288 IEEE SENSORS JOURNAL, VOL. 3, NO. 3, JUNE 2003 A Review of Photodetectors for Sensing Light-Emitting Reporters in Biological Systems Rachel A. Yotter, Member, IEEE, and Denise Michelle Wilson, Member, IEEE Abstract—A review of photodetectors for optical detection in biological applications is presented. The intent is to provide an overview of the performance metrics and trade-offs among pop- ular photodetectors in order to facilitate an easier match among the photodetector, biological stimulus, and optical pathway. The characteristics and nonidealities of fluorescent and phosphores- cent reporters, and the properties of optical components such as filters, lenses, and light sources, are reviewed. By accounting for sources of noise in these components, it is shown how to deter- mine metrics for the optical system that can then be converted to photodetector metrics. Defined photodetector metrics include the quantum efficiency, responsivity, noise-equivalent power, de- tectivity, gain, dark current, response time, and noise spectrum. The operating principles and performance trade-offs of photode- tectors are reviewed, and emphasis is placed on photodetectors for integrated compact systems. Top commercial candidates for photodetectors for detecting light emitted from reporters are the photomultiplier tube, avalanche photodiode, and charge-coupled device. Focus is placed on new developments in complementary metal-oxide-semiconductor structures that can provide low-cost, low-power, and low-voltage alternatives to traditional approaches to biological imaging. Reviewed device structures are presented in the context of supporting the development of laboratory-based in- struments and compact fully-integrated systems. Index Terms—Avalanche photodetectors, biosensors, charge-coupled devices, complementary metal-oxide-semi- conductor (CMOS) photodetectors, dark current, detectivity, fluorescence, integrated optical systems, noise, noise bandwidth, noise spectrum, noise-equivalent power, phosphorescence, pho- todetector, photodiodes, photomultiplier tubes, power spectral density, quantum efficiency, response time, responsivity, review. I. INTRODUCTION P HOTODETECTORS used to detect light-emitting re- porters operate under a different set of restrictions than those used for other common applications. Sensitivity plays a predominant role in the selection of photodetectors or arrays of photodetectors for interpreting events, molecules, proteins, DNA, or other biological segments tagged with fluorescent or phosphorescent probes. Secondary to sensitivity, biological sensing requirements include the wavelength range of the light, response time, and the intensity or number of photons generated in a unit time. Matching the spectral peak of the photodetector to the application is often an assumed require- ment to maximize application sensitivity. Often, a significant Manuscript received May 16, 2002; revised November 12, 2002. This work was supported by the National Institute of Health under Award P50 HG002360-01. The associate editor coordinating the review of this paper and approving it for publication was Dr. Gerard L. Coté. The authors are with the Department of Electrical Engineering, University of Washington, Seattle, WA 98195-2500 USA (e-mail: raytrace@u.wash- ington.edu). Digital Object Identifier 10.1109/JSEN.2003.814651 portion of the light intensity from the fluorescing agent is eliminated prior to photodetection because of emission filters and other elements of the optical train that, in the process of removing interfering light contributions, also remove a significant portion of the signal. In contrast to imaging for biosensing, conventional visual imaging requires high spatial resolution, wide dynamic range, and moderate sensitivity in order to produce the most (spatially) detailed image across a wide range of background illumination conditions. Very high sensitivity is usually not required and individual photodetector response times in an imager are often limited by the ability to scan an entire image within the 30 frame per second limit of human visual capability. Desired spatial resolution is un- bounded in these imagers, limited only by the space consumed by the imager, the amount consumers are willing to pay, and the frame-level response time incurred by ever-increasing numbers of pixels on the focal plane. This paper focuses on the design issues relevant for optical systems and detectors used to detect light-emitting reporters, including design trade-offs and methods to match photodetector performance with the optical system. The operating principles of common photodetectors for these systems are reviewed, and emphasis is placed on new alternative methods that are especially suited for low-power, fully-integrated biological systems. II. BACKGROUND Photodetectors fundamentally operate on the transition of an electron from a lower energy state to a higher energy state as a result of the absorption of a photon. The energy transition can usually be classified into one of the following categories. 1) Photoconductive or photovoltaic: The electron undergoes a transition from the valence band to the conduction band. In pho- toconductive devices, photons generate carriers that lower the resistance of the device. Photovoltaic devices include a metal- lurgical junction in which photons generate a voltage across the depletion region. 2) Photoelectric (photoemissive): The electron undergoes a transition from the conduction band to a vacuum. One electron is released into the vacuum per photon of sufficient energy. 3) Polarization: The electron undergoes a transition to a virtual energy state (as in index of refraction changes and other polarization effects). 4) Phonon generation: The electron under- goes a transition to midgap states and back to an initial relaxed level. This is equivalent to heat generation. 5) Other: The energy is converted to other forms via mechanisms such as excitons. In addition to classification related to the nature of electron transitions, electronic photodetectors can be also classified into two broad categories based on the efficiency of transition: direct 1530-437X/03$17.00 © 2003 IEEE