High dynamic range CMOS-integrated biosensors (2013)

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.