Abstract

We demonstrate high throughput gigapixel fluorescence microscopy with a microlens array. We show, for the first time to the best of our knowledge, the use of a parallelized microscopy system to image samples in micro well plates. We image centimeter-scale regions of 384-well micro well plates at 1.72 μm resolution at a raw pixel throughput of 25.4 Mpx/s. Taking into account the fact that about half the well plate area consists of the plastic support region between wells, this corresponds to a sample pixel throughput of 13.2 Mpx/s, more than double that of the commercial state-of-the-art at the time of writing. Fluorescent imaging of tissue samples through coverslips is also demonstrated.

© 2013 OSA

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2012 (3)

D. J. Brady, M. E. Gehm, R. A. Stack, D. L. Marks, D. S. Kittle, D. R. Golish, E. M. Vera, and S. D. Feller, “Multiscale gigapixel photography,” Nature486(7403), 386–389 (2012).
[CrossRef] [PubMed]

S. O. Isikman, A. Greenbaum, W. Luo, A. F. Coskun, and A. Ozcan, “Giga-Pixel Lens Free Holographic Microscopy and Tomography Using Color Image Sensors,” PLoS ONE7(9), e45044 (2012).
[CrossRef] [PubMed]

A. Orth and K. B. Crozier, “Microscopy with microlens arrays: high throughput, high resolution and light-field imaging,” Opt. Express20(12), 13522–13531 (2012).
[CrossRef] [PubMed]

2011 (2)

E. Schonbrun, P. E. Steinvurzel, and K. B. Crozier, “A microfluidic fluorescence measurement system using an astigmatic diffractive microlens array,” Opt. Express19(2), 1385–1394 (2011).
[CrossRef] [PubMed]

R. W. Cole, T. Jinadasa, and C. M. Brown, “Measuring and interpreting point spread functions to determine confocal microscope resolution and ensure quality control,” Nat. Protoc.6(12), 1929–1941 (2011).
[CrossRef] [PubMed]

2010 (1)

E. Schonbrun, A. R. Abate, P. E. Steinvurzel, D. A. Weitz, and K. B. Crozier, “High-throughput fluorescence detection using an integrated zone-plate array,” Lab Chip10(7), 852–856 (2010).
[CrossRef] [PubMed]

2009 (2)

E. Schonbrun, W. N. Ye, and K. B. Crozier, “Scanning microscopy using a short-focal-length Fresnel zone plate,” Opt. Lett.34(14), 2228–2230 (2009).
[CrossRef] [PubMed]

S. Preibisch, S. Saalfeld, and P. Tomancak, “Globally optimal stitching of tiled 3D microscopic image acquisitions,” Bioinformatics25(11), 1463–1465 (2009).
[CrossRef] [PubMed]

2008 (1)

S. Michael, D. Auld, C. Klumpp, A. Jadhav, W. Zheng, N. Thorne, C. P. Austin, J. Inglese, and A. Simeonov, “A Robotic Platform for Quantitative High-Throughput Screening,” Assay Drug Dev. Technol.6(5), 637–657 (2008).
[CrossRef] [PubMed]

2006 (2)

R. Pepperkok and J. Ellenberg, “High-throughput fluorescence microscopy for systems biology,” Nat. Rev. Mol. Cell Biol.7(9), 690–696 (2006).
[CrossRef] [PubMed]

P. Lang, K. Yeow, A. Nichols, and A. Scheer, “Cellular imaging in drug discovery,” Nat. Rev. Drug Discov.5(4), 343–356 (2006).
[CrossRef] [PubMed]

2005 (1)

P. Capodieci, M. Donovan, H. Buchinsky, Y. Jeffers, C. Cordon-Cardo, W. Gerald, J. Edelson, S. M. Shenoy, and R. H. Singer, “Gene expression profiling in single cells within tissue,” Nat. Methods2(9), 663–665 (2005).
[CrossRef] [PubMed]

2003 (1)

M. V. Kunnavakkam, F. M. Houlihan, M. Schlax, J. A. Liddle, P. Kolonder, O. Nalamasu, and J. A. Rogers, “Low-cost, low-loss microlens array fabricated by soft-lithography replication process,” Appl. Phys. Lett.82, 1152–1154 (2003).

2002 (1)

F. T. O’Neill and J. T. Sheridan, “Photoresist reflow method of microlens production part II: analytic models,” Optik (Stuttg.)113(9), 405–420 (2002).
[CrossRef]

2000 (1)

A. Schilling, R. Merz, C. Ossmann, and H. P. Herzig, “Surface profiles of reflow microlenses under the influence of surface tension and gravity,” Opt. Eng.39(8), 2171–2176 (2000).
[CrossRef]

1998 (1)

J. Kononen, L. Bubendorf, A. Kallioniemi, M. Bärlund, P. Schraml, S. Leighton, J. Torhorst, M. J. Mihatsch, G. Sauter, and O. P. Kallioniemi, “Tissue microarrays for high-throughput molecular profiling of tumor specimens,” Nat. Med.4(7), 844–847 (1998).
[CrossRef] [PubMed]

1997 (1)

P. H. Nussbaum, R. Volkel, H. P. Herzig, M. Eisner, and S. Haselbeck, “Design, fabrication and testing of microlens arrays for sensors and microsystems,” Pure Appl. Opt.6(6), 617–636 (1997).
[CrossRef]

Abate, A. R.

E. Schonbrun, A. R. Abate, P. E. Steinvurzel, D. A. Weitz, and K. B. Crozier, “High-throughput fluorescence detection using an integrated zone-plate array,” Lab Chip10(7), 852–856 (2010).
[CrossRef] [PubMed]

Auld, D.

S. Michael, D. Auld, C. Klumpp, A. Jadhav, W. Zheng, N. Thorne, C. P. Austin, J. Inglese, and A. Simeonov, “A Robotic Platform for Quantitative High-Throughput Screening,” Assay Drug Dev. Technol.6(5), 637–657 (2008).
[CrossRef] [PubMed]

Austin, C. P.

S. Michael, D. Auld, C. Klumpp, A. Jadhav, W. Zheng, N. Thorne, C. P. Austin, J. Inglese, and A. Simeonov, “A Robotic Platform for Quantitative High-Throughput Screening,” Assay Drug Dev. Technol.6(5), 637–657 (2008).
[CrossRef] [PubMed]

Bärlund, M.

J. Kononen, L. Bubendorf, A. Kallioniemi, M. Bärlund, P. Schraml, S. Leighton, J. Torhorst, M. J. Mihatsch, G. Sauter, and O. P. Kallioniemi, “Tissue microarrays for high-throughput molecular profiling of tumor specimens,” Nat. Med.4(7), 844–847 (1998).
[CrossRef] [PubMed]

Brady, D. J.

D. J. Brady, M. E. Gehm, R. A. Stack, D. L. Marks, D. S. Kittle, D. R. Golish, E. M. Vera, and S. D. Feller, “Multiscale gigapixel photography,” Nature486(7403), 386–389 (2012).
[CrossRef] [PubMed]

Brown, C. M.

R. W. Cole, T. Jinadasa, and C. M. Brown, “Measuring and interpreting point spread functions to determine confocal microscope resolution and ensure quality control,” Nat. Protoc.6(12), 1929–1941 (2011).
[CrossRef] [PubMed]

Bubendorf, L.

J. Kononen, L. Bubendorf, A. Kallioniemi, M. Bärlund, P. Schraml, S. Leighton, J. Torhorst, M. J. Mihatsch, G. Sauter, and O. P. Kallioniemi, “Tissue microarrays for high-throughput molecular profiling of tumor specimens,” Nat. Med.4(7), 844–847 (1998).
[CrossRef] [PubMed]

Buchinsky, H.

P. Capodieci, M. Donovan, H. Buchinsky, Y. Jeffers, C. Cordon-Cardo, W. Gerald, J. Edelson, S. M. Shenoy, and R. H. Singer, “Gene expression profiling in single cells within tissue,” Nat. Methods2(9), 663–665 (2005).
[CrossRef] [PubMed]

Capodieci, P.

P. Capodieci, M. Donovan, H. Buchinsky, Y. Jeffers, C. Cordon-Cardo, W. Gerald, J. Edelson, S. M. Shenoy, and R. H. Singer, “Gene expression profiling in single cells within tissue,” Nat. Methods2(9), 663–665 (2005).
[CrossRef] [PubMed]

Cole, R. W.

R. W. Cole, T. Jinadasa, and C. M. Brown, “Measuring and interpreting point spread functions to determine confocal microscope resolution and ensure quality control,” Nat. Protoc.6(12), 1929–1941 (2011).
[CrossRef] [PubMed]

Cordon-Cardo, C.

P. Capodieci, M. Donovan, H. Buchinsky, Y. Jeffers, C. Cordon-Cardo, W. Gerald, J. Edelson, S. M. Shenoy, and R. H. Singer, “Gene expression profiling in single cells within tissue,” Nat. Methods2(9), 663–665 (2005).
[CrossRef] [PubMed]

Coskun, A. F.

S. O. Isikman, A. Greenbaum, W. Luo, A. F. Coskun, and A. Ozcan, “Giga-Pixel Lens Free Holographic Microscopy and Tomography Using Color Image Sensors,” PLoS ONE7(9), e45044 (2012).
[CrossRef] [PubMed]

Crozier, K. B.

Donovan, M.

P. Capodieci, M. Donovan, H. Buchinsky, Y. Jeffers, C. Cordon-Cardo, W. Gerald, J. Edelson, S. M. Shenoy, and R. H. Singer, “Gene expression profiling in single cells within tissue,” Nat. Methods2(9), 663–665 (2005).
[CrossRef] [PubMed]

Edelson, J.

P. Capodieci, M. Donovan, H. Buchinsky, Y. Jeffers, C. Cordon-Cardo, W. Gerald, J. Edelson, S. M. Shenoy, and R. H. Singer, “Gene expression profiling in single cells within tissue,” Nat. Methods2(9), 663–665 (2005).
[CrossRef] [PubMed]

Eisner, M.

P. H. Nussbaum, R. Volkel, H. P. Herzig, M. Eisner, and S. Haselbeck, “Design, fabrication and testing of microlens arrays for sensors and microsystems,” Pure Appl. Opt.6(6), 617–636 (1997).
[CrossRef]

Ellenberg, J.

R. Pepperkok and J. Ellenberg, “High-throughput fluorescence microscopy for systems biology,” Nat. Rev. Mol. Cell Biol.7(9), 690–696 (2006).
[CrossRef] [PubMed]

Feller, S. D.

D. J. Brady, M. E. Gehm, R. A. Stack, D. L. Marks, D. S. Kittle, D. R. Golish, E. M. Vera, and S. D. Feller, “Multiscale gigapixel photography,” Nature486(7403), 386–389 (2012).
[CrossRef] [PubMed]

Gehm, M. E.

D. J. Brady, M. E. Gehm, R. A. Stack, D. L. Marks, D. S. Kittle, D. R. Golish, E. M. Vera, and S. D. Feller, “Multiscale gigapixel photography,” Nature486(7403), 386–389 (2012).
[CrossRef] [PubMed]

Gerald, W.

P. Capodieci, M. Donovan, H. Buchinsky, Y. Jeffers, C. Cordon-Cardo, W. Gerald, J. Edelson, S. M. Shenoy, and R. H. Singer, “Gene expression profiling in single cells within tissue,” Nat. Methods2(9), 663–665 (2005).
[CrossRef] [PubMed]

Golish, D. R.

D. J. Brady, M. E. Gehm, R. A. Stack, D. L. Marks, D. S. Kittle, D. R. Golish, E. M. Vera, and S. D. Feller, “Multiscale gigapixel photography,” Nature486(7403), 386–389 (2012).
[CrossRef] [PubMed]

Greenbaum, A.

S. O. Isikman, A. Greenbaum, W. Luo, A. F. Coskun, and A. Ozcan, “Giga-Pixel Lens Free Holographic Microscopy and Tomography Using Color Image Sensors,” PLoS ONE7(9), e45044 (2012).
[CrossRef] [PubMed]

Haselbeck, S.

P. H. Nussbaum, R. Volkel, H. P. Herzig, M. Eisner, and S. Haselbeck, “Design, fabrication and testing of microlens arrays for sensors and microsystems,” Pure Appl. Opt.6(6), 617–636 (1997).
[CrossRef]

Herzig, H. P.

A. Schilling, R. Merz, C. Ossmann, and H. P. Herzig, “Surface profiles of reflow microlenses under the influence of surface tension and gravity,” Opt. Eng.39(8), 2171–2176 (2000).
[CrossRef]

P. H. Nussbaum, R. Volkel, H. P. Herzig, M. Eisner, and S. Haselbeck, “Design, fabrication and testing of microlens arrays for sensors and microsystems,” Pure Appl. Opt.6(6), 617–636 (1997).
[CrossRef]

Houlihan, F. M.

M. V. Kunnavakkam, F. M. Houlihan, M. Schlax, J. A. Liddle, P. Kolonder, O. Nalamasu, and J. A. Rogers, “Low-cost, low-loss microlens array fabricated by soft-lithography replication process,” Appl. Phys. Lett.82, 1152–1154 (2003).

Inglese, J.

S. Michael, D. Auld, C. Klumpp, A. Jadhav, W. Zheng, N. Thorne, C. P. Austin, J. Inglese, and A. Simeonov, “A Robotic Platform for Quantitative High-Throughput Screening,” Assay Drug Dev. Technol.6(5), 637–657 (2008).
[CrossRef] [PubMed]

Isikman, S. O.

S. O. Isikman, A. Greenbaum, W. Luo, A. F. Coskun, and A. Ozcan, “Giga-Pixel Lens Free Holographic Microscopy and Tomography Using Color Image Sensors,” PLoS ONE7(9), e45044 (2012).
[CrossRef] [PubMed]

Jadhav, A.

S. Michael, D. Auld, C. Klumpp, A. Jadhav, W. Zheng, N. Thorne, C. P. Austin, J. Inglese, and A. Simeonov, “A Robotic Platform for Quantitative High-Throughput Screening,” Assay Drug Dev. Technol.6(5), 637–657 (2008).
[CrossRef] [PubMed]

Jeffers, Y.

P. Capodieci, M. Donovan, H. Buchinsky, Y. Jeffers, C. Cordon-Cardo, W. Gerald, J. Edelson, S. M. Shenoy, and R. H. Singer, “Gene expression profiling in single cells within tissue,” Nat. Methods2(9), 663–665 (2005).
[CrossRef] [PubMed]

Jinadasa, T.

R. W. Cole, T. Jinadasa, and C. M. Brown, “Measuring and interpreting point spread functions to determine confocal microscope resolution and ensure quality control,” Nat. Protoc.6(12), 1929–1941 (2011).
[CrossRef] [PubMed]

Kallioniemi, A.

J. Kononen, L. Bubendorf, A. Kallioniemi, M. Bärlund, P. Schraml, S. Leighton, J. Torhorst, M. J. Mihatsch, G. Sauter, and O. P. Kallioniemi, “Tissue microarrays for high-throughput molecular profiling of tumor specimens,” Nat. Med.4(7), 844–847 (1998).
[CrossRef] [PubMed]

Kallioniemi, O. P.

J. Kononen, L. Bubendorf, A. Kallioniemi, M. Bärlund, P. Schraml, S. Leighton, J. Torhorst, M. J. Mihatsch, G. Sauter, and O. P. Kallioniemi, “Tissue microarrays for high-throughput molecular profiling of tumor specimens,” Nat. Med.4(7), 844–847 (1998).
[CrossRef] [PubMed]

Kittle, D. S.

D. J. Brady, M. E. Gehm, R. A. Stack, D. L. Marks, D. S. Kittle, D. R. Golish, E. M. Vera, and S. D. Feller, “Multiscale gigapixel photography,” Nature486(7403), 386–389 (2012).
[CrossRef] [PubMed]

Klumpp, C.

S. Michael, D. Auld, C. Klumpp, A. Jadhav, W. Zheng, N. Thorne, C. P. Austin, J. Inglese, and A. Simeonov, “A Robotic Platform for Quantitative High-Throughput Screening,” Assay Drug Dev. Technol.6(5), 637–657 (2008).
[CrossRef] [PubMed]

Kolonder, P.

M. V. Kunnavakkam, F. M. Houlihan, M. Schlax, J. A. Liddle, P. Kolonder, O. Nalamasu, and J. A. Rogers, “Low-cost, low-loss microlens array fabricated by soft-lithography replication process,” Appl. Phys. Lett.82, 1152–1154 (2003).

Kononen, J.

J. Kononen, L. Bubendorf, A. Kallioniemi, M. Bärlund, P. Schraml, S. Leighton, J. Torhorst, M. J. Mihatsch, G. Sauter, and O. P. Kallioniemi, “Tissue microarrays for high-throughput molecular profiling of tumor specimens,” Nat. Med.4(7), 844–847 (1998).
[CrossRef] [PubMed]

Kunnavakkam, M. V.

M. V. Kunnavakkam, F. M. Houlihan, M. Schlax, J. A. Liddle, P. Kolonder, O. Nalamasu, and J. A. Rogers, “Low-cost, low-loss microlens array fabricated by soft-lithography replication process,” Appl. Phys. Lett.82, 1152–1154 (2003).

Lang, P.

P. Lang, K. Yeow, A. Nichols, and A. Scheer, “Cellular imaging in drug discovery,” Nat. Rev. Drug Discov.5(4), 343–356 (2006).
[CrossRef] [PubMed]

Leighton, S.

J. Kononen, L. Bubendorf, A. Kallioniemi, M. Bärlund, P. Schraml, S. Leighton, J. Torhorst, M. J. Mihatsch, G. Sauter, and O. P. Kallioniemi, “Tissue microarrays for high-throughput molecular profiling of tumor specimens,” Nat. Med.4(7), 844–847 (1998).
[CrossRef] [PubMed]

Liddle, J. A.

M. V. Kunnavakkam, F. M. Houlihan, M. Schlax, J. A. Liddle, P. Kolonder, O. Nalamasu, and J. A. Rogers, “Low-cost, low-loss microlens array fabricated by soft-lithography replication process,” Appl. Phys. Lett.82, 1152–1154 (2003).

Luo, W.

S. O. Isikman, A. Greenbaum, W. Luo, A. F. Coskun, and A. Ozcan, “Giga-Pixel Lens Free Holographic Microscopy and Tomography Using Color Image Sensors,” PLoS ONE7(9), e45044 (2012).
[CrossRef] [PubMed]

Marks, D. L.

D. J. Brady, M. E. Gehm, R. A. Stack, D. L. Marks, D. S. Kittle, D. R. Golish, E. M. Vera, and S. D. Feller, “Multiscale gigapixel photography,” Nature486(7403), 386–389 (2012).
[CrossRef] [PubMed]

Merz, R.

A. Schilling, R. Merz, C. Ossmann, and H. P. Herzig, “Surface profiles of reflow microlenses under the influence of surface tension and gravity,” Opt. Eng.39(8), 2171–2176 (2000).
[CrossRef]

Michael, S.

S. Michael, D. Auld, C. Klumpp, A. Jadhav, W. Zheng, N. Thorne, C. P. Austin, J. Inglese, and A. Simeonov, “A Robotic Platform for Quantitative High-Throughput Screening,” Assay Drug Dev. Technol.6(5), 637–657 (2008).
[CrossRef] [PubMed]

Mihatsch, M. J.

J. Kononen, L. Bubendorf, A. Kallioniemi, M. Bärlund, P. Schraml, S. Leighton, J. Torhorst, M. J. Mihatsch, G. Sauter, and O. P. Kallioniemi, “Tissue microarrays for high-throughput molecular profiling of tumor specimens,” Nat. Med.4(7), 844–847 (1998).
[CrossRef] [PubMed]

Nalamasu, O.

M. V. Kunnavakkam, F. M. Houlihan, M. Schlax, J. A. Liddle, P. Kolonder, O. Nalamasu, and J. A. Rogers, “Low-cost, low-loss microlens array fabricated by soft-lithography replication process,” Appl. Phys. Lett.82, 1152–1154 (2003).

Nichols, A.

P. Lang, K. Yeow, A. Nichols, and A. Scheer, “Cellular imaging in drug discovery,” Nat. Rev. Drug Discov.5(4), 343–356 (2006).
[CrossRef] [PubMed]

Nussbaum, P. H.

P. H. Nussbaum, R. Volkel, H. P. Herzig, M. Eisner, and S. Haselbeck, “Design, fabrication and testing of microlens arrays for sensors and microsystems,” Pure Appl. Opt.6(6), 617–636 (1997).
[CrossRef]

O’Neill, F. T.

F. T. O’Neill and J. T. Sheridan, “Photoresist reflow method of microlens production part II: analytic models,” Optik (Stuttg.)113(9), 405–420 (2002).
[CrossRef]

Orth, A.

Ossmann, C.

A. Schilling, R. Merz, C. Ossmann, and H. P. Herzig, “Surface profiles of reflow microlenses under the influence of surface tension and gravity,” Opt. Eng.39(8), 2171–2176 (2000).
[CrossRef]

Ozcan, A.

S. O. Isikman, A. Greenbaum, W. Luo, A. F. Coskun, and A. Ozcan, “Giga-Pixel Lens Free Holographic Microscopy and Tomography Using Color Image Sensors,” PLoS ONE7(9), e45044 (2012).
[CrossRef] [PubMed]

Pepperkok, R.

R. Pepperkok and J. Ellenberg, “High-throughput fluorescence microscopy for systems biology,” Nat. Rev. Mol. Cell Biol.7(9), 690–696 (2006).
[CrossRef] [PubMed]

Preibisch, S.

S. Preibisch, S. Saalfeld, and P. Tomancak, “Globally optimal stitching of tiled 3D microscopic image acquisitions,” Bioinformatics25(11), 1463–1465 (2009).
[CrossRef] [PubMed]

Rogers, J. A.

M. V. Kunnavakkam, F. M. Houlihan, M. Schlax, J. A. Liddle, P. Kolonder, O. Nalamasu, and J. A. Rogers, “Low-cost, low-loss microlens array fabricated by soft-lithography replication process,” Appl. Phys. Lett.82, 1152–1154 (2003).

Saalfeld, S.

S. Preibisch, S. Saalfeld, and P. Tomancak, “Globally optimal stitching of tiled 3D microscopic image acquisitions,” Bioinformatics25(11), 1463–1465 (2009).
[CrossRef] [PubMed]

Sauter, G.

J. Kononen, L. Bubendorf, A. Kallioniemi, M. Bärlund, P. Schraml, S. Leighton, J. Torhorst, M. J. Mihatsch, G. Sauter, and O. P. Kallioniemi, “Tissue microarrays for high-throughput molecular profiling of tumor specimens,” Nat. Med.4(7), 844–847 (1998).
[CrossRef] [PubMed]

Scheer, A.

P. Lang, K. Yeow, A. Nichols, and A. Scheer, “Cellular imaging in drug discovery,” Nat. Rev. Drug Discov.5(4), 343–356 (2006).
[CrossRef] [PubMed]

Schilling, A.

A. Schilling, R. Merz, C. Ossmann, and H. P. Herzig, “Surface profiles of reflow microlenses under the influence of surface tension and gravity,” Opt. Eng.39(8), 2171–2176 (2000).
[CrossRef]

Schlax, M.

M. V. Kunnavakkam, F. M. Houlihan, M. Schlax, J. A. Liddle, P. Kolonder, O. Nalamasu, and J. A. Rogers, “Low-cost, low-loss microlens array fabricated by soft-lithography replication process,” Appl. Phys. Lett.82, 1152–1154 (2003).

Schonbrun, E.

Schraml, P.

J. Kononen, L. Bubendorf, A. Kallioniemi, M. Bärlund, P. Schraml, S. Leighton, J. Torhorst, M. J. Mihatsch, G. Sauter, and O. P. Kallioniemi, “Tissue microarrays for high-throughput molecular profiling of tumor specimens,” Nat. Med.4(7), 844–847 (1998).
[CrossRef] [PubMed]

Shenoy, S. M.

P. Capodieci, M. Donovan, H. Buchinsky, Y. Jeffers, C. Cordon-Cardo, W. Gerald, J. Edelson, S. M. Shenoy, and R. H. Singer, “Gene expression profiling in single cells within tissue,” Nat. Methods2(9), 663–665 (2005).
[CrossRef] [PubMed]

Sheridan, J. T.

F. T. O’Neill and J. T. Sheridan, “Photoresist reflow method of microlens production part II: analytic models,” Optik (Stuttg.)113(9), 405–420 (2002).
[CrossRef]

Simeonov, A.

S. Michael, D. Auld, C. Klumpp, A. Jadhav, W. Zheng, N. Thorne, C. P. Austin, J. Inglese, and A. Simeonov, “A Robotic Platform for Quantitative High-Throughput Screening,” Assay Drug Dev. Technol.6(5), 637–657 (2008).
[CrossRef] [PubMed]

Singer, R. H.

P. Capodieci, M. Donovan, H. Buchinsky, Y. Jeffers, C. Cordon-Cardo, W. Gerald, J. Edelson, S. M. Shenoy, and R. H. Singer, “Gene expression profiling in single cells within tissue,” Nat. Methods2(9), 663–665 (2005).
[CrossRef] [PubMed]

Stack, R. A.

D. J. Brady, M. E. Gehm, R. A. Stack, D. L. Marks, D. S. Kittle, D. R. Golish, E. M. Vera, and S. D. Feller, “Multiscale gigapixel photography,” Nature486(7403), 386–389 (2012).
[CrossRef] [PubMed]

Steinvurzel, P. E.

E. Schonbrun, P. E. Steinvurzel, and K. B. Crozier, “A microfluidic fluorescence measurement system using an astigmatic diffractive microlens array,” Opt. Express19(2), 1385–1394 (2011).
[CrossRef] [PubMed]

E. Schonbrun, A. R. Abate, P. E. Steinvurzel, D. A. Weitz, and K. B. Crozier, “High-throughput fluorescence detection using an integrated zone-plate array,” Lab Chip10(7), 852–856 (2010).
[CrossRef] [PubMed]

Thorne, N.

S. Michael, D. Auld, C. Klumpp, A. Jadhav, W. Zheng, N. Thorne, C. P. Austin, J. Inglese, and A. Simeonov, “A Robotic Platform for Quantitative High-Throughput Screening,” Assay Drug Dev. Technol.6(5), 637–657 (2008).
[CrossRef] [PubMed]

Tomancak, P.

S. Preibisch, S. Saalfeld, and P. Tomancak, “Globally optimal stitching of tiled 3D microscopic image acquisitions,” Bioinformatics25(11), 1463–1465 (2009).
[CrossRef] [PubMed]

Torhorst, J.

J. Kononen, L. Bubendorf, A. Kallioniemi, M. Bärlund, P. Schraml, S. Leighton, J. Torhorst, M. J. Mihatsch, G. Sauter, and O. P. Kallioniemi, “Tissue microarrays for high-throughput molecular profiling of tumor specimens,” Nat. Med.4(7), 844–847 (1998).
[CrossRef] [PubMed]

Vera, E. M.

D. J. Brady, M. E. Gehm, R. A. Stack, D. L. Marks, D. S. Kittle, D. R. Golish, E. M. Vera, and S. D. Feller, “Multiscale gigapixel photography,” Nature486(7403), 386–389 (2012).
[CrossRef] [PubMed]

Volkel, R.

P. H. Nussbaum, R. Volkel, H. P. Herzig, M. Eisner, and S. Haselbeck, “Design, fabrication and testing of microlens arrays for sensors and microsystems,” Pure Appl. Opt.6(6), 617–636 (1997).
[CrossRef]

Weitz, D. A.

E. Schonbrun, A. R. Abate, P. E. Steinvurzel, D. A. Weitz, and K. B. Crozier, “High-throughput fluorescence detection using an integrated zone-plate array,” Lab Chip10(7), 852–856 (2010).
[CrossRef] [PubMed]

Ye, W. N.

Yeow, K.

P. Lang, K. Yeow, A. Nichols, and A. Scheer, “Cellular imaging in drug discovery,” Nat. Rev. Drug Discov.5(4), 343–356 (2006).
[CrossRef] [PubMed]

Zheng, W.

S. Michael, D. Auld, C. Klumpp, A. Jadhav, W. Zheng, N. Thorne, C. P. Austin, J. Inglese, and A. Simeonov, “A Robotic Platform for Quantitative High-Throughput Screening,” Assay Drug Dev. Technol.6(5), 637–657 (2008).
[CrossRef] [PubMed]

Appl. Phys. Lett. (1)

M. V. Kunnavakkam, F. M. Houlihan, M. Schlax, J. A. Liddle, P. Kolonder, O. Nalamasu, and J. A. Rogers, “Low-cost, low-loss microlens array fabricated by soft-lithography replication process,” Appl. Phys. Lett.82, 1152–1154 (2003).

Assay Drug Dev. Technol. (1)

S. Michael, D. Auld, C. Klumpp, A. Jadhav, W. Zheng, N. Thorne, C. P. Austin, J. Inglese, and A. Simeonov, “A Robotic Platform for Quantitative High-Throughput Screening,” Assay Drug Dev. Technol.6(5), 637–657 (2008).
[CrossRef] [PubMed]

Bioinformatics (1)

S. Preibisch, S. Saalfeld, and P. Tomancak, “Globally optimal stitching of tiled 3D microscopic image acquisitions,” Bioinformatics25(11), 1463–1465 (2009).
[CrossRef] [PubMed]

Lab Chip (1)

E. Schonbrun, A. R. Abate, P. E. Steinvurzel, D. A. Weitz, and K. B. Crozier, “High-throughput fluorescence detection using an integrated zone-plate array,” Lab Chip10(7), 852–856 (2010).
[CrossRef] [PubMed]

Nat. Med. (1)

J. Kononen, L. Bubendorf, A. Kallioniemi, M. Bärlund, P. Schraml, S. Leighton, J. Torhorst, M. J. Mihatsch, G. Sauter, and O. P. Kallioniemi, “Tissue microarrays for high-throughput molecular profiling of tumor specimens,” Nat. Med.4(7), 844–847 (1998).
[CrossRef] [PubMed]

Nat. Methods (1)

P. Capodieci, M. Donovan, H. Buchinsky, Y. Jeffers, C. Cordon-Cardo, W. Gerald, J. Edelson, S. M. Shenoy, and R. H. Singer, “Gene expression profiling in single cells within tissue,” Nat. Methods2(9), 663–665 (2005).
[CrossRef] [PubMed]

Nat. Protoc. (1)

R. W. Cole, T. Jinadasa, and C. M. Brown, “Measuring and interpreting point spread functions to determine confocal microscope resolution and ensure quality control,” Nat. Protoc.6(12), 1929–1941 (2011).
[CrossRef] [PubMed]

Nat. Rev. Drug Discov. (1)

P. Lang, K. Yeow, A. Nichols, and A. Scheer, “Cellular imaging in drug discovery,” Nat. Rev. Drug Discov.5(4), 343–356 (2006).
[CrossRef] [PubMed]

Nat. Rev. Mol. Cell Biol. (1)

R. Pepperkok and J. Ellenberg, “High-throughput fluorescence microscopy for systems biology,” Nat. Rev. Mol. Cell Biol.7(9), 690–696 (2006).
[CrossRef] [PubMed]

Nature (1)

D. J. Brady, M. E. Gehm, R. A. Stack, D. L. Marks, D. S. Kittle, D. R. Golish, E. M. Vera, and S. D. Feller, “Multiscale gigapixel photography,” Nature486(7403), 386–389 (2012).
[CrossRef] [PubMed]

Opt. Eng. (1)

A. Schilling, R. Merz, C. Ossmann, and H. P. Herzig, “Surface profiles of reflow microlenses under the influence of surface tension and gravity,” Opt. Eng.39(8), 2171–2176 (2000).
[CrossRef]

Opt. Express (2)

Opt. Lett. (1)

Optik (Stuttg.) (1)

F. T. O’Neill and J. T. Sheridan, “Photoresist reflow method of microlens production part II: analytic models,” Optik (Stuttg.)113(9), 405–420 (2002).
[CrossRef]

PLoS ONE (1)

S. O. Isikman, A. Greenbaum, W. Luo, A. F. Coskun, and A. Ozcan, “Giga-Pixel Lens Free Holographic Microscopy and Tomography Using Color Image Sensors,” PLoS ONE7(9), e45044 (2012).
[CrossRef] [PubMed]

Pure Appl. Opt. (1)

P. H. Nussbaum, R. Volkel, H. P. Herzig, M. Eisner, and S. Haselbeck, “Design, fabrication and testing of microlens arrays for sensors and microsystems,” Pure Appl. Opt.6(6), 617–636 (1997).
[CrossRef]

Other (4)

O. Cossairt, D. Miau, and S. K. Nayar, “Gigapixel computational imaging,” IEEE International Conference on Computational Photography, 1–8 (2011).

G. Zheng, X. Ou, and C. Yang, “Towards giga-pixel microscopy,” CLEO 2012. Optical Society of America, Washington, DC, 1–2.

Ibidi μ-Plate 384-well specifications sheet, http://ibidi.com/fileadmin/products/labware/plates/P_8840X_Plate_384well/IN_884XX_384.pdf , accessed 24 Nov 2012.

Molecular Devices ImageXpress Micro product website, http://www.highthroughputimaging.com/screening/imagexpress_micro.html#apps , accessed 24 November 2012.

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Figures (5)

Fig. 1
Fig. 1

Experimental setup. Green rays: laser excitation (λ = 532nm); Red rays: fluorescence emission λ = 575nm); LB: laser beam (green, λ = 532nm); M: mirror; MO: 10 × or 50 × microscope objective; DM: dichroic mirror (cut off λ = 550nm); TL: tube lens (focal length of 200 mm); TTS: tip/tilt stage. Tip and tilt are around the x- and y-axes. MLA: microlens array, focal length of 345μm in water; W: water (immersion fluid); SAM: sample (well plate or tissue slide); PS: piezoelectric stage. The stage is scanned along the x- and y-axes; SLR: SLR camera lens (focal length of 28-80 mm); LP: Long-pass filter (cut on λ = 575nm); CAM: camera; Inset i): A section of a raw camera frame during imaging. Scale bar is 1 mm in object space. Inset ii): Detailed view of a microlens focusing the laser (dashed lines) through water (W) and a #1.5 coverslip (CS) and into the fluorescent sample, depicted as red shape.

Fig. 2
Fig. 2

(a) Micrograph of a portion of the microlens array. (b) Typical intensity line cut of an image of a fluorescent bead (500 nm diameter), obtained by microlens array using water immersion imaging. Dots are experimental data and dashed line is a Gaussian fit (FWHM = 1.74 μm.) Inset: Image of the 500 nm fluorescent sphere, with dashed white line indicating position of line cut for one-dimensional intensity plot.

Fig. 3
Fig. 3

(a) Low resolution image of the 8 × 8 well imaged area. The entire field of view is 3.6 × 3.6 cm, corresponding to the boxed region in (b). (b) Photograph of the 384-well plate showing loaded fluorescent sample (5 μm beads) in the right half of the plate. The white box indicates the FOV in (a). (c) Close up of well B2. (d) Zoom in of the boxed region in well B2 showing fluorescent beads. (e) Close up of well E6 of (c). (f) Zoom-in of the boxed region in well E6 (e) showing fluorescent beads.

Fig. 4
Fig. 4

H&E stained tissue microarray imaging. (a) A low resolution image of the entire imaging area. Cores of interest D6 and H7 are boxed. (b) Close up of core D6. Regions of interest R1 and R2 are boxed. (c) Zoom in of region of interest R1 in core D6 (b). (d) Zoom in of region of interest R2 in core D6 (b). (e) Close up of core H7. A region of interest, R3, is boxed. (e) Zoom in of region of interest R3 from core H7 (e).

Fig. 5
Fig. 5

Imaging of a mouse kidney section (Invitrogen Fluocells prepared slide #3). (a) Image of AlexaFluor 568 Phalloidin fluorophore.distribution. Image has extent 1 × 0.6 cm, and represents the entire tissue section. (b) Zoom-in of boxed region of panel a.

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