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Journal of Biomedical Optics 9 5 913 921 September October 2004 Parallel single molecule detection with a fully integrated single photon 2 2 CMOS detector array Michael Go sch Karolinska Institute Department of Medical Biochemistry and Biophysics S 171 77 Stockholm Sweden and E cole Polytechnique Fe de rale de Lausanne Laboratoire d Optique Biomedicale CH 1015 Lausanne Switzerland Alexandre Serov Tiemo Anhut Theo Lasser E cole Polytechnique Fe de rale de Lausanne Laboratoire d Optique Biomedicale CH 1015 Lausanne Switzerland Alexis Rochas Pierre Andre Besse Radivoje S Popovic E cole Polytechnique Fe de rale de Lausanne Institute of Microelectronics and Microsystems CH 1015 Lausanne Switzerland Hans Blom Royal Institute of Technology Department of Microelectronics and Information Technology Electrum 229 S 16440 Kista Sweden Abstract We present parallel single molecule detection SMD and fluorescence correlation spectroscopy FCS experiments with a fully integrated complementary metal oxide semiconductor CMOS singlephoton 2 2 detector array Multifocal excitation is achieved with a diffractive optical element DOE Special emphasis is placed on parallelization of the total system The performance of the novel singlephoton CMOS detector is investigated and compared to a state of theart single photon detecting module having an actively quenched avalanche photodiode APD by measurements on free diffusing molecules at different concentrations Despite the order of magnitude lower detection efficiency of the CMOS detector compared to the state of the art single photon detecting module we achieve single molecule sensitivity and reliably determine molecule concentrations In addition the CMOS detector performance for the determination of the fraction of slowly diffusing molecules in a primer solution twocomponent analysis is demonstrated The potential of this new technique for high throughput confocal detection based systems is discussed 2004 Society of Photo Optical Instrumentation Engineers DOI 10 1117 1 1781668 Keywords parallel single molecule detection single photon detector complementary metal oxide semiconductor technology detector arrays parallel confocal spectroscopy fluorescence correlation spectroscopy Paper 03104 received Aug 11 2003 revised manuscript received Jan 27 2004 accepted for publication Feb 17 2004 Rudolf Rigler Karolinska Institute Department of Medical Biochemistry and Biophysics SE 171 77 Stockholm Sweden E mail rudolf rigler mbb ki se 1 Introduction Confocal spectroscopy in combination with fluorescence correlation spectroscopy FCS is an experimental technique used for examination of the chemical and photophysical dynamics at the single molecule level see the review in Ref 1 Here an autocorrelation curve is obtained by measuring the random intensity fluctuations of a fluorescent signal generated by the radiative relaxation of light excited molecules 2 4 A remarkable SNR is achieved by inserting a pinhole thereby generating a confocal



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