Arun Manickam

A CMOS Electrochemical Impedance Spectroscopy (EIS) Biosensor Array

In this paper, we present a fully integrated biosensor 10 × 10 array in a standard complementary metal-oxide semiconducor process, which takes advantage of electrochemical impedance spectroscopy (EIS). We also show that this system is able to detect various biological analytes, such as DNA and proteins, in real time and without the need for molecular labels. In each pixel of this array, we implement a biocompatible Au electrode transducer and embedded sensor circuitry which takes advantage of the coherent detector to measure the impedance of the associated electrode-electrolyte interface. This chip is capable of concurrently measuring admittance values as small as 10-8 Ω-1 within the array with the detection dynamic range of more than 90 dB in the frequency range of 10 Hz-50 MHz.

A CMOS electrochemical impedance spectroscopy biosensor array for label-free biomolecular detection

Biosensors are one of the fundamental detection platforms in biotechnology. They take advantage of unique biomolecular interactions to capture and detect specific analytes on a surface. The detection versatility of biosensors has always been their key advantage and it has been demonstrated that they can detect almost any analyte such as DNA, proteins, metabolites, and even micro-organisms. However, the achievable SNR and detection DR of biosensors can be very low. This is due to the fact that the capturing processes in biosensors suffer from a significant amount of biological interference (i.e., non-specific bindings) and biochemical noise which typically necessitate the use of complex biochemical labeling processes and sophisticated detectors [1]. Hence, the main design challenge of biosensors is to increase the SNR and DR while minimizing the complexity of both the assay and the detector. Today, this is the main impediment in point-of-care (PoC) biosensors, particularly in high-performance applications such as molecular diagnostics and forensics.

Interface Design for CMOS-Integrated Electrochemical Impedance Spectroscopy (EIS) Biosensors

Electrochemical Impedance Spectroscopy (EIS) is a powerful electrochemical technique to detect biomolecules. EIS has the potential of carrying out label-free and real-time detection, and in addition, can be easily implemented using electronic integrated circuits (ICs) that are built through standard semiconductor fabrication processes. This paper focuses on the various design and optimization aspects of EIS ICs, particularly the bio-to-semiconductor interface design. We discuss, in detail, considerations such as the choice of the electrode surface in view of IC manufacturing, surface linkers, and development of optimal bio-molecular detection protocols. We also report experimental results, using both macro- and micro-electrodes to demonstrate the design trade-offs and ultimately validate our optimization procedures.

A fully-electronic charge-based DNA sequencing CMOS biochip

A 90×90 fully-electronic biosensor array for charge-based DNA sequence-by-synthesis is implemented in a 0.18μm standard CMOS process. Each 16 μm × 16 μm pixel consists of an integrated charge-sensing electrode connected to an embedded circuitry capable of detecting DNA polymerization and simultaneously measuring the electrode-electrolyte interface capacitance. The detection dynamic range of this sensor is +90dB while consuming 4 mW from a 3.3V supply when operating at 8.1s/frame.

Front-end integrated circuits for high-performance biological and chemical sensing

High-performance biomedical and biotechnological devices require a significant amount of electronics to not only interact with the biological and chemical media, but also amplify, digitize, process, and transmit signals. To create point-of-care (PoC) versions of these complex devices, we often need redesign the whole system to ensure portability, cost-efficiency, robustness, and ease-of-use. This typically mandates the integration of the electronics components. In this paper, we examine the integration of the biological and chemical sensors and discuss their electronic performance challenges and possible solutions. The ultimate goal here is to connect the dots between different sensor classes in these applications and the optimal circuit architectures.

Multiplexed identification, quantification and genotyping of infectious agents using a semiconductor biochip

The emergence of pathogens resistant to existing antimicrobial drugs is a growing worldwide health crisis that threatens a return to the pre-antibiotic era. To decrease the overuse of antibiotics, molecular diagnostics systems are needed that can rapidly identify pathogens in a clinical sample and determine the presence of mutations that confer drug resistance at the point of care. We developed a fully integrated, miniaturized semiconductor biochip and closed-tube detection chemistry that performs multiplex nucleic acid amplification and sequence analysis. The approach had a high dynamic range of quantification of microbial load and was able to perform comprehensive mutation analysis on up to 1,000 sequences or strands simultaneously in <2 h. We detected and quantified multiple DNA and RNA respiratory viruses in clinical samples with complete concordance to a commercially available test. We also identified 54 drug-resistance-associated mutations that were present in six genes of Mycobacterium tuberculosis, all of which were confirmed by next-generation sequencing.

An array-based melt curve analysis method for the identification and classification of closely related pathogen strains

Abstract PCR-based techniques are widely used to identify disease causing bacterial and viral pathogens, especially in point-of-care or near-patient clinical settings that require rapid results and sample-to-answer workflows. However, such techniques often fail to differentiate between closely related species that have highly variable genomes. Here, a homogenous (closed-tube) pathogen identification and classification method is described that combines PCR amplification, array-based amplicon sequence verification, and real-time detection using an inverse fluorescence fluorescence-resonance energy transfer technique. The amplification is designed to satisfy the inclusivity criteria and create ssDNA amplicons, bearing a nonradiating quencher moiety at the 5ʹ-terminus, for all the related species. The array includes fluorescent-labeled probes which preferentially capture the variants of the amplicons and classify them through solid-phase thermal denaturing (melt curve) analysis. Systematic primer and probe design algorithms and empirical validation methods are presented and successfully applied to the challenging example of identification of, and differentiation between, closely related human rhinovirus and human enterovirus strains.

4.2 A fully integrated CMOS fluorescence biochip for multiplex polymerase chain-reaction (PCR) processes

Integration and miniaturization of bio-molecular detection systems into electronic biosensors and lab-on-chip platforms is of great importance. One widely recognized application area for such devices is nucleic acid (DNA and RNA) detection, specifically, nucleic acid amplification testing (NAAT), which relies on enzymatic processes such as polymerase chain reaction (PCR) to increase the copy number of target sequences and detecting them spectroscopically [1,2].

CMOS biochips for hypothesis-driven DNA analysis

High-throughput and highly multiplexed DNA detection platforms require complex and generally bulky instrumentation to perform sensing, signal conditioning and quantification. Integrated CMOS biosensor arrays (CMOS biochips) have the ability to miniaturize such platforms into portable and low cost point-of-care (PoC) devices, that can be instrumental for the adoption of genomics test in molecular diagnostics (MDx). This paper focuses on CMOS biochips for detecting specific DNA sequences in a sample (i.e., hypothesis-driven analysis) employing DNA hybridization arrays. It examines various aspects of CMOS biochips technology including detection modalities, pixel architectures, ease-of-integration into VLSI processes, and limits of performance.

VLSI-enabled DNA sequencing arrays

Massively-parallel, integrated, sensitive and low-cost bio-molecular detectors are an essential part of “next generation” DNA sequencing systems. This paper discusses various design methodologies that leverage the versatility of VLSI technologies, specifically CMOS fabrication processes, to build highly integrated sequencing arrays while addressing the stringent detection and integration requirements. The goal of this paper is to discuss both the advantages and the limitations of next generation VLSI-enabled DNA sequencers.