A. G. Venkatesh

A Multi-Technique Reconfigurable Electrochemical Biosensor: Enabling Personal Health Monitoring in Mobile Devices

This paper describes the design and characterization of a reconfigurable, multi-technique electrochemical biosensor designed for direct integration into smartphone and wearable technologies to enable remote and accurate personal health monitoring. By repurposing components from one mode to the next, the biosensors potentiostat is able reconfigure itself into three different measurements modes to perform amperometric, potentiometric, and impedance spectroscopic tests all with minimal redundant devices. A 3.9 × 1.65 cm2 PCB prototype of the module was developed with discrete components and tested using Googles Project Ara modular smartphone. The amperometric mode has a ±1 nA to ±200 μA measurement range. When used to detect pH, the potentiometric mode achieves a resolution of <; 0.08 pH units. In impedance measurement mode, the device can measure 50 Ω-10 MΩ and has been shown to have <; 6° of phase error. This prototype was used to perform several point-of-care health tracking assays suitable for use with mobile devices: 1) Blood glucose tests were conducted and shown to cover the diagnostic range for Diabetic patients (~200 mg/dL). 2) Lactoferrin, a biomarker for urinary tract infections, was detected with a limit of detection of approximately 1 ng/mL. 3) pH tests of sweat were conducted to track dehydration during exercise. 4) EIS was used to determine the concentration of NeutrAvidin via a label-free assay.

Integration of Faradaic electrochemical impedance spectroscopy into a scalable surface plasmon biosensor for in tandem detection

We present an integrated label-free biosensor based on surface plasmon resonance (SPR) and Faradaic electrochemical impedance spectroscopy (f-EIS) sensing modalities, for the simultaneous detection of biological analytes. Analyte detection is based on the angular spectroscopy of surface plasmon resonance and the extraction of charge transfer resistance values from reduction-oxidation reactions at the gold surface, as responses to functionalized surface binding events. To collocate the measurement areas and fully integrate the modalities, holographically exposed thin-film gold SPR-transducer gratings are patterned into coplanar electrodes for tandem impedance sensing. Mutual non-interference between plasmonic and electrochemical measurement processes is shown, and using our scalable and compact detection system, we experimentally demonstrate biotinylated surface capture of neutravidin concentrations as low as 10 nM detection, with a 5.5 nM limit of detection.

A multitechnique reconfigurable electrochemical biosensor for integration into mobile technologies

This paper describes the design and validation of a reconfigurable, multitechnique electrochemical biosensor intended for direct integration into smartphone and wearable technologies to realize a portable platform for Point-of-Care health monitoring. The reconfigurable potentiostat is able to perform various electrochemical techniques (amperometric, potentiometric, and impedance spectroscopy) and interfaces with several types of interchangeable electrochemical sensors all with a minimal number of components. A prototype of the reconfigurable potentiostat module was developed with discrete components, characterized, and compared against benchtop equipment. To show feasibility as well as flexibility of the platform, the device was used to run pH measurements and a glucose assay with comparable performance.

A hybrid semi-digital transimpedance amplifier for nanopore-based DNA sequencing.

Over the past two decades, nanopores have been a promising technology for next generation deoxyribonucleic acid (DNA) sequencing. As single-stranded DNA translocates through a nanopore, each nucleotide induces a blockage in the ionic channel, creating a unique current signature. However, the fast translocation speed and small current changes, which are superimposed on a much larger baseline current, pose significant technical challenges on the measurement circuitry. Furthermore, the rapid change in the baseline current that occurs during translocation necessitates the step response of the measurement circuitry be minimized. Here we present a hybrid semi-digital transimpedance amplifier to sense these minute current signatures while discharging the baseline current using a semidigital feedback loop. The amplifier achieves fast settling by adaptively altering the bandwidth of the feedback loop when a step input is detected. Measurement results show the performance of the amplifier with 100 MΩ DC gain, 560 kHz flat-gain bandwidth, and 5 fA/√Hz input-referred current noise. The fast settling response is demonstrated by observing the insertion of a protein nanopore in a lipid bilayer.

Smartphone-Based pH Sensor for Home Monitoring of Pulmonary Exacerbations in Cystic Fibrosis

Currently, Cystic Fibrosis (CF) patients lack the ability to track their lung health at home, relying instead on doctor checkups leading to delayed treatment and lung damage. By leveraging the ubiquity of the smartphone to lower costs and increase portability, a smartphone-based peripheral pH measurement device was designed to attach directly to the headphone port to harvest power and communicate with a smartphone application. This platform was tested using prepared pH buffers and sputum samples from CF patients. The system matches within ~0.03 pH of a benchtop pH meter while fully powering itself and communicating with a Samsung Galaxy S3 smartphone paired with either a glass or Iridium Oxide (IrOx) electrode. The IrOx electrodes were found to have 25% higher sensitivity than the glass probes at the expense of larger drift and matrix sensitivity that can be addressed with proper calibration. The smartphone-based platform has been demonstrated as a portable replacement for laboratory pH meters, and supports both highly robust glass probes and the sensitive and miniature IrOx electrodes with calibration. This tool can enable more frequent pH sputum tracking for CF patients to help detect the onset of pulmonary exacerbation to provide timely and appropriate treatment before serious damage occurs.

A Hybrid Semi-Digital Transimpedance Amplifier With Noise Cancellation Technique for Nanopore-Based DNA Sequencing

Over the past two decades, nanopores have been a promising technology for next generation deoxyribonucleic acid (DNA) sequencing. Here, we present a hybrid semi-digital transimpedance amplifier (HSD-TIA) to sense the minute current signatures introduced by single-stranded DNA (ssDNA) translocating through a nanopore, while discharging the baseline current using a semi-digital feedback loop. The amplifier achieves fast settling by adaptively tuning a DC compensation current when a step input is detected. A noise cancellation technique reduces the total input-referred current noise caused by the parasitic input capacitance. Measurement results show the performance of the amplifier with 31.6 M Ω mid-band gain, 950 kHz bandwidth, and 8.5 fA/ √Hz input-referred current noise, a 2× noise reduction due to the noise cancellation technique. The settling response is demonstrated by observing the insertion of a protein nanopore in a lipid bilayer. Using the nanopore, the HSD-TIA was able to measure ssDNA translocation events.

A scalable high-density electrochemical biosensor array for parallelized point-of-care diagnostics

This paper describes the design and verification of a prototype high-density electrochemical biosensor array for miniaturizing and enabling portable diagnostics devices that require high parallelizability. The prototype consists of a low-leakage 16-channel bi-potentiostat capable of running an electrochemical technique known as coulostatic discharge that is scalable for use with high-density sensors. Custom electronics with leakage of less than 100 fA were designed to interface with custom 4×4 nano-feature sensor array chips. By using a reversible redox molecule pair, we verified both preliminary simulated and measurement results of our system to varying redox concentrations.

Live demonstration: A low-cost smartphone-based electrochemical biosensor for point-of-care diagnostics.

By 2015, there will be an estimated 2.03 billion smartphone users worldwide [1]. This wide spread availability of mobile computing has inspired a surge of peripheral devices that add health-oriented functionality to the smartphone, such as the iBGStar® blood glucose meter and the AliveCor® ECG monitor. By similarly leveraging the power and functionality of the smartphone, we have built an electronic module that, when plugged into the audio jack of a smartphone and combined with disposable test chips, creates a low-cost biosensor. The smartphone would control and power the module through the audio port and analyze the measured data sent back by the module. This portable molecular sensor is meant to augment or replace bulky diagnostic equipment usually confined to labs and enable numerous point-of-care (POC) applications, thereby improving the convenience and speed of medical diagnoses.

Clinical detection of Hepatitis C viral infection by yeast-secreted HCV-core:Gold-binding-peptide

Access to affordable and field deployable diagnostics are key barriers to the control and eradication of many endemic and emerging infectious diseases. While cost, accuracy, and usability have all improved in recent years, there remains a pressing need for even less expensive and more scalable technologies. To that end, we explored new methods to inexpensively produce and couple protein-based biosensing molecules (affinity reagents) with scalable electrochemical sensors. Previous whole-cell constructs resulted in confounding measurements in clinical testing due to significant cross-reactivity when probing for host-immune (antibody) response to infection. To address this, we developed two complimentary strategies based on either the release of surface displayed or secretion of fusion proteins. These dual affinity biosensing elements couple antibody recognition (using antigen) and sensor surface adhesion (using gold-binding peptide-GBP) to allow single-step reagent production, purification, and biosensor assembly. As a proof-of-concept, we developed Hepatitis C virus (HCV)-core antigen-GBP fusion proteins. These constructs were first tested and optimized for consistent surface adhesion then the assembled immunosensors were tested for cross-reactivity and evaluated for performance in vitro. We observed loss of function of the released reagents while secreted constructs performed well in in vitro testing with 2 orders of dynamic range, and a limit of detection of 32 nM. Finally, we validated the secreted platform with clinical isolates (n = 3) with statistically significant differentiation of positive vs. non-infected serum (p < 0.0001) demonstrating the ability to clearly distinguish HCV positive and negative clinical samples.

A 64×64 high-density redox amplified coulostatic discharge-based biosensor array in 180nm CMOS

This paper describes the design of a high-density 4,096-pixel electrochemical biosensor array in 180nm CMOS for biomedical applications that require multiple analyte detection from small (5μL) samples. Each pixel of the array contains an exposed 45×45μm2 interdigitated micro-electrode surrounded by a ∼9pL nanowell fabricated using only a standard CMOS process along with a simple electroless gold plating procedure without the need for further post processing. Directly underneath each transducer is a complete ultra-low-leakage (sub-fA) readout circuitry, which leverages the Coulostatic Discharge sensing technique and interdigitated electrode (IDE) geometry to minimize both the complexity and overall size of the array. By evaluating IDE designs with different feature sizes (2–5μm), an average maximum amplification factor of 10.5x was achieved using redox cycling coupled with the higher collection efficiency of trenches formed from opening the passivation. The arrays sensor density is comparable to or better than state-of-the-art sensor arrays, all without augmenting the sensors with additional materials or structures. Using the array, detection of anti-Rubella is demonstrated as progress towards a complete vaccination panel.