1712 IEEE PHOTONICS TECHNOLOGY LETTERS, VOL. 16, NO. 7, JULY 2004 Compact Label-Free Biosensor Using VCSEL-Based Measurement System Carlos F. R. Mateus, Student Member, IEEE, Michael C. Y. Huang, Member, IEEE, Peter Li, Brian T. Cunningham, Member, IEEE, and Connie J. Chang-Hasnain, Fellow, IEEE Abstract—We report an ultracompact label-free biosensor that uses a vertical-cavity surface-emitting laser (VCSEL)-based mea- surement system for the characterization of biomolecular interac- tions. It consists of a VCSEL, a plastic guided-mode resonant filter, and two p-i-n detectors. The system has demonstrated very high sensitivity to molecules on top of the sensor. Index Terms—Biomedical transducer, drugs, dynamic response, label-free, nonintrusive, protein. I. INTRODUCTION B IOASSAYS are important tools used to detect interactions of various biomolecular complexes for pharmaceutical and biomedical applications. In addition, such analysis methods can provide a deep understanding on how proteins, encoded by DNA, interact with enzymes, inhibitors, or other proteins. In general, bioassay techniques can be put into two cat- egories: Labeling with compounds (such as fluorescent, radioactive, or colorimetric) and direct molecule identification. For the majority of bioassays currently performed for life science research and pharmaceutical screening, fluorescent or colorimetric chemical labels are commonly attached to the molecules under study [1]. Labels can be readily visualized and the measurement technique is simple. However, the attachment of labels may substantially increase the assay complexity. It may also alter the functionality of molecules through confor- mational modification or epitope blocking, which ultimately leads to errors in the data interpretation. A label-free sensor is a bioassay tool that enables direct mol- ecule detection, and it is generally desirable due to its nonin- trusive nature of detection. The sensor typically consists of two parts. The first part is the binding surface, which is activated (coated) with a known receptor molecule that has a high affinity to the molecules to be detected. The second part is the detec- tion mechanism that converts a recognizable molecular binding event into a quantifiable signal. The activation step is always done a priori. Assays using this method are much faster than Manuscript received January 12, 2004; revised March 13, 2004. This work was supported by Defense Advanced Research Projects Agency (DARPA) Center for Bio-Optoelectric Sensor Systems (BOSS) under Contract MDA9720010020. The work of C. F. R. Mateus was supported by Brazilian Air Command and CAPES Foundation. C. F. R. Mateus, M. C. Y. Huang, and C. J. Chang-Hasnain are with the Department of Electrical Engineering and Computer Sciences, Uni- versity of California, Berkeley, CA 94720 USA (e-mail: mateus@pho- tonics.eecs.berkeley.edu; cch@eecs.berkeley.edu). P. Li and B. T. Cunningham are with SRU Biosystems, Woburn, MA 01801 USA. Digital Object Identifier 10.1109/LPT.2004.828851 the compound labeled ones, since no additional incubation and activation steps for the attachment of labels are required. Thus, the reduction in assay complexity results in faster screening or developing time. Optical biosensors are well suited for label free sensing and utilize light as their detection mechanism. They have several ad- vantages, such as in situ real-time process monitoring and high sensitivity to surface modifications, where most of the biopro- cesses take place [2]. Optical methods can be measured by dif- ferent quantities, such as angle, polarization, phase, amplitude, and frequency. The versatility of optical methods is noticeable by the success of several devices such as surface plasmon res- onance, output grating couplers, ellipsometry, evanescent wave devices, and reflectance interference spectroscopy [1], [2]. Al- though bioassays using those methods are fairly sensitive, they are still quite slow, bulky, and expensive. In this letter, we present an ultracompact label-free biosensor that uses a vertical-cavity surface-emitting laser (VCSEL)-based measurement system. It has high sensitivity, high resolution, low power consumption, low cost, and the potential advantage of fabrication in two-dimensional (2-D) arrays. II. BIOSENSOR SYSTEM The biosensor system contains a guided-mode resonant (GMR) filter as the activated surface [3]. Light incident onto the GMR in the normal direction can yield a narrow reflectance peak with reflectivity close to unity. The resonant wavelength is a strong function of the optical thickness of the layer immediately above the grating. Hence, the wavelength shift can be used to detect minute changes in thickness and refractive index of the biomolecules that are attached to the grating surface. To date, the GMR method has demonstrated very high sen- sitivity and suitability for both dry and wet samples. Moreover, the GMR can be fabricated from plastic, thus making it very low cost, disposable, and environment-friendly [4]. The previously reported detection system consists of a white light source that il- luminates the GMR sensor through an optical fiber that also col- lects the reflected light to couple it to a spectrometer. The spec- trometer signal is then monitored to detect wavelength shifts [4]. Despite its high sensitivity, resolution will always be limited by the spectrometer pixel-wise nature and the tradeoff between resolution and signal strength can limit further improvements. Major challenges remain on how to make a low-cost, compact, and portable system that has high resolution and throughput. 1041-1135/04$20.00 © 2004 IEEE