Abstract

We present an optical system to measure height maps of non-adherent cells as they flow through a microfluidic channel. The cells are suspended in an index-matching absorbing buffer, where cell height is evaluated by measuring the difference in absorption between the cell and the background. Unlike interferometric microscopes, the measured cell height is nearly independent of the cell’s optical properties. The height maps are captured using a single exposure of a color camera, and consequently the system is capable of high-throughput characterization of large collections of cells. Using this system, we have measured more than 1600 height maps and volumes of three different leukemia cell lines.

© 2013 OSA

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  1. A. Tzur, J. K. Moore, P. Jorgensen, H. M. Shapiro, and M. W. Kirschner, “Optimizing optical flow cytometry for cell volume-based sorting and analysis,” PLoS ONE6(1), e16053 (2011).
    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
  3. T. R. Jones, A. E. Carpenter, M. R. Lamprecht, J. Moffat, S. J. Silver, J. K. Grenier, A. B. Castoreno, U. S. Eggert, D. E. Root, P. Golland, and D. M. Sabatini, “Scoring diverse cellular morphologies in image-based screens with iterative feedback and machine learning,” Proc. Natl. Acad. Sci. U.S.A.106(6), 1826–1831 (2009).
    [CrossRef] [PubMed]
  4. D. A. Basiji, W. E. Ortyn, L. Liang, V. Venkatachalam, and P. Morrissey, “Cellular image analysis and imaging by flow cytometry,” Clin. Lab. Med.27(3), 653–670, viii (2007).
    [CrossRef] [PubMed]
  5. E. Schonbrun, S. S. Gorthi, and D. Schaak, “Microfabricated multiple field of view imaging flow cytometry,” Lab Chip12(2), 268–273 (2011).
    [CrossRef] [PubMed]
  6. J. M. Higgins and L. Mahadevan, “Physiological and pathological population dynamics of circulating human red blood cells,” Proc. Natl. Acad. Sci. U.S.A.107(47), 20587–20592 (2010).
    [CrossRef] [PubMed]
  7. S. Son, A. Tzur, Y. Weng, P. Jorgensen, J. Kim, M. W. Kirschner, and S. R. Manalis, “Direct observation of mammalian cell growth and size regulation,” Nat. Methods9(9), 910–912 (2012).
    [CrossRef] [PubMed]
  8. B. Rappaz, A. Barbul, Y. Emery, R. Korenstein, C. Depeursinge, P. J. Magistretti, and P. Marquet, “Comparative study of human erythrocytes by digital holographic microscopy, confocal microscopy, and impedance volume analyzer,” Cytometry A73A(10), 895–903 (2008).
    [CrossRef] [PubMed]
  9. G. Popescu, T. Ikeda, R. R. Dasari, and M. S. Feld, “Diffraction phase microscopy for quantifying cell structure and dynamics,” Opt. Lett.31(6), 775–777 (2006).
    [CrossRef] [PubMed]
  10. B. Kemper and G. von Bally, “Digital holographic microscopy for live cell applications and technical inspection,” Appl. Opt.47(4), A52–A61 (2008).
    [CrossRef] [PubMed]
  11. G. Di Caprio, M. A. Gioffre, N. Saffioti, S. Grilli, P. Ferraro, R. Puglisi, D. Balduzzi, A. Galli, and G. Coppola, “Quantitative label-free animal sperm imaging by means of digital holographic microscopy,” IEEE J. Sel. Top. Quantum Electron.16(4), 833–840 (2010).
    [CrossRef]
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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
  14. W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods4(9), 717–719 (2007).
    [CrossRef] [PubMed]
  15. M. L. Gray, R. A. Hoffman, and W. P. Hansen, “A new method for cell volume measurement based on volume exclusion of a fluorescent dye,” Cytometry3(6), 428–434 (1983).
    [CrossRef] [PubMed]
  16. M. A. Model, A. K. Khitrin, and J. L. Blank, “Measurement of the absorption of concentrated dyes and their use for quantitative imaging of surface topography,” J. Microsc.231(1), 156–167 (2008).
    [CrossRef] [PubMed]
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  18. R. Barer and S. Joseph, “Refractometry of living cells,” Q. J. Microsc. Sci.95, 399–423 (1954).
  19. McCormick® Yellow Food Color.
  20. J. Dai and M. P. Sheetz, “Membrane tether formation from blebbing cells,” Biophys. J.77(6), 3363–3370 (1999).
    [CrossRef] [PubMed]

2012

M. Wendel, L. Bazhenova, R. Boshuizen, A. Kolatkar, M. Honnatti, E. H. Cho, D. Marrinucci, A. Sandhu, A. Perricone, P. Thistlethwaite, K. Bethel, J. Nieva, M. van den Heuvel, and P. Kuhn, “Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology,” Phys. Biol.9(1), 016005 (2012).
[CrossRef] [PubMed]

S. Son, A. Tzur, Y. Weng, P. Jorgensen, J. Kim, M. W. Kirschner, and S. R. Manalis, “Direct observation of mammalian cell growth and size regulation,” Nat. Methods9(9), 910–912 (2012).
[CrossRef] [PubMed]

A. Greenbaum, W. Luo, T. W. Su, Z. Göröcs, L. Xue, S. O. Isikman, A. F. Coskun, O. Mudanyali, and A. Ozcan, “Imaging without lenses: achievements and remaining challenges of wide-field on-chip microscopy,” Nat. Methods9(9), 889–895 (2012).
[CrossRef] [PubMed]

S. S. Gorthi and E. Schonbrun, “Phase imaging flow cytometry using a focus-stack collecting microscope,” Opt. Lett.37(4), 707–709 (2012).
[CrossRef] [PubMed]

J. C. M. Antón, J. Alonso, J. A. G. Pedrero, and J. A. Quiroga, “Topographic optical profilometry by absorption in liquids,” Opt. Express20(27), 28631–28640 (2012).
[CrossRef] [PubMed]

2011

A. Tzur, J. K. Moore, P. Jorgensen, H. M. Shapiro, and M. W. Kirschner, “Optimizing optical flow cytometry for cell volume-based sorting and analysis,” PLoS ONE6(1), e16053 (2011).
[CrossRef] [PubMed]

E. Schonbrun, S. S. Gorthi, and D. Schaak, “Microfabricated multiple field of view imaging flow cytometry,” Lab Chip12(2), 268–273 (2011).
[CrossRef] [PubMed]

2010

J. M. Higgins and L. Mahadevan, “Physiological and pathological population dynamics of circulating human red blood cells,” Proc. Natl. Acad. Sci. U.S.A.107(47), 20587–20592 (2010).
[CrossRef] [PubMed]

G. Di Caprio, M. A. Gioffre, N. Saffioti, S. Grilli, P. Ferraro, R. Puglisi, D. Balduzzi, A. Galli, and G. Coppola, “Quantitative label-free animal sperm imaging by means of digital holographic microscopy,” IEEE J. Sel. Top. Quantum Electron.16(4), 833–840 (2010).
[CrossRef]

2009

T. R. Jones, A. E. Carpenter, M. R. Lamprecht, J. Moffat, S. J. Silver, J. K. Grenier, A. B. Castoreno, U. S. Eggert, D. E. Root, P. Golland, and D. M. Sabatini, “Scoring diverse cellular morphologies in image-based screens with iterative feedback and machine learning,” Proc. Natl. Acad. Sci. U.S.A.106(6), 1826–1831 (2009).
[CrossRef] [PubMed]

2008

B. Kemper and G. von Bally, “Digital holographic microscopy for live cell applications and technical inspection,” Appl. Opt.47(4), A52–A61 (2008).
[CrossRef] [PubMed]

B. Rappaz, A. Barbul, Y. Emery, R. Korenstein, C. Depeursinge, P. J. Magistretti, and P. Marquet, “Comparative study of human erythrocytes by digital holographic microscopy, confocal microscopy, and impedance volume analyzer,” Cytometry A73A(10), 895–903 (2008).
[CrossRef] [PubMed]

M. A. Model, A. K. Khitrin, and J. L. Blank, “Measurement of the absorption of concentrated dyes and their use for quantitative imaging of surface topography,” J. Microsc.231(1), 156–167 (2008).
[CrossRef] [PubMed]

2007

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods4(9), 717–719 (2007).
[CrossRef] [PubMed]

D. A. Basiji, W. E. Ortyn, L. Liang, V. Venkatachalam, and P. Morrissey, “Cellular image analysis and imaging by flow cytometry,” Clin. Lab. Med.27(3), 653–670, viii (2007).
[CrossRef] [PubMed]

2006

1999

J. Dai and M. P. Sheetz, “Membrane tether formation from blebbing cells,” Biophys. J.77(6), 3363–3370 (1999).
[CrossRef] [PubMed]

1983

M. L. Gray, R. A. Hoffman, and W. P. Hansen, “A new method for cell volume measurement based on volume exclusion of a fluorescent dye,” Cytometry3(6), 428–434 (1983).
[CrossRef] [PubMed]

1954

R. Barer and S. Joseph, “Refractometry of living cells,” Q. J. Microsc. Sci.95, 399–423 (1954).

Alonso, J.

Antón, J. C. M.

Badizadegan, K.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods4(9), 717–719 (2007).
[CrossRef] [PubMed]

Balduzzi, D.

G. Di Caprio, M. A. Gioffre, N. Saffioti, S. Grilli, P. Ferraro, R. Puglisi, D. Balduzzi, A. Galli, and G. Coppola, “Quantitative label-free animal sperm imaging by means of digital holographic microscopy,” IEEE J. Sel. Top. Quantum Electron.16(4), 833–840 (2010).
[CrossRef]

Barbul, A.

B. Rappaz, A. Barbul, Y. Emery, R. Korenstein, C. Depeursinge, P. J. Magistretti, and P. Marquet, “Comparative study of human erythrocytes by digital holographic microscopy, confocal microscopy, and impedance volume analyzer,” Cytometry A73A(10), 895–903 (2008).
[CrossRef] [PubMed]

Barer, R.

R. Barer and S. Joseph, “Refractometry of living cells,” Q. J. Microsc. Sci.95, 399–423 (1954).

Basiji, D. A.

D. A. Basiji, W. E. Ortyn, L. Liang, V. Venkatachalam, and P. Morrissey, “Cellular image analysis and imaging by flow cytometry,” Clin. Lab. Med.27(3), 653–670, viii (2007).
[CrossRef] [PubMed]

Bazhenova, L.

M. Wendel, L. Bazhenova, R. Boshuizen, A. Kolatkar, M. Honnatti, E. H. Cho, D. Marrinucci, A. Sandhu, A. Perricone, P. Thistlethwaite, K. Bethel, J. Nieva, M. van den Heuvel, and P. Kuhn, “Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology,” Phys. Biol.9(1), 016005 (2012).
[CrossRef] [PubMed]

Bethel, K.

M. Wendel, L. Bazhenova, R. Boshuizen, A. Kolatkar, M. Honnatti, E. H. Cho, D. Marrinucci, A. Sandhu, A. Perricone, P. Thistlethwaite, K. Bethel, J. Nieva, M. van den Heuvel, and P. Kuhn, “Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology,” Phys. Biol.9(1), 016005 (2012).
[CrossRef] [PubMed]

Blank, J. L.

M. A. Model, A. K. Khitrin, and J. L. Blank, “Measurement of the absorption of concentrated dyes and their use for quantitative imaging of surface topography,” J. Microsc.231(1), 156–167 (2008).
[CrossRef] [PubMed]

Boshuizen, R.

M. Wendel, L. Bazhenova, R. Boshuizen, A. Kolatkar, M. Honnatti, E. H. Cho, D. Marrinucci, A. Sandhu, A. Perricone, P. Thistlethwaite, K. Bethel, J. Nieva, M. van den Heuvel, and P. Kuhn, “Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology,” Phys. Biol.9(1), 016005 (2012).
[CrossRef] [PubMed]

Carpenter, A. E.

T. R. Jones, A. E. Carpenter, M. R. Lamprecht, J. Moffat, S. J. Silver, J. K. Grenier, A. B. Castoreno, U. S. Eggert, D. E. Root, P. Golland, and D. M. Sabatini, “Scoring diverse cellular morphologies in image-based screens with iterative feedback and machine learning,” Proc. Natl. Acad. Sci. U.S.A.106(6), 1826–1831 (2009).
[CrossRef] [PubMed]

Castoreno, A. B.

T. R. Jones, A. E. Carpenter, M. R. Lamprecht, J. Moffat, S. J. Silver, J. K. Grenier, A. B. Castoreno, U. S. Eggert, D. E. Root, P. Golland, and D. M. Sabatini, “Scoring diverse cellular morphologies in image-based screens with iterative feedback and machine learning,” Proc. Natl. Acad. Sci. U.S.A.106(6), 1826–1831 (2009).
[CrossRef] [PubMed]

Cho, E. H.

M. Wendel, L. Bazhenova, R. Boshuizen, A. Kolatkar, M. Honnatti, E. H. Cho, D. Marrinucci, A. Sandhu, A. Perricone, P. Thistlethwaite, K. Bethel, J. Nieva, M. van den Heuvel, and P. Kuhn, “Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology,” Phys. Biol.9(1), 016005 (2012).
[CrossRef] [PubMed]

Choi, W.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods4(9), 717–719 (2007).
[CrossRef] [PubMed]

Coppola, G.

G. Di Caprio, M. A. Gioffre, N. Saffioti, S. Grilli, P. Ferraro, R. Puglisi, D. Balduzzi, A. Galli, and G. Coppola, “Quantitative label-free animal sperm imaging by means of digital holographic microscopy,” IEEE J. Sel. Top. Quantum Electron.16(4), 833–840 (2010).
[CrossRef]

Coskun, A. F.

A. Greenbaum, W. Luo, T. W. Su, Z. Göröcs, L. Xue, S. O. Isikman, A. F. Coskun, O. Mudanyali, and A. Ozcan, “Imaging without lenses: achievements and remaining challenges of wide-field on-chip microscopy,” Nat. Methods9(9), 889–895 (2012).
[CrossRef] [PubMed]

Dai, J.

J. Dai and M. P. Sheetz, “Membrane tether formation from blebbing cells,” Biophys. J.77(6), 3363–3370 (1999).
[CrossRef] [PubMed]

Dasari, R. R.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods4(9), 717–719 (2007).
[CrossRef] [PubMed]

G. Popescu, T. Ikeda, R. R. Dasari, and M. S. Feld, “Diffraction phase microscopy for quantifying cell structure and dynamics,” Opt. Lett.31(6), 775–777 (2006).
[CrossRef] [PubMed]

Depeursinge, C.

B. Rappaz, A. Barbul, Y. Emery, R. Korenstein, C. Depeursinge, P. J. Magistretti, and P. Marquet, “Comparative study of human erythrocytes by digital holographic microscopy, confocal microscopy, and impedance volume analyzer,” Cytometry A73A(10), 895–903 (2008).
[CrossRef] [PubMed]

Di Caprio, G.

G. Di Caprio, M. A. Gioffre, N. Saffioti, S. Grilli, P. Ferraro, R. Puglisi, D. Balduzzi, A. Galli, and G. Coppola, “Quantitative label-free animal sperm imaging by means of digital holographic microscopy,” IEEE J. Sel. Top. Quantum Electron.16(4), 833–840 (2010).
[CrossRef]

Eggert, U. S.

T. R. Jones, A. E. Carpenter, M. R. Lamprecht, J. Moffat, S. J. Silver, J. K. Grenier, A. B. Castoreno, U. S. Eggert, D. E. Root, P. Golland, and D. M. Sabatini, “Scoring diverse cellular morphologies in image-based screens with iterative feedback and machine learning,” Proc. Natl. Acad. Sci. U.S.A.106(6), 1826–1831 (2009).
[CrossRef] [PubMed]

Emery, Y.

B. Rappaz, A. Barbul, Y. Emery, R. Korenstein, C. Depeursinge, P. J. Magistretti, and P. Marquet, “Comparative study of human erythrocytes by digital holographic microscopy, confocal microscopy, and impedance volume analyzer,” Cytometry A73A(10), 895–903 (2008).
[CrossRef] [PubMed]

Fang-Yen, C.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods4(9), 717–719 (2007).
[CrossRef] [PubMed]

Feld, M. S.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods4(9), 717–719 (2007).
[CrossRef] [PubMed]

G. Popescu, T. Ikeda, R. R. Dasari, and M. S. Feld, “Diffraction phase microscopy for quantifying cell structure and dynamics,” Opt. Lett.31(6), 775–777 (2006).
[CrossRef] [PubMed]

Ferraro, P.

G. Di Caprio, M. A. Gioffre, N. Saffioti, S. Grilli, P. Ferraro, R. Puglisi, D. Balduzzi, A. Galli, and G. Coppola, “Quantitative label-free animal sperm imaging by means of digital holographic microscopy,” IEEE J. Sel. Top. Quantum Electron.16(4), 833–840 (2010).
[CrossRef]

Galli, A.

G. Di Caprio, M. A. Gioffre, N. Saffioti, S. Grilli, P. Ferraro, R. Puglisi, D. Balduzzi, A. Galli, and G. Coppola, “Quantitative label-free animal sperm imaging by means of digital holographic microscopy,” IEEE J. Sel. Top. Quantum Electron.16(4), 833–840 (2010).
[CrossRef]

Gioffre, M. A.

G. Di Caprio, M. A. Gioffre, N. Saffioti, S. Grilli, P. Ferraro, R. Puglisi, D. Balduzzi, A. Galli, and G. Coppola, “Quantitative label-free animal sperm imaging by means of digital holographic microscopy,” IEEE J. Sel. Top. Quantum Electron.16(4), 833–840 (2010).
[CrossRef]

Golland, P.

T. R. Jones, A. E. Carpenter, M. R. Lamprecht, J. Moffat, S. J. Silver, J. K. Grenier, A. B. Castoreno, U. S. Eggert, D. E. Root, P. Golland, and D. M. Sabatini, “Scoring diverse cellular morphologies in image-based screens with iterative feedback and machine learning,” Proc. Natl. Acad. Sci. U.S.A.106(6), 1826–1831 (2009).
[CrossRef] [PubMed]

Göröcs, Z.

A. Greenbaum, W. Luo, T. W. Su, Z. Göröcs, L. Xue, S. O. Isikman, A. F. Coskun, O. Mudanyali, and A. Ozcan, “Imaging without lenses: achievements and remaining challenges of wide-field on-chip microscopy,” Nat. Methods9(9), 889–895 (2012).
[CrossRef] [PubMed]

Gorthi, S. S.

S. S. Gorthi and E. Schonbrun, “Phase imaging flow cytometry using a focus-stack collecting microscope,” Opt. Lett.37(4), 707–709 (2012).
[CrossRef] [PubMed]

E. Schonbrun, S. S. Gorthi, and D. Schaak, “Microfabricated multiple field of view imaging flow cytometry,” Lab Chip12(2), 268–273 (2011).
[CrossRef] [PubMed]

Gray, M. L.

M. L. Gray, R. A. Hoffman, and W. P. Hansen, “A new method for cell volume measurement based on volume exclusion of a fluorescent dye,” Cytometry3(6), 428–434 (1983).
[CrossRef] [PubMed]

Greenbaum, A.

A. Greenbaum, W. Luo, T. W. Su, Z. Göröcs, L. Xue, S. O. Isikman, A. F. Coskun, O. Mudanyali, and A. Ozcan, “Imaging without lenses: achievements and remaining challenges of wide-field on-chip microscopy,” Nat. Methods9(9), 889–895 (2012).
[CrossRef] [PubMed]

Grenier, J. K.

T. R. Jones, A. E. Carpenter, M. R. Lamprecht, J. Moffat, S. J. Silver, J. K. Grenier, A. B. Castoreno, U. S. Eggert, D. E. Root, P. Golland, and D. M. Sabatini, “Scoring diverse cellular morphologies in image-based screens with iterative feedback and machine learning,” Proc. Natl. Acad. Sci. U.S.A.106(6), 1826–1831 (2009).
[CrossRef] [PubMed]

Grilli, S.

G. Di Caprio, M. A. Gioffre, N. Saffioti, S. Grilli, P. Ferraro, R. Puglisi, D. Balduzzi, A. Galli, and G. Coppola, “Quantitative label-free animal sperm imaging by means of digital holographic microscopy,” IEEE J. Sel. Top. Quantum Electron.16(4), 833–840 (2010).
[CrossRef]

Hansen, W. P.

M. L. Gray, R. A. Hoffman, and W. P. Hansen, “A new method for cell volume measurement based on volume exclusion of a fluorescent dye,” Cytometry3(6), 428–434 (1983).
[CrossRef] [PubMed]

Higgins, J. M.

J. M. Higgins and L. Mahadevan, “Physiological and pathological population dynamics of circulating human red blood cells,” Proc. Natl. Acad. Sci. U.S.A.107(47), 20587–20592 (2010).
[CrossRef] [PubMed]

Hoffman, R. A.

M. L. Gray, R. A. Hoffman, and W. P. Hansen, “A new method for cell volume measurement based on volume exclusion of a fluorescent dye,” Cytometry3(6), 428–434 (1983).
[CrossRef] [PubMed]

Honnatti, M.

M. Wendel, L. Bazhenova, R. Boshuizen, A. Kolatkar, M. Honnatti, E. H. Cho, D. Marrinucci, A. Sandhu, A. Perricone, P. Thistlethwaite, K. Bethel, J. Nieva, M. van den Heuvel, and P. Kuhn, “Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology,” Phys. Biol.9(1), 016005 (2012).
[CrossRef] [PubMed]

Ikeda, T.

Isikman, S. O.

A. Greenbaum, W. Luo, T. W. Su, Z. Göröcs, L. Xue, S. O. Isikman, A. F. Coskun, O. Mudanyali, and A. Ozcan, “Imaging without lenses: achievements and remaining challenges of wide-field on-chip microscopy,” Nat. Methods9(9), 889–895 (2012).
[CrossRef] [PubMed]

Jones, T. R.

T. R. Jones, A. E. Carpenter, M. R. Lamprecht, J. Moffat, S. J. Silver, J. K. Grenier, A. B. Castoreno, U. S. Eggert, D. E. Root, P. Golland, and D. M. Sabatini, “Scoring diverse cellular morphologies in image-based screens with iterative feedback and machine learning,” Proc. Natl. Acad. Sci. U.S.A.106(6), 1826–1831 (2009).
[CrossRef] [PubMed]

Jorgensen, P.

S. Son, A. Tzur, Y. Weng, P. Jorgensen, J. Kim, M. W. Kirschner, and S. R. Manalis, “Direct observation of mammalian cell growth and size regulation,” Nat. Methods9(9), 910–912 (2012).
[CrossRef] [PubMed]

A. Tzur, J. K. Moore, P. Jorgensen, H. M. Shapiro, and M. W. Kirschner, “Optimizing optical flow cytometry for cell volume-based sorting and analysis,” PLoS ONE6(1), e16053 (2011).
[CrossRef] [PubMed]

Joseph, S.

R. Barer and S. Joseph, “Refractometry of living cells,” Q. J. Microsc. Sci.95, 399–423 (1954).

Kemper, B.

Khitrin, A. K.

M. A. Model, A. K. Khitrin, and J. L. Blank, “Measurement of the absorption of concentrated dyes and their use for quantitative imaging of surface topography,” J. Microsc.231(1), 156–167 (2008).
[CrossRef] [PubMed]

Kim, J.

S. Son, A. Tzur, Y. Weng, P. Jorgensen, J. Kim, M. W. Kirschner, and S. R. Manalis, “Direct observation of mammalian cell growth and size regulation,” Nat. Methods9(9), 910–912 (2012).
[CrossRef] [PubMed]

Kirschner, M. W.

S. Son, A. Tzur, Y. Weng, P. Jorgensen, J. Kim, M. W. Kirschner, and S. R. Manalis, “Direct observation of mammalian cell growth and size regulation,” Nat. Methods9(9), 910–912 (2012).
[CrossRef] [PubMed]

A. Tzur, J. K. Moore, P. Jorgensen, H. M. Shapiro, and M. W. Kirschner, “Optimizing optical flow cytometry for cell volume-based sorting and analysis,” PLoS ONE6(1), e16053 (2011).
[CrossRef] [PubMed]

Kolatkar, A.

M. Wendel, L. Bazhenova, R. Boshuizen, A. Kolatkar, M. Honnatti, E. H. Cho, D. Marrinucci, A. Sandhu, A. Perricone, P. Thistlethwaite, K. Bethel, J. Nieva, M. van den Heuvel, and P. Kuhn, “Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology,” Phys. Biol.9(1), 016005 (2012).
[CrossRef] [PubMed]

Korenstein, R.

B. Rappaz, A. Barbul, Y. Emery, R. Korenstein, C. Depeursinge, P. J. Magistretti, and P. Marquet, “Comparative study of human erythrocytes by digital holographic microscopy, confocal microscopy, and impedance volume analyzer,” Cytometry A73A(10), 895–903 (2008).
[CrossRef] [PubMed]

Kuhn, P.

M. Wendel, L. Bazhenova, R. Boshuizen, A. Kolatkar, M. Honnatti, E. H. Cho, D. Marrinucci, A. Sandhu, A. Perricone, P. Thistlethwaite, K. Bethel, J. Nieva, M. van den Heuvel, and P. Kuhn, “Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology,” Phys. Biol.9(1), 016005 (2012).
[CrossRef] [PubMed]

Lamprecht, M. R.

T. R. Jones, A. E. Carpenter, M. R. Lamprecht, J. Moffat, S. J. Silver, J. K. Grenier, A. B. Castoreno, U. S. Eggert, D. E. Root, P. Golland, and D. M. Sabatini, “Scoring diverse cellular morphologies in image-based screens with iterative feedback and machine learning,” Proc. Natl. Acad. Sci. U.S.A.106(6), 1826–1831 (2009).
[CrossRef] [PubMed]

Liang, L.

D. A. Basiji, W. E. Ortyn, L. Liang, V. Venkatachalam, and P. Morrissey, “Cellular image analysis and imaging by flow cytometry,” Clin. Lab. Med.27(3), 653–670, viii (2007).
[CrossRef] [PubMed]

Lue, N.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods4(9), 717–719 (2007).
[CrossRef] [PubMed]

Luo, W.

A. Greenbaum, W. Luo, T. W. Su, Z. Göröcs, L. Xue, S. O. Isikman, A. F. Coskun, O. Mudanyali, and A. Ozcan, “Imaging without lenses: achievements and remaining challenges of wide-field on-chip microscopy,” Nat. Methods9(9), 889–895 (2012).
[CrossRef] [PubMed]

Magistretti, P. J.

B. Rappaz, A. Barbul, Y. Emery, R. Korenstein, C. Depeursinge, P. J. Magistretti, and P. Marquet, “Comparative study of human erythrocytes by digital holographic microscopy, confocal microscopy, and impedance volume analyzer,” Cytometry A73A(10), 895–903 (2008).
[CrossRef] [PubMed]

Mahadevan, L.

J. M. Higgins and L. Mahadevan, “Physiological and pathological population dynamics of circulating human red blood cells,” Proc. Natl. Acad. Sci. U.S.A.107(47), 20587–20592 (2010).
[CrossRef] [PubMed]

Manalis, S. R.

S. Son, A. Tzur, Y. Weng, P. Jorgensen, J. Kim, M. W. Kirschner, and S. R. Manalis, “Direct observation of mammalian cell growth and size regulation,” Nat. Methods9(9), 910–912 (2012).
[CrossRef] [PubMed]

Marquet, P.

B. Rappaz, A. Barbul, Y. Emery, R. Korenstein, C. Depeursinge, P. J. Magistretti, and P. Marquet, “Comparative study of human erythrocytes by digital holographic microscopy, confocal microscopy, and impedance volume analyzer,” Cytometry A73A(10), 895–903 (2008).
[CrossRef] [PubMed]

Marrinucci, D.

M. Wendel, L. Bazhenova, R. Boshuizen, A. Kolatkar, M. Honnatti, E. H. Cho, D. Marrinucci, A. Sandhu, A. Perricone, P. Thistlethwaite, K. Bethel, J. Nieva, M. van den Heuvel, and P. Kuhn, “Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology,” Phys. Biol.9(1), 016005 (2012).
[CrossRef] [PubMed]

Model, M. A.

M. A. Model, A. K. Khitrin, and J. L. Blank, “Measurement of the absorption of concentrated dyes and their use for quantitative imaging of surface topography,” J. Microsc.231(1), 156–167 (2008).
[CrossRef] [PubMed]

Moffat, J.

T. R. Jones, A. E. Carpenter, M. R. Lamprecht, J. Moffat, S. J. Silver, J. K. Grenier, A. B. Castoreno, U. S. Eggert, D. E. Root, P. Golland, and D. M. Sabatini, “Scoring diverse cellular morphologies in image-based screens with iterative feedback and machine learning,” Proc. Natl. Acad. Sci. U.S.A.106(6), 1826–1831 (2009).
[CrossRef] [PubMed]

Moore, J. K.

A. Tzur, J. K. Moore, P. Jorgensen, H. M. Shapiro, and M. W. Kirschner, “Optimizing optical flow cytometry for cell volume-based sorting and analysis,” PLoS ONE6(1), e16053 (2011).
[CrossRef] [PubMed]

Morrissey, P.

D. A. Basiji, W. E. Ortyn, L. Liang, V. Venkatachalam, and P. Morrissey, “Cellular image analysis and imaging by flow cytometry,” Clin. Lab. Med.27(3), 653–670, viii (2007).
[CrossRef] [PubMed]

Mudanyali, O.

A. Greenbaum, W. Luo, T. W. Su, Z. Göröcs, L. Xue, S. O. Isikman, A. F. Coskun, O. Mudanyali, and A. Ozcan, “Imaging without lenses: achievements and remaining challenges of wide-field on-chip microscopy,” Nat. Methods9(9), 889–895 (2012).
[CrossRef] [PubMed]

Nieva, J.

M. Wendel, L. Bazhenova, R. Boshuizen, A. Kolatkar, M. Honnatti, E. H. Cho, D. Marrinucci, A. Sandhu, A. Perricone, P. Thistlethwaite, K. Bethel, J. Nieva, M. van den Heuvel, and P. Kuhn, “Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology,” Phys. Biol.9(1), 016005 (2012).
[CrossRef] [PubMed]

Oh, S.

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods4(9), 717–719 (2007).
[CrossRef] [PubMed]

Ortyn, W. E.

D. A. Basiji, W. E. Ortyn, L. Liang, V. Venkatachalam, and P. Morrissey, “Cellular image analysis and imaging by flow cytometry,” Clin. Lab. Med.27(3), 653–670, viii (2007).
[CrossRef] [PubMed]

Ozcan, A.

A. Greenbaum, W. Luo, T. W. Su, Z. Göröcs, L. Xue, S. O. Isikman, A. F. Coskun, O. Mudanyali, and A. Ozcan, “Imaging without lenses: achievements and remaining challenges of wide-field on-chip microscopy,” Nat. Methods9(9), 889–895 (2012).
[CrossRef] [PubMed]

Pedrero, J. A. G.

Perricone, A.

M. Wendel, L. Bazhenova, R. Boshuizen, A. Kolatkar, M. Honnatti, E. H. Cho, D. Marrinucci, A. Sandhu, A. Perricone, P. Thistlethwaite, K. Bethel, J. Nieva, M. van den Heuvel, and P. Kuhn, “Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology,” Phys. Biol.9(1), 016005 (2012).
[CrossRef] [PubMed]

Popescu, G.

Puglisi, R.

G. Di Caprio, M. A. Gioffre, N. Saffioti, S. Grilli, P. Ferraro, R. Puglisi, D. Balduzzi, A. Galli, and G. Coppola, “Quantitative label-free animal sperm imaging by means of digital holographic microscopy,” IEEE J. Sel. Top. Quantum Electron.16(4), 833–840 (2010).
[CrossRef]

Quiroga, J. A.

Rappaz, B.

B. Rappaz, A. Barbul, Y. Emery, R. Korenstein, C. Depeursinge, P. J. Magistretti, and P. Marquet, “Comparative study of human erythrocytes by digital holographic microscopy, confocal microscopy, and impedance volume analyzer,” Cytometry A73A(10), 895–903 (2008).
[CrossRef] [PubMed]

Root, D. E.

T. R. Jones, A. E. Carpenter, M. R. Lamprecht, J. Moffat, S. J. Silver, J. K. Grenier, A. B. Castoreno, U. S. Eggert, D. E. Root, P. Golland, and D. M. Sabatini, “Scoring diverse cellular morphologies in image-based screens with iterative feedback and machine learning,” Proc. Natl. Acad. Sci. U.S.A.106(6), 1826–1831 (2009).
[CrossRef] [PubMed]

Sabatini, D. M.

T. R. Jones, A. E. Carpenter, M. R. Lamprecht, J. Moffat, S. J. Silver, J. K. Grenier, A. B. Castoreno, U. S. Eggert, D. E. Root, P. Golland, and D. M. Sabatini, “Scoring diverse cellular morphologies in image-based screens with iterative feedback and machine learning,” Proc. Natl. Acad. Sci. U.S.A.106(6), 1826–1831 (2009).
[CrossRef] [PubMed]

Saffioti, N.

G. Di Caprio, M. A. Gioffre, N. Saffioti, S. Grilli, P. Ferraro, R. Puglisi, D. Balduzzi, A. Galli, and G. Coppola, “Quantitative label-free animal sperm imaging by means of digital holographic microscopy,” IEEE J. Sel. Top. Quantum Electron.16(4), 833–840 (2010).
[CrossRef]

Sandhu, A.

M. Wendel, L. Bazhenova, R. Boshuizen, A. Kolatkar, M. Honnatti, E. H. Cho, D. Marrinucci, A. Sandhu, A. Perricone, P. Thistlethwaite, K. Bethel, J. Nieva, M. van den Heuvel, and P. Kuhn, “Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology,” Phys. Biol.9(1), 016005 (2012).
[CrossRef] [PubMed]

Schaak, D.

E. Schonbrun, S. S. Gorthi, and D. Schaak, “Microfabricated multiple field of view imaging flow cytometry,” Lab Chip12(2), 268–273 (2011).
[CrossRef] [PubMed]

Schonbrun, E.

S. S. Gorthi and E. Schonbrun, “Phase imaging flow cytometry using a focus-stack collecting microscope,” Opt. Lett.37(4), 707–709 (2012).
[CrossRef] [PubMed]

E. Schonbrun, S. S. Gorthi, and D. Schaak, “Microfabricated multiple field of view imaging flow cytometry,” Lab Chip12(2), 268–273 (2011).
[CrossRef] [PubMed]

Shapiro, H. M.

A. Tzur, J. K. Moore, P. Jorgensen, H. M. Shapiro, and M. W. Kirschner, “Optimizing optical flow cytometry for cell volume-based sorting and analysis,” PLoS ONE6(1), e16053 (2011).
[CrossRef] [PubMed]

Sheetz, M. P.

J. Dai and M. P. Sheetz, “Membrane tether formation from blebbing cells,” Biophys. J.77(6), 3363–3370 (1999).
[CrossRef] [PubMed]

Silver, S. J.

T. R. Jones, A. E. Carpenter, M. R. Lamprecht, J. Moffat, S. J. Silver, J. K. Grenier, A. B. Castoreno, U. S. Eggert, D. E. Root, P. Golland, and D. M. Sabatini, “Scoring diverse cellular morphologies in image-based screens with iterative feedback and machine learning,” Proc. Natl. Acad. Sci. U.S.A.106(6), 1826–1831 (2009).
[CrossRef] [PubMed]

Son, S.

S. Son, A. Tzur, Y. Weng, P. Jorgensen, J. Kim, M. W. Kirschner, and S. R. Manalis, “Direct observation of mammalian cell growth and size regulation,” Nat. Methods9(9), 910–912 (2012).
[CrossRef] [PubMed]

Su, T. W.

A. Greenbaum, W. Luo, T. W. Su, Z. Göröcs, L. Xue, S. O. Isikman, A. F. Coskun, O. Mudanyali, and A. Ozcan, “Imaging without lenses: achievements and remaining challenges of wide-field on-chip microscopy,” Nat. Methods9(9), 889–895 (2012).
[CrossRef] [PubMed]

Thistlethwaite, P.

M. Wendel, L. Bazhenova, R. Boshuizen, A. Kolatkar, M. Honnatti, E. H. Cho, D. Marrinucci, A. Sandhu, A. Perricone, P. Thistlethwaite, K. Bethel, J. Nieva, M. van den Heuvel, and P. Kuhn, “Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology,” Phys. Biol.9(1), 016005 (2012).
[CrossRef] [PubMed]

Tzur, A.

S. Son, A. Tzur, Y. Weng, P. Jorgensen, J. Kim, M. W. Kirschner, and S. R. Manalis, “Direct observation of mammalian cell growth and size regulation,” Nat. Methods9(9), 910–912 (2012).
[CrossRef] [PubMed]

A. Tzur, J. K. Moore, P. Jorgensen, H. M. Shapiro, and M. W. Kirschner, “Optimizing optical flow cytometry for cell volume-based sorting and analysis,” PLoS ONE6(1), e16053 (2011).
[CrossRef] [PubMed]

van den Heuvel, M.

M. Wendel, L. Bazhenova, R. Boshuizen, A. Kolatkar, M. Honnatti, E. H. Cho, D. Marrinucci, A. Sandhu, A. Perricone, P. Thistlethwaite, K. Bethel, J. Nieva, M. van den Heuvel, and P. Kuhn, “Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology,” Phys. Biol.9(1), 016005 (2012).
[CrossRef] [PubMed]

Venkatachalam, V.

D. A. Basiji, W. E. Ortyn, L. Liang, V. Venkatachalam, and P. Morrissey, “Cellular image analysis and imaging by flow cytometry,” Clin. Lab. Med.27(3), 653–670, viii (2007).
[CrossRef] [PubMed]

von Bally, G.

Wendel, M.

M. Wendel, L. Bazhenova, R. Boshuizen, A. Kolatkar, M. Honnatti, E. H. Cho, D. Marrinucci, A. Sandhu, A. Perricone, P. Thistlethwaite, K. Bethel, J. Nieva, M. van den Heuvel, and P. Kuhn, “Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology,” Phys. Biol.9(1), 016005 (2012).
[CrossRef] [PubMed]

Weng, Y.

S. Son, A. Tzur, Y. Weng, P. Jorgensen, J. Kim, M. W. Kirschner, and S. R. Manalis, “Direct observation of mammalian cell growth and size regulation,” Nat. Methods9(9), 910–912 (2012).
[CrossRef] [PubMed]

Xue, L.

A. Greenbaum, W. Luo, T. W. Su, Z. Göröcs, L. Xue, S. O. Isikman, A. F. Coskun, O. Mudanyali, and A. Ozcan, “Imaging without lenses: achievements and remaining challenges of wide-field on-chip microscopy,” Nat. Methods9(9), 889–895 (2012).
[CrossRef] [PubMed]

Appl. Opt.

Biophys. J.

J. Dai and M. P. Sheetz, “Membrane tether formation from blebbing cells,” Biophys. J.77(6), 3363–3370 (1999).
[CrossRef] [PubMed]

Clin. Lab. Med.

D. A. Basiji, W. E. Ortyn, L. Liang, V. Venkatachalam, and P. Morrissey, “Cellular image analysis and imaging by flow cytometry,” Clin. Lab. Med.27(3), 653–670, viii (2007).
[CrossRef] [PubMed]

Cytometry

M. L. Gray, R. A. Hoffman, and W. P. Hansen, “A new method for cell volume measurement based on volume exclusion of a fluorescent dye,” Cytometry3(6), 428–434 (1983).
[CrossRef] [PubMed]

Cytometry A

B. Rappaz, A. Barbul, Y. Emery, R. Korenstein, C. Depeursinge, P. J. Magistretti, and P. Marquet, “Comparative study of human erythrocytes by digital holographic microscopy, confocal microscopy, and impedance volume analyzer,” Cytometry A73A(10), 895–903 (2008).
[CrossRef] [PubMed]

IEEE J. Sel. Top. Quantum Electron.

G. Di Caprio, M. A. Gioffre, N. Saffioti, S. Grilli, P. Ferraro, R. Puglisi, D. Balduzzi, A. Galli, and G. Coppola, “Quantitative label-free animal sperm imaging by means of digital holographic microscopy,” IEEE J. Sel. Top. Quantum Electron.16(4), 833–840 (2010).
[CrossRef]

J. Microsc.

M. A. Model, A. K. Khitrin, and J. L. Blank, “Measurement of the absorption of concentrated dyes and their use for quantitative imaging of surface topography,” J. Microsc.231(1), 156–167 (2008).
[CrossRef] [PubMed]

Lab Chip

E. Schonbrun, S. S. Gorthi, and D. Schaak, “Microfabricated multiple field of view imaging flow cytometry,” Lab Chip12(2), 268–273 (2011).
[CrossRef] [PubMed]

Nat. Methods

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods4(9), 717–719 (2007).
[CrossRef] [PubMed]

S. Son, A. Tzur, Y. Weng, P. Jorgensen, J. Kim, M. W. Kirschner, and S. R. Manalis, “Direct observation of mammalian cell growth and size regulation,” Nat. Methods9(9), 910–912 (2012).
[CrossRef] [PubMed]

A. Greenbaum, W. Luo, T. W. Su, Z. Göröcs, L. Xue, S. O. Isikman, A. F. Coskun, O. Mudanyali, and A. Ozcan, “Imaging without lenses: achievements and remaining challenges of wide-field on-chip microscopy,” Nat. Methods9(9), 889–895 (2012).
[CrossRef] [PubMed]

Opt. Express

Opt. Lett.

Phys. Biol.

M. Wendel, L. Bazhenova, R. Boshuizen, A. Kolatkar, M. Honnatti, E. H. Cho, D. Marrinucci, A. Sandhu, A. Perricone, P. Thistlethwaite, K. Bethel, J. Nieva, M. van den Heuvel, and P. Kuhn, “Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology,” Phys. Biol.9(1), 016005 (2012).
[CrossRef] [PubMed]

PLoS ONE

A. Tzur, J. K. Moore, P. Jorgensen, H. M. Shapiro, and M. W. Kirschner, “Optimizing optical flow cytometry for cell volume-based sorting and analysis,” PLoS ONE6(1), e16053 (2011).
[CrossRef] [PubMed]

Proc. Natl. Acad. Sci. U.S.A.

T. R. Jones, A. E. Carpenter, M. R. Lamprecht, J. Moffat, S. J. Silver, J. K. Grenier, A. B. Castoreno, U. S. Eggert, D. E. Root, P. Golland, and D. M. Sabatini, “Scoring diverse cellular morphologies in image-based screens with iterative feedback and machine learning,” Proc. Natl. Acad. Sci. U.S.A.106(6), 1826–1831 (2009).
[CrossRef] [PubMed]

J. M. Higgins and L. Mahadevan, “Physiological and pathological population dynamics of circulating human red blood cells,” Proc. Natl. Acad. Sci. U.S.A.107(47), 20587–20592 (2010).
[CrossRef] [PubMed]

Q. J. Microsc. Sci.

R. Barer and S. Joseph, “Refractometry of living cells,” Q. J. Microsc. Sci.95, 399–423 (1954).

Other

McCormick® Yellow Food Color.

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Figures (3)

Fig. 1
Fig. 1

The dye exclusion microfluidic (DEM) microscope. (a) Schematic of the experimental setup. A microfluidic channel is illuminated by a green and a blue LED combined with a dichroic mirror. C1, C2, and C3 are condenser lenses. The microfluidic channel is imaged using a 40 × , 0.75 NA Nikon Fluorite objective lens (O) onto a Pike 032c CCD camera from Allied Vision located at the image plane. (b) The transmission spectrum of the absorbing buffer and the emission spectrum of the green and blue LEDs.

Fig. 2
Fig. 2

Dye exclusion imaging of an HL60 cell. (a) Shows a composite image of the HL60 cell captured by the color camera under green and blue illumination. (b,c) Show normalized images of the green and blue channel, respectively. The scale bars show the normalized transmission values, with the background having a value of one. (d-f) Show the reconstructed height surface, height map, and a cross-section through the cell. All scale bars are 5 μm.

Fig. 3
Fig. 3

Height map image sets of three leukemia cell lines. For each image set a volume histogram is shown and four representative height maps are displayed below. (a) Image set of Molt4 cells. (b) Image set of HL60 cells. (c) Image set of K562 cells. N is the number of cells in each histogram. All scale bars are 5 μm.

Equations (1)

Equations on this page are rendered with MathJax. Learn more.

h( x,y )=t+ log e ( I cell ( x,y ) / I ill ( x,y ) ) / α.

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