Integrated impedance spectroscopy biosensors

textAffinity-based biosensors, or in short biosensors, are extremely powerful and versatile analytical tools which are used for the detection of a wide variety of bio-molecules. In recent times, there has been a need for developing low-cost and portable affinity-based biosensor platforms. Such systems need to have a high density of detection sites (i.e biosensing elements) in order to simultaneously detect multiple analytes in a single sample. This has led to the creation of integrated biosensors, which make use of integrated circuits (ICs) for bio-molecular detection. In such systems, it has been demonstrated that by taking advantage of the capabilities of semiconductor and very large scale integrated (VLSI) circuit fabrication processes, it is possible to build compact miniaturized biosensors, which can be used in wide variety of applications such as in molecular diagnostics and for environmental monitoring. Among the various detection modalities for biosensors, Electrochemical Impedance Spectroscopy (EIS) permits real-time detection and has label-free detection capabilities. EIS is fully electronic in nature. Hence, it can be implemented using standard IC technologies. The versatility and ease of integration of EIS makes it a promising candidate for developing integrated biosensor platforms. In this thesis, we first examine the underlying principles of EIS method of biosensing. By analyzing an immunosensor assay as an example, we show that EIS based biosensing is a highly sensitive detection method, which can be used for the detection of a wide variety of analytes. Since EIS relies on small impedance changes in order to perform detection, it requires highly accurate models for the electrode-electrolyte systems. Hence, we also introduce a compact modeling technique for the distributed electrode-electrolyte systems with non-uniform electric fields, which is capable of modelling noise and other non-idealities in EIS. In the second part of this thesis, we describe the design and implementation of an integrated EIS biosensor array, built using a standard complementary metal-oxide-semiconductor (CMOS) process. The chip is capable of measuring admittance values as small as 10nS and has a wide dynamic range (90dB) over a wide range of frequencies (10Hz-50MHz). We also report the results obtained from the DNA and protein detection experiments performed using this chip.Electrical and Computer Engineerin

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

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

Proposal for fourth generation of Maintenance and the future trends &amp; challenges in Production

Maintenance has evolved over centuries and has played significant role for growth of organizations. Maintenance history is differentiated by three generations, the development of maintenance considered from being “necessary evil” to “profit contributor”. Many literatures have discussed maintenance for optimization and increasing profitability but little on the factors which influence on the future of maintenance. Maintenance should be considered as a “competitive factor” in the future. Many trends have evolved in production and every trend had a major contribution towards production development. The successful implementation of the trends is considered to be a major challenge. Little literatures have talked on the emerging trends and challenges in production. The thesis reviews the historical development of maintenance over generations and presents the key factors which play a major role during the fourth generation, and also identifies the emerging trends and challenges to be faced by production. The literature review, interviews and surveys were used in this thesis. Academic researchers and industrial experts from both maintenance and production department answered the interview and survey questions for this research. The key factors for the proposal of fourth generation of maintenance and the emerging trends and challenges to be faced by production are presented. The result from the research questions and the empirical findings are summarized in a framework that will enable readers to know the historical development of maintenance, the key factors to be considered for the fourth generation of maintenance and the emerging trends and challenges to be faced by production in future. In addition, the thesis also discusses the impact of information technology on the future of maintenance and the effect of sustainability in the future of production.

Integrated electro-analytical biosensor array

A biosensor pixel for measuring current that flows through the electrode surface in response to electrochemical interactions and a biosensor array architecture that includes such biosensor pixels. The biosensor pixel includes an electrode transducer configured to measure a current generated by electrochemical interactions occurring at a recognition layer placed directly on top of it in response to an electrical voltage placed across an electrode transducer-electrolyte interface. The biosensor pixel further includes a trans-impedance amplifier connected to the electrode transducer, where the trans-impedance amplifier is configured to convert the current into a voltage signal as the electrochemical interactions occur. Additionally, the biosensor pixel includes a 1-bit comparator coupled to the trans-impedance amplifier and a 1-bit digital-to-analog converter coupled to the 1-bit comparator, where the 1-bit digital-to-analog converter injects different levels of charge into an input of the trans-impedance amplifier at each cycle based on an output of the 1-bit comparator.Board of Regents, University of Texas Syste

Integrated optical biosensor array including charge injection circuit and quantizer circuit

An optical biosensor pixel for detecting the amount of light that is generated by the biosensing process and a biosensor array architecture that includes such biosensor pixels. The optical biosensor pixel includes a photodiode configured to convert an incident photon flux into a current. Additionally, the optical biosensor pixel includes an optical filter configured to select specific wavelengths and/or photon flux angles to reach the photodiode from a biological sample. The biosensor pixel further includes a trans-impedance amplifier coupled to the photodiode, where the trans-impedance amplifier is configured to convert the current into a voltage signal. Additionally, the biosensor pixel includes a 1-bit comparator coupled to the trans-impedance amplifier and a 1-bit digital-to-analog converter coupled to the 1-bit comparator, where the 1-bit digital-to-analog converter injects different levels of charge into an input of the trans-impedance amplifier at each cycle based on an output of the 1-bit comparator.Board of Regents, University of Texas Syste

Incorporating CMOS integrated circuits in the design of affinity-based biosensor systems

A biosensor system incorporating CMOS integrated circuits. In one type of biosensor system, the biosensor system includes a silicon substrate. The biosensor system further includes active devices fabricated on the silicon substrate. Additionally, the biosensor system includes a plurality of metal layers stacked on top of the active devices. Furthermore, the biosensor system includes a passivation layer covering a top metal layer, where the passivation layer includes an opening configured to expose the top metal layer, where the opening is used as a sensing electrode. Additionally, the biosensor system includes a plurality of probes attached to the sensing electrode.Board of Regents, University of Texas Syste

Active-electrode integrated biosensor array and methods for use thereof

A method and device for performing DNA sequencing and extracting structural information from unknown nucleic acid strands. The device includes a microwell structure, where identical DNA strands are immobilized within the microwell structure on a surface of a micro-bead, an active electrode or a porous polymer. The device further includes a CMOS-integrated semiconductor integrated circuit, where the CMOS-integrated semiconductor integrated circuit includes metal layers on a silicon substrate, where the metal layers form an active electrode biosensor. In addition, a sensing electrode is formed by creating openings in a passivation layer of the CMOS-integrated semiconductor integrated circuit to hold a single bead, on which the DNA strands are immobilized.Board of Regents, University of Texas Syste

Role of fluorodeoxyglucose positron emission tomography-Computed tomography in thyroid malignancy

The role of FDG PET CT in thyroid malignancy is not clearly established. Malignancy of the thyroid remains poses issues very different from the squamous carcinomas of the upper aerodigestive tract where PET-CT is usually used. Though this is the most common endocrine malignancy, many a times it is difficult to diagnose malignancy in thyroid nodules. The biology of well differentiated thyroid cancer, medullary carcinoma, poorly differentiated carcinoma and anaplastic carcinoma varies significantly and management strategies differ dramatically. FDG PET can be used as a wonderful tool in thyroid malignancy for selected indications