Integrated CMOS optical sensors for fluorescence detection and contact imaging

Abstract

The growing interest in analyzing single cells or even single molecules has inspired a great deal of research and engineering in developing low cost, high throughput, and high sensitivity biosensor systems. This work focuses on integrated CMOS optical sensors for fluorescence detection and contact imaging. Among many relevant techniques available for biological testing and molecular detection, fluorescence-based methods generally achieve the highest sensitivity and are the most widely used. We describe several contributions towards incorporating fluorescence sensing into low cost miniaturized platforms. We first investigated the spectral responsivities of photodetectors available in a commercially available CMOS process in order to assess the need for additional optical filtering. Further, we developed a low noise photodetector in a standard CMOS process. Both the reset noise and readout noise of the sensor were significantly improved compared to a conventional pixel structure widely used as a CMOS image sensor. The sensor successfully detected nanomolar concentrations of fluorescence indicator, 2 orders of magnitude less than the recommended assay concentration for commercial fluorescence detection devices. Miniaturized high-throughput biosensor systems for single cell characterization require the ability to steer microscale biological cells to distinct locations without macroscale imaging systems. One simple and promising approach to building a miniaturized imaging system with microscale resolution is to directly couple the sensor array with the sample of interest. To investigate this approach, we explored the theoretical limitations of contact imaging with the aid of an optics simulator. Experimental results confirmed the theoretical predictions. Two possible applications of contact imaging were also demonstrated. We further describe a contact image sensor with improved spatial resolution. A novel pixel structure is developed for suppressing increased dark current in a commercially available 0.18 µm CMOS process. Simple on-chip processing was implemented to alleviate the need for subsequent image processing for locating small particles. The original contributions of this thesis include: low noise active pixel sensor (APS); demonstration of integrated fluorescence sensing; simulation of contact imaging; experimental validation and demonstration of contact imaging applications; low dark current APS pixel; architecture for threshold generation and on-chip particle detection.