active metabolites called phenazines. We characterize phenazine production in both wild-type and mutant Pseudomonas aeruginosa PA14 colony biofilms, and find correlations with fluorescent reporter imaging of phenazine biosynthetic gene expression.