Affinity-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. / text

Biosensors are extremely powerful analytical tools instrumental for detection and quantification of bio-molecules such as DNA, peptides and even metabolites. The recent decade has seen a surge in biosensing applications ranging from molecular diagnostics, environmental monitoring, basic life science research, forensics and biothreat monitoring. The existing biosensor systems of today, however, have several limitations. They are expensive, bulky in size, power hungry, hard to use and with access limited to core facilities. Among other disadvantages, these impediments discourage the availability of point-of-care testing and low cost in-vitro diagnostics (IVD) in locations such as developing and third world countries. The main bottleneck in the development of low-cost and compact biosensors is the effective and efficient integration of several complex components present inside a typical biosensor. These components are the sample preparation, biomolecular recognition, signal transduction and data analysis. With vii the recent advancements in very large scale integration (VLSI) and fabrication technologies, it is now possible to integrate several of these biosensing components into a small form factor. This thesis proposes leveraging the utilization of VLSI technology to develop a low-cost, miniature, portable, fast analysis, high throughput and low power consumption biosensor solution. Apart from the miniaturization bene- fits, employing VLSI technology facilitates low-cost, high yield and low process variation. We present complementary metal-oxide semiconductor (CMOS) integrated microsystem solutions for fluorescence, bioluminescence and electrochemical biosensing. Simulation models are provided for the microsystems and the specifications for the constituent components derived. A common problem in the transducer development of biosensors that we specifically focus on, is the presence of a large non-informative signal called the background signal. This background signal can be several orders of magnitudes higher than the signal of interest and it reduces the overall sensitivity of the biosensor. Existing transducer solutions rely on very high dynamic range, expensive and power hungry solutions to solve the problem of high background signal. To address the problem of overwhelming background signal, this thesis proposes an active background subtraction architecture merged with a Σ∆ modulator. The robust, versatile architecture can be conveniently employed for optical and electrochemical sensing. The proposed architecture attenuates the background signal very early in the signal chain, achieving high dyviii namic range while significantly relaxing the performance requirements of the subsequent circuit blocks in terms of power dissipation, area and bandwidth requirements. To validate the proposed solution, two CMOS IC prototypes were developed for optical and electrochemical sensing respectively. A 12 × 12 array of Σ∆ photodetector with in-pixel background subtraction was developed in 0.18µm standard CMOS technology. The pixel performance has been validated with over 140dB dynamic range and the ability of subtract the background subtraction current validated from 10nA to 10fA. Real time pyrosequencing experiment has also been performed utilizing the photodetector array. A 12 × 12 array of Σ∆ electrochemical sensor with in-pixel background subtraction was developed in 0.18µm standard CMOS technology. Capacitive charge redistribution circuit architecture for bipolar current measurements was employed. The circuit performance was validated over the wide input current range of 100nA to 1pA. / text