Publications – 2011

Rosenstein, J. ; Bioelectron. Syst. Lab., Columbia Univ., New York, NY, USA ; Sorgenfrei, S. ; Shepard, K.L.”Noise and bandwidth performance of single-molecule biosensors,” Custom Integrated Circuits Conference (CICC), 2011 IEEE

Abstract

Technological advances in fluorescent probes, solid-state imagers, and microscopy techniques have enabled biomolecular studies at the single-molecule level. Fluorescent techniques are highly specific but their bandwidth is fundamentally limited by the number of photons that can be collected. New electronic sensors including nanopores and nanotube field-effect transistors offer different tradeoffs between bandwidth and noise levels. Here, we discuss the performance of these direct solid-state interfaces and their potential for sensing single-molecule dynamics at shorter timescales.

Rosenstein, J.; Ray, V.; Drndic, M.; Shepard, K.L.; “Nanopore DNA sensors in CMOS with on-chip low-noise preamplifiers,” Solid-State Sensors, Actuators, and Microsystems Conference (Transducers), 2011.

Abstract

Technological advances in fluorescent probes, solid-state imagers, and microscopy techniques have enabled biomolecular studies at the single-molecule level. Fluorescent techniques are highly specific but their bandwidth is fundamentally limited by the number of photons that can be collected. New electronic sensors including nanopores and nanotube field-effect transistors offer different tradeoffs between bandwidth and noise levels. Here, we discuss the performance of these direct solid-state interfaces and their potential for sensing single-molecule dynamics at shorter timescales.

Rosenstein, J.; Ray, V.; Drndic, M.; Shepard, K.L.; “Solid-state nanopores integrated with low-noise preamplifiers for high-bandwidth DNA analysis,” IEEE/NIH Life Science Systems and Applications Workshop (LiSSA), 2011.

Abstract

Nanopore sensing platforms have been limited in bandwidth and noise performance by the use of external measurement electronics with significant parasitic impedances. In this work, we describe progress toward integrating detection electronics with solid-state nanopore sensors. This new platform for high-bandwidth single molecule electrochemical DNA analysis includes a low-noise 8-channel 0.13µm CMOS preamplifier with integrated Ag/AgCl microelectrodes. We also demonstrate monolithic integration of solid-state nanopores in the amplifier chip. This arrangement provides an opportunity to extend the useful bandwidth of nanopore sensors by a factor of ten or more.

G-H. Lee, Y-J. Yu, C. Lee, C. Dean, K. L. Shepard, P. Kim, and J. Hone, “Electron tunneling through atomically flat and ultrathin hexagonal boron nitride,” Applied Physcis Letters, 99, 243114 (2011).

Abstract

Electron tunneling through atomically flat and ultrathin hexagonal boron nitride (h-BN) on gold-coated mica was investigated using conductive atomic force microscopy. Low-bias direct tunneling was observed in mono-, bi-, and tri-layer h-BN. For all thicknesses, Fowler-Nordheim tunneling (FNT) occurred at high bias, showing an increase of breakdown voltage with thickness. Based on the FNT model, the barrier height for tunneling (3.07 eV) and dielectric strength (7.94 MV/cm) of h-BN are obtained; these values are comparable to those of SiO2.

I. Meric, C. Dean, S. J. Han, L. Wang, K. A. Jenking, J. Hone, and K. L. Shepard, “High-frequency performance of graphene field effect transistors with saturating IV-characteristics,” International Electron Devices Meeting, 2011, pp. 2.1.1-2.1.4. [ Data Download ]

Abstract

High-frequency performance of graphene field-effect transistors (GFETs) with boron-nitride gate dielectrics is investigated. Devices show saturating IV characteristics and fmax values as high as 34 GHz at 600-nm channel length. Bias dependence of fT and fmax and the effect of the ambipolar channel on transconductance and output resistance are also examined.

N. Sturcken, M. Petracca, S. Warren, L. P. Carloni, A. V. Peterchev, and K. L. Shepard “An Integrated Four-Phase Buck Converter Delivering 1A/mm2 with 700ps Controller Delay and Network-on-Chip Load in 45-nm SOI” IEEE Custom Integrated Circuits Conference, 2011.

Abstract

We present a four-phase integrated buck converter in 45nm SOI technology. The controller uses unlatched pulse-width modulation (PWM) with nonlinear gain to provide both stable small-signal dynamics and fast response (~700ps) to large input and output transients. This fast control approach reduces the required output capacitance by 5X in comparison to a controller with latched PWM at similar operating point. The converter switches at 80MHz and delivers 1A/mm2 at 83% efficiency and 0.66 conversion ratio.

S. Sorgenfrei, C.-Y. Chiu, M. Johnston, C. Nuckolls, and K. L. Shepard, “Debye Screening in Single-Molecule Carbon Nanotube Field-Effect Sensors,” Nano Letters 11(9), pp. 3739-3743, 2011.

Abstract

Point-functionalized carbon nanotube !eld-e”ect transistors can serve as highly sensitive detectors for biomolecules. With a probemolecule covalently bound to a defect in the nanotube sidewall, two-level random telegraph noise (RTN) in the conductance of the device is observed as a result of a charged target biomolecule binding and unbinding at the defect site. Charge in proximity to the defect modulates the potential (and transmission) of the conductance-limiting barrier created by the defect. In this Letter, we study how these single molecule electronic sensors are a”ected by ionic screening. Both charge in proximity to the defect site and bu”er concentration are found to a”ect RTN amplitude in a manner that follows from simple Debye length considerations. RTN amplitude is also dependent on the potential of the electrolyte gate as applied to the reference electrode; at high enough gate potentials, the target DNA is completely repelled and RTN is suppressed.

N. Lei, S. Ramamkrishnan, P. Shi, J. S. Orcutt, R. Yuste, L. C. Kam, and K. L. Shepard, “High-resolution extracellular stimulation of dispersed hippocampal culture with high-density CMOS multielectrode array based on non-Faradaic electrodes,” J. Neural Eng. 8 (2011) 044003.

Abstract

We introduce a method to electrically stimulate individual neurons at single-cell resolution in arbitrary spatiotemporal patterns with precise control over stimulation thresholds. By exploiting a custom microelectronic chip, up to 65 000 non-Faradaic electrodes can be uniquely addressed with electrode density exceeding 6500 electrodes mm−2. We demonstrate extracellular stimulation of dispersed primary hippocampal neuronal cultures using the chip at single-cell resolution.

Jacob Rosenstein, Sebastian Sorgenfrei, and K. L. Shepard, “Noise and Bandwidth Performance of Single-Molecule Biosensors,” 2011 Custom Integrated Circuits Conference

Abstract

Technological advances in fluorescent probes, solid-state imagers, and microscopy techniques have enabled biomolecular studies at the single-molecule level. Fluorescent techniques are highly specific but their bandwidth is fundamentally limited by the number of photons that can be collected. New electronic sensors including nanopores and nanotube field-effect transistors offer different tradeoffs between bandwidth and noise levels. Here, we discuss the performance of these direct solid-state interfaces and their potential for sensing single-molecule dynamics at shorter timescales.

C. R. Dean, A. F. Young, P. Cadden-Zimansky, L. Wang, H. Ren, K. Watanabe, T. Taniguchi, P. Kim, J. Hone, and K. L. Shepard, “Multicomponent fractional quantum Hall effect in graphene,” Nature Physics 7, pp. 693-696, 2011.

Abstract

The fractional quantum Hall effect1–4 (FQHE) in an electron gas with multiple internal degrees of freedom provides a model system to study the interplay between symmetry breaking and emergent topological order5. In graphene, the structure of the honeycomb lattice endows the electron wave functions with an additional quantum number, termed valley isospin, which, combined with the usual electron spin, yields fourfold degenerate Landau levels (LLs; refs 6,7). This additional symmetry modifies the FQHE and is conjectured to produce new incompressible ground states in graphene8–17. Here we report multiterminal measurements of the FQHE in high mobility graphene devices fabricated on hexagonal boron nitride substrates18. The measured energy gaps are large, particularly in the second Landau level, where they are up to 10 times larger than those reported in the cleanest conventional systems. In the lowest Landau level the hierarchy of FQH states reflects the additional valley degeneracy.

N. Lei, S. Ramakrishnan, P. Shi, J. Orcutt, R. Yuste, L. Kam, and K.L. Shepard, “An electrically stimulate optically record microsystem based on active CMOS multi-electrode array for dissociated cell cultures“, Proceedings of IEEE/NIH Life Science Systems and Applications Workshop 2011.

Abstract

Calcium fluorescence-based optical recording combined with patch-clamp stimulation has become the standard technique for analyzing neural network behavior. At best, stimulation is limited to only a few channels in this case. Passive multielectrode arrays for two-dimensional electrophysiology only offer electrode densities of 60 electrodes per mm2. Here, we report an active multielectrode array, constructed with a standard complementary metal-oxide-semiconductor (CMOS) technology, to perform localized extracellular stimulation of dispersed cell cultures. A 256×256 array integrated with in-pixel stimulators on a 4-by-4 mm2 CMOS chip noninvasively stimulate hippocampal cells cultured on chip at cellular resolution. Combined with calcium imaging using high affinity indicators, we demonstrate the ability to observe spatiotemporal dynamics of neural activity.

S. Sorgenfrei and K.L. Shepard, “Single-molecule electronic detection using nanoscale field-effect devices,” Design and Automation Conference (DAC), June 2011 (invited paper).

Abstract

Traditionally, biomolecular systems have been studied in ensemble. While much can be determined with ensemble measurements, scientific and technological interest is rapidly moving to single-molecule techniques, which rely primarily on fluorescent markers and advanced microscopy techniques. In this paper, we describe recent work using nanoscale transistors based on carbon nanotubes as charge-sensitive detectors. We show carbon nanotubes can be used for ensemble studies through sidewall adsorption. Sensitivity can be greatly enhanced though an engineered defect in the nanotube. Biomolecular interactions are characterized by random-telegraph-noise response, which can be analyzed to study single-molecule kinetics and thermodynamics.

S. Sorgenfrei, C.-Y. Chiu, C. Nuckolls, and K.L. Shepard, “Ultra-sensitive carbon nanotubes for single-molecule detection of DNA hybridization kinetics using conductance-based correlation spectroscopy,” Proc. of 16th International Conference on Solid-State Sensors, Actuators & Microsystems (Transducers ’11), June 2011.

Abstract

We present a label-free single-molecule based sensing platform using a carbon nanotube field-effect transistor. By point functionalizing a carbon nanotube through an electrochemical oxidation reaction, the conductance becomes sensitive and chemically reactive at a single point to which we can covalently attach a probe DNA molecule. Two-level fluctuations appear in the conductance of the carbon nanotube when it is immersed in a liquid buffer solution containing complementary target DNA. We show that the autocorrelation of the conductance can be used to extract DNA hybridization kinetics. The results are comparable to the one extracted through a hidden Markov model.

S. Sorgenfrei, C.-Y. Chiu, C. Nuckolls, and K.L. Shepard, “Charge sensing using point-functionalized carbon-nanotube transistors for single-molecule detection,” Proc. of IEEE/NIH Life Science Systems and Applications Workshop 2011 (LiSSA ’11).

Abstract

We have demonstrated that carbon-nanotube fieldeffect transistors act as highly sensitive single-molecule detectors when point functionalized. The hybridization kinetics of two complementary strands of DNA are associated with two-level fluctuations in the conductance of the nanotube to which the DNA is bound. We have studied the temperature dependence of the nanotube conductance and shown that the transport mechanism is consistent with Frenkel Poole emission, in which negatively charged DNA modulates a tunnel barrier at the point functionalized defect site. These transistors represent an important potential sensing platform for label-free single-molecule diagnostics.

S. Realov and K. L. Shepard, “On-Chip Combined C-V/I-V Transistor Characterization System in 45-nm CMOS,” Symposium on VLSI Circuits, 2011.

Abstract

An on-chip transistor characterization system for combined C-V/I-V characterization is presented. Capacitance measurement uses a quasi-static charged-based measurement technique with atto-Farad resolution. Random and systematic variability in device I-V and C-V characteristics is studied. The random variability in intrinsic gate capacitance is shown to exhibit Pelgrom scaling. Correlation between I-V and C-V measurements is used to identify systematic channel-length variation gradients in a device array.

Ta-chien D. Huang, Sunirmal Paul, Ping Gong, Rastislav Levicky, John Kymissis, Sally A. Amundson, Kenneth L. Shepard, “Gene expression analysis with an integrated CMOS microarray by time-resolved fluorescence detection,” Biosensors and Bioelectronics, Volume 26, Issue 5, 15 January 2011, Pages 2660-2665

Abstract

DNA microarrays have proven extraordinarily powerful for differential expression studies across thousands of genes in a single experiment. Microarrays also have the potential for clinical applications, including the detection of infectious and immunological diseases and cancer, if they can be rendered both reliable and cost-effective. Here we report the first practical application of an active microarray based on integrated circuit technology, completely obviating the need for external measurement instrumentation while employing protocols compatible with traditional fluorescence-based surface bioassays. In a gene expression biodosimetry study, we determine the differential activity of genes from leucocytes in irradiated human blood. Quantum dots are used as fluorescence labels to realize filterless, time-gated fluorescence detection on an active complementary metal-oxide-semiconductor (CMOS) microarray with 100-pM sensitivity. Improvements in surface chemistry should allow sensitivities that approach the microarray hardware limit of less than 10 pM. Techniques for covalent attachment of DNA capture strands to the CMOS active microarrays allow integrated sensors to be placed in immediate proximity to hybridized analyte strands, maximizing photon collection efficiencies.

Inanc Meric, Cory R. Dean, Andrea F. Young, Natalia Baklitskaya, Noah J. Tremblay, Colin Nuckolls, Philip Kim, and Kenneth L. Shepard, “Channel Length Scaling in Graphene Field-Effect Transistors Studied with Pulsed Current−Voltage Measurements,” Nano Letters 11(3), pp. 1093-1097, 2011.

Abstract

We investigate current saturation at short channel lengths in graphene field-effect transistors (GFETs). Saturation is necessary to achieve low-output conductance required for device power gain. Dual-channel pulsed current-voltage measurements are performed to eliminate the significant effects of trapped charge in the gate dielectric, a problem common to all oxide-based dielectric films on graphene. With pulsed measurements, graphene transistors with channel lengths as small as 130 nm achieve output conductance as low as 0.3 mS/μm in saturation. The transconductance of the devices is independent of channel length, consistent with a velocity saturation model of high-field transport. Saturation velocities have a density dependence consistent with diffusive transport limited by optical phonon emission.

S. Sorgenfrei, C-Y Chiu, R. Gonzalez, Y.-J. Yu, P. Kim, C. Nuckolls, and K. L. Shepard, “Label-free single-molecule detection of DNA hybridization kinetics with a carbon nanotube field-effect transistor,” Nature Nanotechnology 6, pp. 126-132, 2011.

Abstract

Single-molecule measurements of biomolecules can provide information about the molecular interactions and kinetics that are hidden in ensemble measurements. However, there is a requirement for techniques with improved sensitivity and time resolution for use in exploring biomolecular systems with fast dynamics. Here, we report the detection of DNA hybridization at the single-molecule level using a carbon nanotube field-effect transistor. By covalently attaching a single-stranded probe DNA sequence to a point defect in a carbon nanotube, we are able to measure two-level fluctuations in the conductance of the nanotube in the presence of a complementary DNA target. The kinetics of the system are studied as a function of temperature, allowing the measurement of rate constants, melting curves and activation energies for different sequences and target concentrations. The kinetics demonstrate non-Arrhenius behaviour, in agreement with DNA hybridization experiments using fluorescence correlation spectroscopy. This technique is label-free and could be used to probe single-molecule dynamics at microsecond timescales.