Abstract

We have developed a multifocal diffractive-optical fluorescence correlation spectroscopy system for parallel excitation and detection of single tetramethylrhodamine biomolecules in microarrays. Multifocal excitation was made possible through the use of a 2 × 2 fan-out diffractive-optical element with uniform intensity in all foci. Characterization of the 2 × 2 fan-out diffractive-optical element shows formation of almost perfect Gaussian foci of submicrometer lateral diameter, as analyzed by thermal motion of tetramethylrhodamine dye molecules in solution. Results of parallel excitation and detection in a high-density microarray of circular wells show single-biomolecule sensitivity in all four foci simultaneously.

© 2002 Optical Society of America

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    [CrossRef]
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    [CrossRef]

2002

2001

D. S. Mehta, C. Y. Lee, A. Chiou, “Multipoint parallel excitation and CCD-based imaging system for high-throughput fluorescence detection of biochip micro-arrays,” Opt. Commun. 190, 59–68 (2001).
[CrossRef]

M. Sauer, B. Angerer, W. Ankenbauer, Z. Földes-Papp, F. Göbel, K.-T. Han, R. Rigler, A. Schultz, J. Wolfrum, C. Zanders, “Single molecule DNA sequencing in submicrometer channels: State of the art and future prospects,” J. Biotechnol. 86, 181–201 (2001).
[CrossRef] [PubMed]

2000

D. P. Herten, P. Tinnenfeld, M. Sauer, “Identification of single fluorescently labelled mononucleotide molecules in solution by spectrally resolved time-correlated single photon counting,” Appl. Phys. B 71, 765–771 (2000).
[CrossRef]

A. Holmberg, “DNA-microarrays: novel techniques to study aging and guide gerentologic medicine,” Exp. Gerentol. 36, 1189–1198 (2000).
[CrossRef]

D. J. Lockhart, E. A. Winzeler, “Genomics, gene expression and DNA arrays,” Nature (London) 405, 827–836 (2000).
[CrossRef]

D. R. Walt, “Bead based fiber-optical arrays,” Science 287, 451–452 (2000).
[CrossRef] [PubMed]

Y. Chen, J. D. Müller, S. Y. Tetin, J. D. Tyner, E. Gratton, “Probing ligand protein binding equilibria with fluorescence fluctuation spectroscopy,” Biophys. J. 79, 1074–1084 (2000).
[CrossRef] [PubMed]

F. J. Steemers, J. A. Ferguson, D. R. Walt, “Screening unlabeled DNA targets with randomly ordered fiber-optic gene arrays,” Nat. Biotechnol. 18, 91–94 (2000).
[CrossRef] [PubMed]

1999

L. O. Tjernberg, A. Pramanik, S. Björling, P. Thyberg, J. Thyberg, C. Nordstedt, K. D. Berndt, R. Rigler, “Amyloid β-peptide polymerisation studied using fluorescence correlation spectroscopy,” Chem. Biol. 6, 53–62 (1999).
[CrossRef] [PubMed]

P. Kask, K. Palo, D. Ullmann, K. Gall, “Fluorescence-intensity distribution analysis and its application in biomolecular detection technology,” Proc. Natl. Acad. Sci. USA 96, 13756–13761 (1999).
[CrossRef] [PubMed]

J. Uppenbrink, D. Clery, “Single molecules,” Science 283, 1667–1695 (1999).
[CrossRef]

H. Martinsson, J. Bengtsson, M. Ghisoni, A. Larsson, “Monolithic integration of VCSEL and diffractive optical element for advanced beam shaping,” IEEE Photonics Technol. Lett. 11, 503–505 (1999).
[CrossRef]

R. J. Lipshutz, S. P. Fodor, T. R. Gingeras, D. J. Lockhart, “High density synthetic oligonucleotide arrays,” Nature Genet. 21, 20–24 (1999).
[CrossRef] [PubMed]

V. G. Cheung, M. Morley, F. Aguilar, A. Massimi, R. Kucherlapati, G. Childs, “Making and reading microarrays,” Nature Genet. Suppl. 2, 15–19 (1999).
[CrossRef]

S. J. Brinac, R. Gangadharan, M. MacMahon, J. Denman, R. Gonzales, L. G. Mendoza, M. Eggers, “A proximal CCD imaging system for high-throughput detection of microarray-based assays,” IEEE Eng. Med. Biol. Mag. 18, 120–122 (1999).
[CrossRef]

1998

D. G. Wang, J.-B. Fang, C.-J. Siao, A. Berno, P. Young, R. Sopolsky, G. Ghandour, N. Perkins, E. Winchester, J. Spencer, L. Kruglyak, L. Stein, L. Hsie, T. Topaloglou, E. Hubbel, F. Robinson, M. Mittmann, M. S. Morris, N. Shen, D. Kilburn, J. Rioux, C. Nusbaum, S. Rozen, T. J. Hudson, R. Lipshuts, M. Chee, E. S. Lander, “Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome,” Science 280, 1077–1082 (1998).
[CrossRef] [PubMed]

D. Whitecomb, C. R. Newton, S. Little, “Advantages in approaches to DNA-based diagnostics,” Curr. Opin. Biotechnol. 9, 602–608 (1998).
[CrossRef]

N. S. Gray, L. Wodicka, A.-M. W. H. Thunnissen, T. C. Norman, S. Kwon, F. H. Espinoza, D. O. Morgan, G. Barnes, S. LeClerc, L. Meijer, S.-H. Kim, D. J. Lockhart, P. G. Schultz, “Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors,” Science 281, 533–538 (1998).
[CrossRef] [PubMed]

M. J. Marton, J. L. DeRisi, H. A. Bennett, V. R. Iyer, M. R. Meyer, C. J. Roberts, R. Stoughton, J. Burchard, D. Slade, H. Dai, D. E. Bassett, L. H. Hartwell, P. O. Brown, S. H. Friend, “Drug target validation and identification of secondary drug target effects using DNA microarrays,” Nat. Med. (N.Y.) 4, 1293–1301 (1998).
[CrossRef]

1997

S. A. Fodor, “DNA sequencing: massively parallel genomics,” Science 277, 393–395 (1997).
[CrossRef]

P. Schwille, F. J. Meyer-Almes, R. Rigler, “Dual-color fluorescence cross-correlation spectroscopy for multicomponent diffusional analysis in solutions,” Biophys. J. 72, 1878–1886 (1997).
[CrossRef] [PubMed]

1996

R. A. Keller, W. P. Ambrose, P. M. Goodwin, J. H. Jett, J. C. Martin, W. Ming, “Single-molecule fluorescence analysis in solution,” Appl. Spectrosc. 50, 12A–32A (1996).
[CrossRef]

G. McGall, J. Labadie, P. Brock, G. Wallraff, T. Nguyen, W. Hinsberg, “Light-directed synthesis of high-density oligonucleotide arrays using semiconductor photoresists,” Proc. Natl. Acad. Sci. USA 93, 13555–13560 (1996).
[CrossRef] [PubMed]

L. Edman, Ü. Mets, R. Rigler, “Conformational transitions monitored for single molecules in solution,” Proc. Natl. Acad. Sci. USA 93, 6710–6715 (1996).
[CrossRef] [PubMed]

1995

J. Widengren, Ü. Mets, R. Rigler, “Fluorescence correlation spectroscopy of triplet states in solution: a theoretical and experimental study,” J. Phys. Chem. 99, 13368–13379 (1995).
[CrossRef]

M. Kinjo, R. Rigler, “Ultrasensitive hybridization analysis using fluorescence correlation spectroscopy,” Nucleic Acids Res. 23, 1795–1799 (1995).
[CrossRef] [PubMed]

M. Schena, D. Shalon, R. W. Davis, P. O. Brown, “Quantitative monitoring of gene expression patterns with a complementary DNA microarray,” Science 270, 467–470 (1995).
[CrossRef] [PubMed]

1994

M. Eigen, R. Rigler, “Sorting single molecules: application to diagnostics and evolutionary biotechnology,” Proc. Natl. Acad. Sci. USA 91, 5740–5747 (1994).
[CrossRef] [PubMed]

M. Larson, M. Ekberg, F. Nikolajeff, S. Härd, “Successive development optimization of resist kinoforms manufactured with direct electron-beam lithography,” Appl. Opt. 33, 1176–1179 (1994).
[CrossRef]

1993

R. Rigler, Ü. Mets, J. Widengren, P. Kask, “Fluorescence correlation spectroscopy with high count rate and low background: analysis of translational motion,” Eur. Biophys. J. 22, 169–175 (1993).
[CrossRef]

1974

E. L. Elson, D. Magde, “Fluorescence correlation spectroscopy. 1. Conceptual basis and theory,” Biopolymers 13, 1–27 (1974).
[CrossRef]

Aguilar, F.

V. G. Cheung, M. Morley, F. Aguilar, A. Massimi, R. Kucherlapati, G. Childs, “Making and reading microarrays,” Nature Genet. Suppl. 2, 15–19 (1999).
[CrossRef]

Ambrose, W. P.

Angerer, B.

M. Sauer, B. Angerer, W. Ankenbauer, Z. Földes-Papp, F. Göbel, K.-T. Han, R. Rigler, A. Schultz, J. Wolfrum, C. Zanders, “Single molecule DNA sequencing in submicrometer channels: State of the art and future prospects,” J. Biotechnol. 86, 181–201 (2001).
[CrossRef] [PubMed]

Ankenbauer, W.

M. Sauer, B. Angerer, W. Ankenbauer, Z. Földes-Papp, F. Göbel, K.-T. Han, R. Rigler, A. Schultz, J. Wolfrum, C. Zanders, “Single molecule DNA sequencing in submicrometer channels: State of the art and future prospects,” J. Biotechnol. 86, 181–201 (2001).
[CrossRef] [PubMed]

Barnes, G.

N. S. Gray, L. Wodicka, A.-M. W. H. Thunnissen, T. C. Norman, S. Kwon, F. H. Espinoza, D. O. Morgan, G. Barnes, S. LeClerc, L. Meijer, S.-H. Kim, D. J. Lockhart, P. G. Schultz, “Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors,” Science 281, 533–538 (1998).
[CrossRef] [PubMed]

Bassett, D. E.

M. J. Marton, J. L. DeRisi, H. A. Bennett, V. R. Iyer, M. R. Meyer, C. J. Roberts, R. Stoughton, J. Burchard, D. Slade, H. Dai, D. E. Bassett, L. H. Hartwell, P. O. Brown, S. H. Friend, “Drug target validation and identification of secondary drug target effects using DNA microarrays,” Nat. Med. (N.Y.) 4, 1293–1301 (1998).
[CrossRef]

Bengtsson, J.

J. Bengtsson, M. Johansson, “Fan-out diffractive optical elements designed for increased fabrication tolerances to linear relief depth errors,” Appl. Opt. 41, 281–289 (2002).
[CrossRef] [PubMed]

H. Martinsson, J. Bengtsson, M. Ghisoni, A. Larsson, “Monolithic integration of VCSEL and diffractive optical element for advanced beam shaping,” IEEE Photonics Technol. Lett. 11, 503–505 (1999).
[CrossRef]

Bennett, H. A.

M. J. Marton, J. L. DeRisi, H. A. Bennett, V. R. Iyer, M. R. Meyer, C. J. Roberts, R. Stoughton, J. Burchard, D. Slade, H. Dai, D. E. Bassett, L. H. Hartwell, P. O. Brown, S. H. Friend, “Drug target validation and identification of secondary drug target effects using DNA microarrays,” Nat. Med. (N.Y.) 4, 1293–1301 (1998).
[CrossRef]

Berndt, K. D.

L. O. Tjernberg, A. Pramanik, S. Björling, P. Thyberg, J. Thyberg, C. Nordstedt, K. D. Berndt, R. Rigler, “Amyloid β-peptide polymerisation studied using fluorescence correlation spectroscopy,” Chem. Biol. 6, 53–62 (1999).
[CrossRef] [PubMed]

Berno, A.

D. G. Wang, J.-B. Fang, C.-J. Siao, A. Berno, P. Young, R. Sopolsky, G. Ghandour, N. Perkins, E. Winchester, J. Spencer, L. Kruglyak, L. Stein, L. Hsie, T. Topaloglou, E. Hubbel, F. Robinson, M. Mittmann, M. S. Morris, N. Shen, D. Kilburn, J. Rioux, C. Nusbaum, S. Rozen, T. J. Hudson, R. Lipshuts, M. Chee, E. S. Lander, “Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome,” Science 280, 1077–1082 (1998).
[CrossRef] [PubMed]

Björling, S.

L. O. Tjernberg, A. Pramanik, S. Björling, P. Thyberg, J. Thyberg, C. Nordstedt, K. D. Berndt, R. Rigler, “Amyloid β-peptide polymerisation studied using fluorescence correlation spectroscopy,” Chem. Biol. 6, 53–62 (1999).
[CrossRef] [PubMed]

Brinac, S. J.

S. J. Brinac, R. Gangadharan, M. MacMahon, J. Denman, R. Gonzales, L. G. Mendoza, M. Eggers, “A proximal CCD imaging system for high-throughput detection of microarray-based assays,” IEEE Eng. Med. Biol. Mag. 18, 120–122 (1999).
[CrossRef]

Brock, P.

G. McGall, J. Labadie, P. Brock, G. Wallraff, T. Nguyen, W. Hinsberg, “Light-directed synthesis of high-density oligonucleotide arrays using semiconductor photoresists,” Proc. Natl. Acad. Sci. USA 93, 13555–13560 (1996).
[CrossRef] [PubMed]

Brown, P. O.

M. J. Marton, J. L. DeRisi, H. A. Bennett, V. R. Iyer, M. R. Meyer, C. J. Roberts, R. Stoughton, J. Burchard, D. Slade, H. Dai, D. E. Bassett, L. H. Hartwell, P. O. Brown, S. H. Friend, “Drug target validation and identification of secondary drug target effects using DNA microarrays,” Nat. Med. (N.Y.) 4, 1293–1301 (1998).
[CrossRef]

M. Schena, D. Shalon, R. W. Davis, P. O. Brown, “Quantitative monitoring of gene expression patterns with a complementary DNA microarray,” Science 270, 467–470 (1995).
[CrossRef] [PubMed]

Burchard, J.

M. J. Marton, J. L. DeRisi, H. A. Bennett, V. R. Iyer, M. R. Meyer, C. J. Roberts, R. Stoughton, J. Burchard, D. Slade, H. Dai, D. E. Bassett, L. H. Hartwell, P. O. Brown, S. H. Friend, “Drug target validation and identification of secondary drug target effects using DNA microarrays,” Nat. Med. (N.Y.) 4, 1293–1301 (1998).
[CrossRef]

Chee, M.

D. G. Wang, J.-B. Fang, C.-J. Siao, A. Berno, P. Young, R. Sopolsky, G. Ghandour, N. Perkins, E. Winchester, J. Spencer, L. Kruglyak, L. Stein, L. Hsie, T. Topaloglou, E. Hubbel, F. Robinson, M. Mittmann, M. S. Morris, N. Shen, D. Kilburn, J. Rioux, C. Nusbaum, S. Rozen, T. J. Hudson, R. Lipshuts, M. Chee, E. S. Lander, “Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome,” Science 280, 1077–1082 (1998).
[CrossRef] [PubMed]

Chen, Y.

Y. Chen, J. D. Müller, S. Y. Tetin, J. D. Tyner, E. Gratton, “Probing ligand protein binding equilibria with fluorescence fluctuation spectroscopy,” Biophys. J. 79, 1074–1084 (2000).
[CrossRef] [PubMed]

Cheung, V. G.

V. G. Cheung, M. Morley, F. Aguilar, A. Massimi, R. Kucherlapati, G. Childs, “Making and reading microarrays,” Nature Genet. Suppl. 2, 15–19 (1999).
[CrossRef]

Childs, G.

V. G. Cheung, M. Morley, F. Aguilar, A. Massimi, R. Kucherlapati, G. Childs, “Making and reading microarrays,” Nature Genet. Suppl. 2, 15–19 (1999).
[CrossRef]

Chiou, A.

D. S. Mehta, C. Y. Lee, A. Chiou, “Multipoint parallel excitation and CCD-based imaging system for high-throughput fluorescence detection of biochip micro-arrays,” Opt. Commun. 190, 59–68 (2001).
[CrossRef]

Clery, D.

J. Uppenbrink, D. Clery, “Single molecules,” Science 283, 1667–1695 (1999).
[CrossRef]

Dai, H.

M. J. Marton, J. L. DeRisi, H. A. Bennett, V. R. Iyer, M. R. Meyer, C. J. Roberts, R. Stoughton, J. Burchard, D. Slade, H. Dai, D. E. Bassett, L. H. Hartwell, P. O. Brown, S. H. Friend, “Drug target validation and identification of secondary drug target effects using DNA microarrays,” Nat. Med. (N.Y.) 4, 1293–1301 (1998).
[CrossRef]

Davis, R. W.

M. Schena, D. Shalon, R. W. Davis, P. O. Brown, “Quantitative monitoring of gene expression patterns with a complementary DNA microarray,” Science 270, 467–470 (1995).
[CrossRef] [PubMed]

M. Schena, R. W. Davis, “Genes, genomes and chips,” in DNA Microarrays: A Practical Approach, M. Schena, ed. (Oxford U. Press, Oxford, UK, 1999).

Denman, J.

S. J. Brinac, R. Gangadharan, M. MacMahon, J. Denman, R. Gonzales, L. G. Mendoza, M. Eggers, “A proximal CCD imaging system for high-throughput detection of microarray-based assays,” IEEE Eng. Med. Biol. Mag. 18, 120–122 (1999).
[CrossRef]

DeRisi, J. L.

M. J. Marton, J. L. DeRisi, H. A. Bennett, V. R. Iyer, M. R. Meyer, C. J. Roberts, R. Stoughton, J. Burchard, D. Slade, H. Dai, D. E. Bassett, L. H. Hartwell, P. O. Brown, S. H. Friend, “Drug target validation and identification of secondary drug target effects using DNA microarrays,” Nat. Med. (N.Y.) 4, 1293–1301 (1998).
[CrossRef]

Edman, L.

L. Edman, Ü. Mets, R. Rigler, “Conformational transitions monitored for single molecules in solution,” Proc. Natl. Acad. Sci. USA 93, 6710–6715 (1996).
[CrossRef] [PubMed]

Eggers, M.

S. J. Brinac, R. Gangadharan, M. MacMahon, J. Denman, R. Gonzales, L. G. Mendoza, M. Eggers, “A proximal CCD imaging system for high-throughput detection of microarray-based assays,” IEEE Eng. Med. Biol. Mag. 18, 120–122 (1999).
[CrossRef]

Eigen, M.

M. Eigen, R. Rigler, “Sorting single molecules: application to diagnostics and evolutionary biotechnology,” Proc. Natl. Acad. Sci. USA 91, 5740–5747 (1994).
[CrossRef] [PubMed]

Ekberg, M.

Elson, E. L.

E. L. Elson, D. Magde, “Fluorescence correlation spectroscopy. 1. Conceptual basis and theory,” Biopolymers 13, 1–27 (1974).
[CrossRef]

Espinoza, F. H.

N. S. Gray, L. Wodicka, A.-M. W. H. Thunnissen, T. C. Norman, S. Kwon, F. H. Espinoza, D. O. Morgan, G. Barnes, S. LeClerc, L. Meijer, S.-H. Kim, D. J. Lockhart, P. G. Schultz, “Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors,” Science 281, 533–538 (1998).
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Fang, J.-B.

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L. Edman, Ü. Mets, R. Rigler, “Conformational transitions monitored for single molecules in solution,” Proc. Natl. Acad. Sci. USA 93, 6710–6715 (1996).
[CrossRef] [PubMed]

J. Widengren, Ü. Mets, R. Rigler, “Fluorescence correlation spectroscopy of triplet states in solution: a theoretical and experimental study,” J. Phys. Chem. 99, 13368–13379 (1995).
[CrossRef]

M. Kinjo, R. Rigler, “Ultrasensitive hybridization analysis using fluorescence correlation spectroscopy,” Nucleic Acids Res. 23, 1795–1799 (1995).
[CrossRef] [PubMed]

M. Eigen, R. Rigler, “Sorting single molecules: application to diagnostics and evolutionary biotechnology,” Proc. Natl. Acad. Sci. USA 91, 5740–5747 (1994).
[CrossRef] [PubMed]

R. Rigler, Ü. Mets, J. Widengren, P. Kask, “Fluorescence correlation spectroscopy with high count rate and low background: analysis of translational motion,” Eur. Biophys. J. 22, 169–175 (1993).
[CrossRef]

Rioux, J.

D. G. Wang, J.-B. Fang, C.-J. Siao, A. Berno, P. Young, R. Sopolsky, G. Ghandour, N. Perkins, E. Winchester, J. Spencer, L. Kruglyak, L. Stein, L. Hsie, T. Topaloglou, E. Hubbel, F. Robinson, M. Mittmann, M. S. Morris, N. Shen, D. Kilburn, J. Rioux, C. Nusbaum, S. Rozen, T. J. Hudson, R. Lipshuts, M. Chee, E. S. Lander, “Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome,” Science 280, 1077–1082 (1998).
[CrossRef] [PubMed]

Roberts, C. J.

M. J. Marton, J. L. DeRisi, H. A. Bennett, V. R. Iyer, M. R. Meyer, C. J. Roberts, R. Stoughton, J. Burchard, D. Slade, H. Dai, D. E. Bassett, L. H. Hartwell, P. O. Brown, S. H. Friend, “Drug target validation and identification of secondary drug target effects using DNA microarrays,” Nat. Med. (N.Y.) 4, 1293–1301 (1998).
[CrossRef]

Robinson, F.

D. G. Wang, J.-B. Fang, C.-J. Siao, A. Berno, P. Young, R. Sopolsky, G. Ghandour, N. Perkins, E. Winchester, J. Spencer, L. Kruglyak, L. Stein, L. Hsie, T. Topaloglou, E. Hubbel, F. Robinson, M. Mittmann, M. S. Morris, N. Shen, D. Kilburn, J. Rioux, C. Nusbaum, S. Rozen, T. J. Hudson, R. Lipshuts, M. Chee, E. S. Lander, “Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome,” Science 280, 1077–1082 (1998).
[CrossRef] [PubMed]

Rozen, S.

D. G. Wang, J.-B. Fang, C.-J. Siao, A. Berno, P. Young, R. Sopolsky, G. Ghandour, N. Perkins, E. Winchester, J. Spencer, L. Kruglyak, L. Stein, L. Hsie, T. Topaloglou, E. Hubbel, F. Robinson, M. Mittmann, M. S. Morris, N. Shen, D. Kilburn, J. Rioux, C. Nusbaum, S. Rozen, T. J. Hudson, R. Lipshuts, M. Chee, E. S. Lander, “Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome,” Science 280, 1077–1082 (1998).
[CrossRef] [PubMed]

Sauer, M.

M. Sauer, B. Angerer, W. Ankenbauer, Z. Földes-Papp, F. Göbel, K.-T. Han, R. Rigler, A. Schultz, J. Wolfrum, C. Zanders, “Single molecule DNA sequencing in submicrometer channels: State of the art and future prospects,” J. Biotechnol. 86, 181–201 (2001).
[CrossRef] [PubMed]

D. P. Herten, P. Tinnenfeld, M. Sauer, “Identification of single fluorescently labelled mononucleotide molecules in solution by spectrally resolved time-correlated single photon counting,” Appl. Phys. B 71, 765–771 (2000).
[CrossRef]

Schena, M.

M. Schena, D. Shalon, R. W. Davis, P. O. Brown, “Quantitative monitoring of gene expression patterns with a complementary DNA microarray,” Science 270, 467–470 (1995).
[CrossRef] [PubMed]

M. Schena, R. W. Davis, “Genes, genomes and chips,” in DNA Microarrays: A Practical Approach, M. Schena, ed. (Oxford U. Press, Oxford, UK, 1999).

Schultz, A.

M. Sauer, B. Angerer, W. Ankenbauer, Z. Földes-Papp, F. Göbel, K.-T. Han, R. Rigler, A. Schultz, J. Wolfrum, C. Zanders, “Single molecule DNA sequencing in submicrometer channels: State of the art and future prospects,” J. Biotechnol. 86, 181–201 (2001).
[CrossRef] [PubMed]

Schultz, P. G.

N. S. Gray, L. Wodicka, A.-M. W. H. Thunnissen, T. C. Norman, S. Kwon, F. H. Espinoza, D. O. Morgan, G. Barnes, S. LeClerc, L. Meijer, S.-H. Kim, D. J. Lockhart, P. G. Schultz, “Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors,” Science 281, 533–538 (1998).
[CrossRef] [PubMed]

Schwille, P.

P. Schwille, F. J. Meyer-Almes, R. Rigler, “Dual-color fluorescence cross-correlation spectroscopy for multicomponent diffusional analysis in solutions,” Biophys. J. 72, 1878–1886 (1997).
[CrossRef] [PubMed]

Shalon, D.

M. Schena, D. Shalon, R. W. Davis, P. O. Brown, “Quantitative monitoring of gene expression patterns with a complementary DNA microarray,” Science 270, 467–470 (1995).
[CrossRef] [PubMed]

Shen, N.

D. G. Wang, J.-B. Fang, C.-J. Siao, A. Berno, P. Young, R. Sopolsky, G. Ghandour, N. Perkins, E. Winchester, J. Spencer, L. Kruglyak, L. Stein, L. Hsie, T. Topaloglou, E. Hubbel, F. Robinson, M. Mittmann, M. S. Morris, N. Shen, D. Kilburn, J. Rioux, C. Nusbaum, S. Rozen, T. J. Hudson, R. Lipshuts, M. Chee, E. S. Lander, “Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome,” Science 280, 1077–1082 (1998).
[CrossRef] [PubMed]

Siao, C.-J.

D. G. Wang, J.-B. Fang, C.-J. Siao, A. Berno, P. Young, R. Sopolsky, G. Ghandour, N. Perkins, E. Winchester, J. Spencer, L. Kruglyak, L. Stein, L. Hsie, T. Topaloglou, E. Hubbel, F. Robinson, M. Mittmann, M. S. Morris, N. Shen, D. Kilburn, J. Rioux, C. Nusbaum, S. Rozen, T. J. Hudson, R. Lipshuts, M. Chee, E. S. Lander, “Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome,” Science 280, 1077–1082 (1998).
[CrossRef] [PubMed]

Slade, D.

M. J. Marton, J. L. DeRisi, H. A. Bennett, V. R. Iyer, M. R. Meyer, C. J. Roberts, R. Stoughton, J. Burchard, D. Slade, H. Dai, D. E. Bassett, L. H. Hartwell, P. O. Brown, S. H. Friend, “Drug target validation and identification of secondary drug target effects using DNA microarrays,” Nat. Med. (N.Y.) 4, 1293–1301 (1998).
[CrossRef]

Sopolsky, R.

D. G. Wang, J.-B. Fang, C.-J. Siao, A. Berno, P. Young, R. Sopolsky, G. Ghandour, N. Perkins, E. Winchester, J. Spencer, L. Kruglyak, L. Stein, L. Hsie, T. Topaloglou, E. Hubbel, F. Robinson, M. Mittmann, M. S. Morris, N. Shen, D. Kilburn, J. Rioux, C. Nusbaum, S. Rozen, T. J. Hudson, R. Lipshuts, M. Chee, E. S. Lander, “Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome,” Science 280, 1077–1082 (1998).
[CrossRef] [PubMed]

Spencer, J.

D. G. Wang, J.-B. Fang, C.-J. Siao, A. Berno, P. Young, R. Sopolsky, G. Ghandour, N. Perkins, E. Winchester, J. Spencer, L. Kruglyak, L. Stein, L. Hsie, T. Topaloglou, E. Hubbel, F. Robinson, M. Mittmann, M. S. Morris, N. Shen, D. Kilburn, J. Rioux, C. Nusbaum, S. Rozen, T. J. Hudson, R. Lipshuts, M. Chee, E. S. Lander, “Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome,” Science 280, 1077–1082 (1998).
[CrossRef] [PubMed]

Steemers, F. J.

F. J. Steemers, J. A. Ferguson, D. R. Walt, “Screening unlabeled DNA targets with randomly ordered fiber-optic gene arrays,” Nat. Biotechnol. 18, 91–94 (2000).
[CrossRef] [PubMed]

Stein, L.

D. G. Wang, J.-B. Fang, C.-J. Siao, A. Berno, P. Young, R. Sopolsky, G. Ghandour, N. Perkins, E. Winchester, J. Spencer, L. Kruglyak, L. Stein, L. Hsie, T. Topaloglou, E. Hubbel, F. Robinson, M. Mittmann, M. S. Morris, N. Shen, D. Kilburn, J. Rioux, C. Nusbaum, S. Rozen, T. J. Hudson, R. Lipshuts, M. Chee, E. S. Lander, “Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome,” Science 280, 1077–1082 (1998).
[CrossRef] [PubMed]

Stoughton, R.

M. J. Marton, J. L. DeRisi, H. A. Bennett, V. R. Iyer, M. R. Meyer, C. J. Roberts, R. Stoughton, J. Burchard, D. Slade, H. Dai, D. E. Bassett, L. H. Hartwell, P. O. Brown, S. H. Friend, “Drug target validation and identification of secondary drug target effects using DNA microarrays,” Nat. Med. (N.Y.) 4, 1293–1301 (1998).
[CrossRef]

Tetin, S. Y.

Y. Chen, J. D. Müller, S. Y. Tetin, J. D. Tyner, E. Gratton, “Probing ligand protein binding equilibria with fluorescence fluctuation spectroscopy,” Biophys. J. 79, 1074–1084 (2000).
[CrossRef] [PubMed]

Thunnissen, A.-M. W. H.

N. S. Gray, L. Wodicka, A.-M. W. H. Thunnissen, T. C. Norman, S. Kwon, F. H. Espinoza, D. O. Morgan, G. Barnes, S. LeClerc, L. Meijer, S.-H. Kim, D. J. Lockhart, P. G. Schultz, “Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors,” Science 281, 533–538 (1998).
[CrossRef] [PubMed]

Thyberg, J.

L. O. Tjernberg, A. Pramanik, S. Björling, P. Thyberg, J. Thyberg, C. Nordstedt, K. D. Berndt, R. Rigler, “Amyloid β-peptide polymerisation studied using fluorescence correlation spectroscopy,” Chem. Biol. 6, 53–62 (1999).
[CrossRef] [PubMed]

Thyberg, P.

L. O. Tjernberg, A. Pramanik, S. Björling, P. Thyberg, J. Thyberg, C. Nordstedt, K. D. Berndt, R. Rigler, “Amyloid β-peptide polymerisation studied using fluorescence correlation spectroscopy,” Chem. Biol. 6, 53–62 (1999).
[CrossRef] [PubMed]

Tinnenfeld, P.

D. P. Herten, P. Tinnenfeld, M. Sauer, “Identification of single fluorescently labelled mononucleotide molecules in solution by spectrally resolved time-correlated single photon counting,” Appl. Phys. B 71, 765–771 (2000).
[CrossRef]

Tjernberg, L. O.

L. O. Tjernberg, A. Pramanik, S. Björling, P. Thyberg, J. Thyberg, C. Nordstedt, K. D. Berndt, R. Rigler, “Amyloid β-peptide polymerisation studied using fluorescence correlation spectroscopy,” Chem. Biol. 6, 53–62 (1999).
[CrossRef] [PubMed]

Topaloglou, T.

D. G. Wang, J.-B. Fang, C.-J. Siao, A. Berno, P. Young, R. Sopolsky, G. Ghandour, N. Perkins, E. Winchester, J. Spencer, L. Kruglyak, L. Stein, L. Hsie, T. Topaloglou, E. Hubbel, F. Robinson, M. Mittmann, M. S. Morris, N. Shen, D. Kilburn, J. Rioux, C. Nusbaum, S. Rozen, T. J. Hudson, R. Lipshuts, M. Chee, E. S. Lander, “Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome,” Science 280, 1077–1082 (1998).
[CrossRef] [PubMed]

Tyner, J. D.

Y. Chen, J. D. Müller, S. Y. Tetin, J. D. Tyner, E. Gratton, “Probing ligand protein binding equilibria with fluorescence fluctuation spectroscopy,” Biophys. J. 79, 1074–1084 (2000).
[CrossRef] [PubMed]

Ullmann, D.

P. Kask, K. Palo, D. Ullmann, K. Gall, “Fluorescence-intensity distribution analysis and its application in biomolecular detection technology,” Proc. Natl. Acad. Sci. USA 96, 13756–13761 (1999).
[CrossRef] [PubMed]

Uppenbrink, J.

J. Uppenbrink, D. Clery, “Single molecules,” Science 283, 1667–1695 (1999).
[CrossRef]

Wallraff, G.

G. McGall, J. Labadie, P. Brock, G. Wallraff, T. Nguyen, W. Hinsberg, “Light-directed synthesis of high-density oligonucleotide arrays using semiconductor photoresists,” Proc. Natl. Acad. Sci. USA 93, 13555–13560 (1996).
[CrossRef] [PubMed]

Walt, D. R.

D. R. Walt, “Bead based fiber-optical arrays,” Science 287, 451–452 (2000).
[CrossRef] [PubMed]

F. J. Steemers, J. A. Ferguson, D. R. Walt, “Screening unlabeled DNA targets with randomly ordered fiber-optic gene arrays,” Nat. Biotechnol. 18, 91–94 (2000).
[CrossRef] [PubMed]

Wang, D. G.

D. G. Wang, J.-B. Fang, C.-J. Siao, A. Berno, P. Young, R. Sopolsky, G. Ghandour, N. Perkins, E. Winchester, J. Spencer, L. Kruglyak, L. Stein, L. Hsie, T. Topaloglou, E. Hubbel, F. Robinson, M. Mittmann, M. S. Morris, N. Shen, D. Kilburn, J. Rioux, C. Nusbaum, S. Rozen, T. J. Hudson, R. Lipshuts, M. Chee, E. S. Lander, “Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome,” Science 280, 1077–1082 (1998).
[CrossRef] [PubMed]

Whitecomb, D.

D. Whitecomb, C. R. Newton, S. Little, “Advantages in approaches to DNA-based diagnostics,” Curr. Opin. Biotechnol. 9, 602–608 (1998).
[CrossRef]

Widengren, J.

J. Widengren, Ü. Mets, R. Rigler, “Fluorescence correlation spectroscopy of triplet states in solution: a theoretical and experimental study,” J. Phys. Chem. 99, 13368–13379 (1995).
[CrossRef]

R. Rigler, Ü. Mets, J. Widengren, P. Kask, “Fluorescence correlation spectroscopy with high count rate and low background: analysis of translational motion,” Eur. Biophys. J. 22, 169–175 (1993).
[CrossRef]

Winchester, E.

D. G. Wang, J.-B. Fang, C.-J. Siao, A. Berno, P. Young, R. Sopolsky, G. Ghandour, N. Perkins, E. Winchester, J. Spencer, L. Kruglyak, L. Stein, L. Hsie, T. Topaloglou, E. Hubbel, F. Robinson, M. Mittmann, M. S. Morris, N. Shen, D. Kilburn, J. Rioux, C. Nusbaum, S. Rozen, T. J. Hudson, R. Lipshuts, M. Chee, E. S. Lander, “Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome,” Science 280, 1077–1082 (1998).
[CrossRef] [PubMed]

Winzeler, E. A.

D. J. Lockhart, E. A. Winzeler, “Genomics, gene expression and DNA arrays,” Nature (London) 405, 827–836 (2000).
[CrossRef]

Wodicka, L.

N. S. Gray, L. Wodicka, A.-M. W. H. Thunnissen, T. C. Norman, S. Kwon, F. H. Espinoza, D. O. Morgan, G. Barnes, S. LeClerc, L. Meijer, S.-H. Kim, D. J. Lockhart, P. G. Schultz, “Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors,” Science 281, 533–538 (1998).
[CrossRef] [PubMed]

Wolfrum, J.

M. Sauer, B. Angerer, W. Ankenbauer, Z. Földes-Papp, F. Göbel, K.-T. Han, R. Rigler, A. Schultz, J. Wolfrum, C. Zanders, “Single molecule DNA sequencing in submicrometer channels: State of the art and future prospects,” J. Biotechnol. 86, 181–201 (2001).
[CrossRef] [PubMed]

Young, P.

D. G. Wang, J.-B. Fang, C.-J. Siao, A. Berno, P. Young, R. Sopolsky, G. Ghandour, N. Perkins, E. Winchester, J. Spencer, L. Kruglyak, L. Stein, L. Hsie, T. Topaloglou, E. Hubbel, F. Robinson, M. Mittmann, M. S. Morris, N. Shen, D. Kilburn, J. Rioux, C. Nusbaum, S. Rozen, T. J. Hudson, R. Lipshuts, M. Chee, E. S. Lander, “Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome,” Science 280, 1077–1082 (1998).
[CrossRef] [PubMed]

Zanders, C.

M. Sauer, B. Angerer, W. Ankenbauer, Z. Földes-Papp, F. Göbel, K.-T. Han, R. Rigler, A. Schultz, J. Wolfrum, C. Zanders, “Single molecule DNA sequencing in submicrometer channels: State of the art and future prospects,” J. Biotechnol. 86, 181–201 (2001).
[CrossRef] [PubMed]

Appl. Opt.

Appl. Phys. B

D. P. Herten, P. Tinnenfeld, M. Sauer, “Identification of single fluorescently labelled mononucleotide molecules in solution by spectrally resolved time-correlated single photon counting,” Appl. Phys. B 71, 765–771 (2000).
[CrossRef]

Appl. Spectrosc.

Biophys. J.

P. Schwille, F. J. Meyer-Almes, R. Rigler, “Dual-color fluorescence cross-correlation spectroscopy for multicomponent diffusional analysis in solutions,” Biophys. J. 72, 1878–1886 (1997).
[CrossRef] [PubMed]

Y. Chen, J. D. Müller, S. Y. Tetin, J. D. Tyner, E. Gratton, “Probing ligand protein binding equilibria with fluorescence fluctuation spectroscopy,” Biophys. J. 79, 1074–1084 (2000).
[CrossRef] [PubMed]

Biopolymers

E. L. Elson, D. Magde, “Fluorescence correlation spectroscopy. 1. Conceptual basis and theory,” Biopolymers 13, 1–27 (1974).
[CrossRef]

Chem. Biol.

L. O. Tjernberg, A. Pramanik, S. Björling, P. Thyberg, J. Thyberg, C. Nordstedt, K. D. Berndt, R. Rigler, “Amyloid β-peptide polymerisation studied using fluorescence correlation spectroscopy,” Chem. Biol. 6, 53–62 (1999).
[CrossRef] [PubMed]

Curr. Opin. Biotechnol.

D. Whitecomb, C. R. Newton, S. Little, “Advantages in approaches to DNA-based diagnostics,” Curr. Opin. Biotechnol. 9, 602–608 (1998).
[CrossRef]

Eur. Biophys. J.

R. Rigler, Ü. Mets, J. Widengren, P. Kask, “Fluorescence correlation spectroscopy with high count rate and low background: analysis of translational motion,” Eur. Biophys. J. 22, 169–175 (1993).
[CrossRef]

Exp. Gerentol.

A. Holmberg, “DNA-microarrays: novel techniques to study aging and guide gerentologic medicine,” Exp. Gerentol. 36, 1189–1198 (2000).
[CrossRef]

IEEE Eng. Med. Biol. Mag.

S. J. Brinac, R. Gangadharan, M. MacMahon, J. Denman, R. Gonzales, L. G. Mendoza, M. Eggers, “A proximal CCD imaging system for high-throughput detection of microarray-based assays,” IEEE Eng. Med. Biol. Mag. 18, 120–122 (1999).
[CrossRef]

IEEE Photonics Technol. Lett.

H. Martinsson, J. Bengtsson, M. Ghisoni, A. Larsson, “Monolithic integration of VCSEL and diffractive optical element for advanced beam shaping,” IEEE Photonics Technol. Lett. 11, 503–505 (1999).
[CrossRef]

J. Biotechnol.

M. Sauer, B. Angerer, W. Ankenbauer, Z. Földes-Papp, F. Göbel, K.-T. Han, R. Rigler, A. Schultz, J. Wolfrum, C. Zanders, “Single molecule DNA sequencing in submicrometer channels: State of the art and future prospects,” J. Biotechnol. 86, 181–201 (2001).
[CrossRef] [PubMed]

J. Phys. Chem.

J. Widengren, Ü. Mets, R. Rigler, “Fluorescence correlation spectroscopy of triplet states in solution: a theoretical and experimental study,” J. Phys. Chem. 99, 13368–13379 (1995).
[CrossRef]

Nat. Biotechnol.

F. J. Steemers, J. A. Ferguson, D. R. Walt, “Screening unlabeled DNA targets with randomly ordered fiber-optic gene arrays,” Nat. Biotechnol. 18, 91–94 (2000).
[CrossRef] [PubMed]

Nat. Med. (N.Y.)

M. J. Marton, J. L. DeRisi, H. A. Bennett, V. R. Iyer, M. R. Meyer, C. J. Roberts, R. Stoughton, J. Burchard, D. Slade, H. Dai, D. E. Bassett, L. H. Hartwell, P. O. Brown, S. H. Friend, “Drug target validation and identification of secondary drug target effects using DNA microarrays,” Nat. Med. (N.Y.) 4, 1293–1301 (1998).
[CrossRef]

Nature (London)

D. J. Lockhart, E. A. Winzeler, “Genomics, gene expression and DNA arrays,” Nature (London) 405, 827–836 (2000).
[CrossRef]

Nature Genet.

R. J. Lipshutz, S. P. Fodor, T. R. Gingeras, D. J. Lockhart, “High density synthetic oligonucleotide arrays,” Nature Genet. 21, 20–24 (1999).
[CrossRef] [PubMed]

Nature Genet. Suppl.

V. G. Cheung, M. Morley, F. Aguilar, A. Massimi, R. Kucherlapati, G. Childs, “Making and reading microarrays,” Nature Genet. Suppl. 2, 15–19 (1999).
[CrossRef]

Nucleic Acids Res.

M. Kinjo, R. Rigler, “Ultrasensitive hybridization analysis using fluorescence correlation spectroscopy,” Nucleic Acids Res. 23, 1795–1799 (1995).
[CrossRef] [PubMed]

Opt. Commun.

D. S. Mehta, C. Y. Lee, A. Chiou, “Multipoint parallel excitation and CCD-based imaging system for high-throughput fluorescence detection of biochip micro-arrays,” Opt. Commun. 190, 59–68 (2001).
[CrossRef]

Proc. Natl. Acad. Sci. USA

G. McGall, J. Labadie, P. Brock, G. Wallraff, T. Nguyen, W. Hinsberg, “Light-directed synthesis of high-density oligonucleotide arrays using semiconductor photoresists,” Proc. Natl. Acad. Sci. USA 93, 13555–13560 (1996).
[CrossRef] [PubMed]

M. Eigen, R. Rigler, “Sorting single molecules: application to diagnostics and evolutionary biotechnology,” Proc. Natl. Acad. Sci. USA 91, 5740–5747 (1994).
[CrossRef] [PubMed]

P. Kask, K. Palo, D. Ullmann, K. Gall, “Fluorescence-intensity distribution analysis and its application in biomolecular detection technology,” Proc. Natl. Acad. Sci. USA 96, 13756–13761 (1999).
[CrossRef] [PubMed]

L. Edman, Ü. Mets, R. Rigler, “Conformational transitions monitored for single molecules in solution,” Proc. Natl. Acad. Sci. USA 93, 6710–6715 (1996).
[CrossRef] [PubMed]

Science

J. Uppenbrink, D. Clery, “Single molecules,” Science 283, 1667–1695 (1999).
[CrossRef]

S. A. Fodor, “DNA sequencing: massively parallel genomics,” Science 277, 393–395 (1997).
[CrossRef]

M. Schena, D. Shalon, R. W. Davis, P. O. Brown, “Quantitative monitoring of gene expression patterns with a complementary DNA microarray,” Science 270, 467–470 (1995).
[CrossRef] [PubMed]

N. S. Gray, L. Wodicka, A.-M. W. H. Thunnissen, T. C. Norman, S. Kwon, F. H. Espinoza, D. O. Morgan, G. Barnes, S. LeClerc, L. Meijer, S.-H. Kim, D. J. Lockhart, P. G. Schultz, “Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors,” Science 281, 533–538 (1998).
[CrossRef] [PubMed]

D. R. Walt, “Bead based fiber-optical arrays,” Science 287, 451–452 (2000).
[CrossRef] [PubMed]

D. G. Wang, J.-B. Fang, C.-J. Siao, A. Berno, P. Young, R. Sopolsky, G. Ghandour, N. Perkins, E. Winchester, J. Spencer, L. Kruglyak, L. Stein, L. Hsie, T. Topaloglou, E. Hubbel, F. Robinson, M. Mittmann, M. S. Morris, N. Shen, D. Kilburn, J. Rioux, C. Nusbaum, S. Rozen, T. J. Hudson, R. Lipshuts, M. Chee, E. S. Lander, “Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome,” Science 280, 1077–1082 (1998).
[CrossRef] [PubMed]

Other

M. Schena, R. W. Davis, “Genes, genomes and chips,” in DNA Microarrays: A Practical Approach, M. Schena, ed. (Oxford U. Press, Oxford, UK, 1999).

See papers in Fluorescence Correlation Spectroscopy-Theory and Applications, R. Rigler, E. S. Elson, eds. (Springer-Verlag, Berlin, Heidelberg, 2001).

M. W. Farn, “New iterative algorithm for the design of phase-only gratings,” in Computer and Optically Generated Holographic Optics, I. Cindrich, S. H. Lee, eds., Proc. SPIE1555, 34–42 (1991).

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Figures (6)

Fig. 1
Fig. 1

Laser excitation pattern from the DOE. The ring (diameter 25 mm) shows the spatial filtration of the central 2 × 2 pattern done by the second collimator lens (cf. Fig. 3).

Fig. 3
Fig. 3

A schematic illustration of the setup for parallel excitation and detection. Only the central 2 × 2 pattern (cf. Fig. 1) is imaged by the multimode fibers. OD, optical density.

Fig. 2
Fig. 2

Scanning electron microscopy pictures showing the biochip microarray with 70-µm diameter wells. On the edge, the 300-µm Si and the 170-µm glass are visible.

Fig. 5
Fig. 5

Fluorescence trace signals from all four 2 × 2 foci in separate wells with TMR-4-dUTP biomolecules.

Fig. 4
Fig. 4

Measured autocorrelation curve (stars) of a TMR solution in one of the four DOE foci. The number of dye molecules within the volume element, deduced from inverse of the curve amplitude fit (solid curve), is found to be N = 12.

Fig. 6
Fig. 6

Autocorrelation curves deduced from the trace signals in Fig. 5.

Equations (3)

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gτ=1+δI0δIτI2,
gτ=1+1N1+ττD-11+w02z02ττD-1/2,
Px, y, z=P0 exp-x2+y22w02exp-z22z02,

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