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CMOS detector array

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Parallel single molecule detection with a fully integratedsingle-photon 2Ã2 CMOS detector arrayMichael Go¨schKarolinska InstituteDepartment of Medical Biochemistry and BiophysicsS-171 77 Stockholm, SwedenandE´cole Polytechnique Fe´de´rale de LausanneLaboratoire d’Optique BiomedicaleCH-1015 Lausanne, SwitzerlandAlexandre SerovTiemo AnhutTheo LasserE´cole Polytechnique Fe´de´rale de LausanneLaboratoire d⬙Optique BiomedicaleCH-1015 Lausanne, SwitzerlandAlexis RochasPierre-Andre´BesseRadivoje S. PopovicE´cole Polytechnique Fe´de´rale de LausanneInstitute of Microelectronics and MicrosystemsCH-1015 Lausanne, SwitzerlandHans BlomRoyal Institute of TechnologyDepartment of Microelectronics and InformationTechnologyElectrum 229S-16440 Kista, SwedenRudolf RiglerKarolinska InstituteDepartment of Medical Biochemistry and BiophysicsSE-171 77 Stockholm, SwedenE-mail: [email protected]. We present parallel single molecule detection (SMD) andfluorescence correlation spectroscopy (FCS) experiments with a fullyintegrated complementary metal oxide semiconductor (CMOS) single-photon2⫻ 2 detector array. Multifocal excitation is achieved with adiffractive optical element (DOE). Special emphasis is placed on par-allelization of the total system. The performance of the novel single-photon CMOS detector is investigated and compared to a state-of-the-art single-photon detecting module [having an actively quenchedavalanche photodiode (APD)] by measurements on free diffusing mol-ecules at different concentrations. Despite the order of magnitudelower detection efficiency of the CMOS detector compared to thestate-of-the-art single-photon detecting module, we achieve singlemolecule sensitivity and reliably determine molecule concentrations.In addition, the CMOS detector performance for the determination ofthe fraction of slowly diffusing molecules in a primer solution (two-component analysis) is demonstrated. The potential of this new tech-nique for high-throughput confocal-detection-based systems is dis-cussed.©2004 Society of Photo-Optical Instrumentation Engineers.[DOI: 10.1117/1.1781668]Keywords: parallel single molecule detection; single-photon detector; complemen-tary metal oxide semiconductor technology; detector arrays; parallel confocal spec-troscopy; fluorescence correlation spectroscopy.Paper 03104 received Aug. 11, 2003; revised manuscript received Jan. 27, 2004;accepted for publication Feb. 17, 2004.1 IntroductionConfocal spectroscopy in combination with fluorescence cor-relation spectroscopy 共FCS兲 is an experimental techniqueused for examination of the chemical and photophysical dy-namics at the single-molecule level 共see the review in Ref. 1兲.Here, an autocorrelation curve is obtained by measuring therandom intensity fluctuations of a fluorescent signal generatedby the radiative relaxation of light-excited molecules.2–4Aremarkable SNR is achieved by inserting a pinhole, therebygenerating a confocal detection volume of femtoliter order.5Recently, FCS has emerged as a powerful method for analyz-ing dynamic processes at the molecular level: molecularinteractions,2,3conformational changes,6,7chemical reactions,8protein binding to cell membranes,9photophysicaldynamics,10and transport or flow properties11are examples ofsubjects examined by FCS. In addition, FCS can also be apowerful tool for drug discovery and development and diag-nostic tests in medicine.1,12,13Further development of FCS requires the design of newdevices, e.g., detectors in our case, with improved perfor-mance, extended capacities, and reliable throughput features.One of the rapidly developing markets where this technique isused is biochip microarray analysis. Today’s microarray sys-tems feature from a few up to a hundred thousand13–15sampled spots on a single biochip. Therefore, a high-spatial-resolution technique is required for both the fabrication pro-cess and detection. The measurement time for scanning a mi-croarray with confocal FCS is directly proportional to thenumber of measured spots and often can reach a few hours.The use of intensified CCDs, with several thousand detectorelements, is not a solution for parallel FCS detection of singlemolecules, as CCD-based systems have a much longer read-out time compared to the 1-ns to 1-ms dynamics of single-photon events 共although single-photon sensitivity can beachieved with a cooled system兲. To increase the detectionspeed it is necessary to achieve multiplexing 共parallelism兲with high spatial resolution. Obviously, a parallel detectionapproach will enable enhanced analysis speed as compared toa single confocal laser focus. This would extend the range ofAddress all correspondence to Rudolf Rigler, Karolinska Institute, Department ofMedical Biochemistry and Biophysics, SE-171 77 Stockholm, Sweden. Tel: +41-21-693-8700; Fax: +41-21-693-8700; E-mail: [email protected]/2004/$15.00 © 2004 SPIEJournal of Biomedical Optics 9(5), 913–921 (September/October 2004)Journal of Biomedical Optics䊉September/October 2004䊉Vol. 9 No. 5 913applications of FCS, particularly for use with high-densitymicroarrays and for the detection of molecules at very low共picomolar兲 concentrations.Recently, a first spatial multiplexing experiment at thesingle-molecule level was reported by Blom et al.14,16Multi-focal excitation with a2⫻ 2 fan-out diffractive optical ele-ment 共DOE兲, resulting in four confocal volume elements, wasperformed. The detection of the fluorescence signal was real-ized through four optical fibers coupled to commerciallyavailable single-photon detection modules. The feasibility ofthe parallel approach was demonstrated by measurements ondye labeled nucleotides. However, the use of fiber optics islimited to a small number of parallel channels, because oth-erwise the detection stage adjustment would become unman-ageably complex.In this paper, we report confocal detection experiments uti-lizing a fully integrated2⫻ 2 array of Geiger-mode avalanchephotodiodes made by an industrial complimentary metal-oxide semiconductor 共CMOS兲 process, which we will hence-forth refer to as the CMOS single-photon avalanche detector共CMOS SPAD兲. Single pixels as well as detector arrays inte-grated with the driving electronics were optically character-ized by Rochas et al.17,18Despite the low detection efficiencyof the CMOS SPAD we nonetheless demonstrate, with anarray of such detectors, the feasibility of a parallel FCS


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