Peter M. Levine

Real-time, multiplexed electrochemical DNA detection using an active complementary metal-oxide-semiconductor biosensor array with integrated sensor electronics

Optical biosensing based on fluorescence detection has arguably become the standard technique for quantifying extents of hybridization between surface-immobilized probes and fluorophore-labeled analyte targets in DNA microarrays. However, electrochemical detection techniques are emerging which could eliminate the need for physically bulky optical instrumentation, enabling the design of portable devices for point-of-care applications. Unlike fluorescence detection, which can function well using a passive substrate (one without integrated electronics), multiplexed electrochemical detection requires an electronically active substrate to analyze each array site and benefits from the addition of integrated electronic instrumentation to further reduce platform size and eliminate the electromagnetic interference that can result from bringing non-amplified signals off chip. We report on an active electrochemical biosensor array, constructed with a standard complementary metal-oxide-semiconductor (CMOS) technology, to perform quantitative DNA hybridization detection on chip using targets conjugated with ferrocene redox labels. A 4 x 4 array of gold working electrodes and integrated potentiostat electronics, consisting of control amplifiers and current-input analog-to-digital converters, on a custom-designed 5 mm x 3 mm CMOS chip drive redox reactions using cyclic voltammetry, sense DNA binding, and transmit digital data off chip for analysis. We demonstrate multiplexed and specific detection of DNA targets as well as real-time monitoring of hybridization, a task that is difficult, if not impossible, with traditional fluorescence-based microarrays.

Integrated circuit-based electrochemical sensor for spatially resolved detection of redox-active metabolites in biofilms

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 produced by microbial biofilms, which can drastically affect colony development. Here we present an integrated circuit-based electrochemical sensing platform featuring an array of working electrodes and parallel potentiostat channels. “Images” over a 3.25 × 0.9 mm 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.

A high-resolution flash time-to-digital converter and calibration scheme

Flash time-to-digital converters (TDCs) are well-suited for use in on-chip timing measurement systems because they can be operated at high speeds, offer low test time, and are relatively easy to integrate. However, clock jitter in modern integrated circuits is often on the same order of magnitude as the temporal resolution of the TDC itself. Therefore, techniques are required to increase the resolution of these devices, while ensuring timing accuracy. This work presents a high-resolution flash TDC that exploits the random offsets on flip-flops or arbiters to perform time quantization. It also describes a novel technique based on additive temporal noise to accurately calibrate the measurement device. Simulation and experimental results reveal that the latter method can calibrate the high-resolution flash TDC down to 5 ps within reasonable error limits. In addition, accurate timing measurement of jitter below 14 ps has been experimentally validated using a high-resolution flash TDC fabricated in a 0.18-/spl mu/m CMOS process.

Active CMOS Array for Electrochemical Sensing of Biomolecules

We describe the design of a 4times4 active sensor array for multiplexed electrochemical biomolecular detection in a 0.25-mum-CMOS process. Integrated potentiostats sense the current flowing through the on-chip Au electrodes that result from reactions occurring at the chip surface. Preliminary experimental results include cyclic voltammetry of several redox species and application to DNA probe coverage characterization.

A calibration technique for a high-resolution flash time-to-digital converter

Traditional flash time-to-digital converters (TDCs) make use of buffers delays and flip-flops or arbiters to quantize a time interval. To achieve high resolution without delay buffers however, offsets caused by mismatches in arbiter layout can be used for time quantization. Such a flash converter requires a calibration technique to determine these offsets. This paper describes a direct calibration method based on the addition of a temporal noise to the arbiter input. Such a technique eliminates the need for very small input times as in a traditional direct calibration. Simulation results reveal that the proposed calibration technique, followed by a curve-fitting procedure, can be used to accurately determine arbiter offset down to picoseconds.

Linear filter assisted envelope memory polynomial for analog/radio frequency predistortion of power amplifiers

In this paper, a linear filter assisted envelope memory polynomial (EMP) architecture, for use in a low power analog/radio frequency (RF) predistortion scheme, is presented. The linear filter and the EMP are combined to compensate for the linear memory distortion and the dynamic non-linearity exhibited by an RF power amplifier (PA) driven by wideband modulated signals. A 20-W wideband GaN Doherty PA was used to assess the proposed architectures performance experimentally. The addition of the linear filter improved the performance of the EMP for wideband signals to the extent that results were comparable to those of the memory polynomial approach, while maintaining the structural simplicity of the EMP approach.

Noise analysis and measurement of integrator-based sensor interface circuits for fluorescence detection in lab-on-a-chip applications

This paper examines the impact of integrator-based sensor interface circuit parameters, optical parameters, and noise on the limit of detection (LOD) of a fluorescence measurement lab-on-a-chip (LOC) device. Fluorescence detection is a powerful form of signal measurement for LOC-based bio-diagnostic assays. Reduction of the LOD enables a lower concentration of analyte to be measured, diversifying applications of LOC technology. An optical system model of a proposed LOC device is described. This device contains a photodiode and a capacitive transimpedance amplifier (CTIA) sensor interface constructed in a standard complementary metal-oxide-semiconductor (CMOS) technology. Analysis of the noise produced by the interface electronics and photodiode is then carried out, enabling the LOD of the system to be parametrized. The impact of circuit and system parameters on the LOD is then evaluated and compared to simulated and measured results.

CMOS transimpedance amplifier for biosensor signal acquisition

We present a 1-GΩ CMOS transimpedance amplifier (TIA) suitable for processing sub-nA-level currents in electrochemical biosensor signal-acquisition circuits. Use of a two-stage active transconductor provides resistive feedback in place of a single large-area linear resistor. We engineer the TIA feedback loop to suppress output offset caused by dc input leakage currents of ±0.9 nA. We also implement a mechanism to tune the low-frequency cutoff of the TIA from 0.7 Hz to 500 Hz which permits operation under variable environmental conditions. We report simulated and experimental results from our custom TIA fabricated in a 3.3-V 0.35-μm CMOS process.

Digitally Assisted Analog/RF Predistorter With a Small-Signal-Assisted Parameter Identification Algorithm

This paper proposes a digitally assisted analog/radio frequency predistorter (ARFPD) and a linear small-signal-assisted parameter identification algorithm suitable for the linearization of power amplifiers driven with wideband and carrier aggregated communication signals. It starts by describing the newly proposed finite-impulse-response assisted envelope memory polynomial (FIR-EMP) model which allows for reduction of hardware implementation complexity while maintaining good linearization capacity and low power overhead. Furthermore, a linear two-step small-signal-assisted parameter identification algorithm is devised to estimate the parameters of the two main blocks of the FIR-EMP model. Measurement results obtained by using the FIR-EMP predistorter demonstrate its excellent linearization capacity when used to compensate for distortion exhibited by gallium nitride Doherty power amplifiers driven by digitally modulated signals with a bandwidth up to 80 MHz. This confirms the potential of ARFPD as a very promising candidate for the linearization of small cell base stations power amplifiers while simultaneously reducing the power overhead compared to the popular digital predistortion technique.

Direct-Conversion CMOS X-Ray Imager With

We report a monolithic direct-conversion X-ray imager capable of detecting diagnostic level X-rays. The imager is constructed by combining a custom 32×32 CMOS four-transistor active pixel sensor (4T APS) array with an amorphous selenium photoconductive layer deposited on top of the array via a post processing step. A 4T APS with an explicit per-pixel integration capacitor is employed to increase the pixel dynamic range. Under dark conditions, an input-referred electronic noise of <;90 electrons (rms) is estimated based on measured noise data for a 40-ms integration time. The very first X-ray images of copper and stainless-steel objects are included to demonstrate the performance of what is, to the best of our knowledge, a direct-conversion X-ray imager with the smallest pixel pitch reported to date.