Abstract

Quantitative measurement of diffusive and directional processes of intracellular structures is not only critical in understanding cell mechanics and functions, but also has many applications, such as investigation of cellular responses to therapeutic agents. We introduce a label-free optical technique that allows non-perturbative characterization of localized intracellular dynamics. The method combines a field-based dynamic light scattering analysis with a confocal interferometric microscope to provide a statistical measure of the diffusive and directional motion of scattering structures inside a microscopic probe volume. To demonstrate the potential of this technique, we examined the localized intracellular dynamics in human epithelial ovarian cancer cells. We observed the distinctive temporal regimes of intracellular dynamics, which transitions from random to directional processes on a timescale of ~0.01 sec. In addition, we observed disrupted directional processes on the timescale of 1~5 sec by the application of a microtubule polymerization inhibitor, Colchicine, and ATP depletion.

© 2010 OSA

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2009 (1)

H. Ding, F. Nguyen, S. A. Boppart, and G. Popescu, “Optical properties of tissues quantified by Fourier-transform light scattering,” Opt. Lett. 34(9), 1372–1374 (2009).
[CrossRef] [PubMed]

2008 (2)

H. Ding, Z. Wang, F. Nguyen, S. A. Boppart, and G. Popescu, “Fourier transform light scattering of inhomogeneous and dynamic structures,” Phys. Rev. Lett. 101(23), 238102 (2008).
[CrossRef] [PubMed]

W. Choi, C.-C. Yu, C. Fang-Yen, K. Badizadegan, R. R. Dasari, and M. S. Feld, “Field-based angle-resolved light-scattering study of single live cells,” Opt. Lett. 33(14), 1596–1598 (2008).
[CrossRef] [PubMed]

2007 (6)

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods 4(9), 717–719 (2007).
[CrossRef] [PubMed]

S. Tang, C.-H. Sun, T. B. Krasieva, Z. Chen, and B. J. Tromberg, “Imaging subcellular scattering contrast by using combined optical coherence and multiphoton microscopy,” Opt. Lett. 32(5), 503–505 (2007).
[CrossRef] [PubMed]

G. Lenormand, J. Chopin, P. Bursac, J. J. Fredberg, and J. P. Butler, “Directional memory and caged dynamics in cytoskeletal remodelling,” Biochem. Biophys. Res. Commun. 360(4), 797–801 (2007).
[CrossRef] [PubMed]

I. Itzkan, L. Qiu, H. Fang, M. M. Zaman, E. Vitkin, I. C. Ghiran, S. Salahuddin, M. Modell, C. Andersson, L. M. Kimerer, P. B. Cipolloni, K.-H. Lim, S. D. Freedman, I. Bigio, B. P. Sachs, E. B. Hanlon, and L. T. Perelman, “Confocal light absorption and scattering spectroscopic microscopy monitors organelles in live cells with no exogenous labels,” Proc. Natl. Acad. Sci. U.S.A. 104(44), 17255–17260 (2007).
[CrossRef] [PubMed]

A. E. Desjardins, B. J. Vakoc, G. J. Tearney, and B. E. Bouma, “Backscattering spectroscopic contrast with angle-resolved optical coherence tomography,” Opt. Lett. 32(21), 3158–3160 (2007).
[CrossRef] [PubMed]

J. Li, G. Lykotrafitis, M. Dao, and S. Suresh, “Cytoskeletal dynamics of human erythrocyte,” Proc. Natl. Acad. Sci. U.S.A. 104(12), 4937–4942 (2007).
[CrossRef] [PubMed]

2006 (4)

L. Deng, X. Trepat, J. P. Butler, E. Millet, K. G. Morgan, D. A. Weitz, and J. J. Fredberg, “Fast and slow dynamics of the cytoskeleton,” Nat. Mater. 5(8), 636–640 (2006).
[CrossRef] [PubMed]

K. M. Van Citters, B. D. Hoffman, G. Massiera, and J. C. Crocker, “The role of F-actin and myosin in epithelial cell rheology,” Biophys. J. 91(10), 3946–3956 (2006).
[CrossRef] [PubMed]

R. P. Singh, V. K. Jaiswal, and V. K. Jain, “Study of smoke aerosols under a controlled environment by using dynamic light scattering,” Appl. Opt. 45(10), 2217–2221 (2006).
[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]

2005 (4)

C. Joo, T. Akkin, B. Cense, B. H. Park, and J. F. de Boer, “Spectral-domain optical coherence phase microscopy for quantitative phase-contrast imaging,” Opt. Lett. 30(16), 2131–2133 (2005).
[CrossRef] [PubMed]

M. A. Choma, A. K. Ellerbee, C. Yang, T. L. Creazzo, and J. A. Izatt, “Spectral-domain phase microscopy,” Opt. Lett. 30(10), 1162–1164 (2005).
[CrossRef] [PubMed]

P. Bursac, G. Lenormand, B. Fabry, M. Oliver, D. A. Weitz, V. Viasnoff, J. P. Butler, and J. J. Fredberg, “Cytoskeletal remodelling and slow dynamics in the living cell,” Nat. Mater. 4(7), 557–561 (2005).
[CrossRef] [PubMed]

R. P. Kulkarni, D. D. Wu, M. E. Davis, and S. E. Fraser, “Quantitating intracellular transport of polyplexes by spatio-temporal image correlation spectroscopy,” Proc. Natl. Acad. Sci. U.S.A. 102(21), 7523–7528 (2005).
[CrossRef] [PubMed]

2004 (3)

R. Dzakpasu and D. Axelrod, “Dynamic light scattering microscopy. A novel optical technique to image submicroscopic motions. I: theory,” Biophys. J. 87(2), 1279–1287 (2004).
[CrossRef] [PubMed]

R. Dzakpasu and D. Axelrod, “Dynamic light scattering microscopy. A novel optical technique to image submicroscopic motions. II: Experimental applications,” Biophys. J. 87(2), 1288–1297 (2004).
[CrossRef] [PubMed]

J. W. Pyhtila and A. Wax, “Rapid, depth-resolved light scattering measurements using Fourier domain, angle-resolved low coherence interferometry,” Opt. Express 12(25), 6178–6183 (2004).
[CrossRef]

2002 (2)

S. Yazdanfar and J. A. Izatt, “Self-referenced Doppler optical coherence tomography,” Opt. Lett. 27(23), 2085–2087 (2002).
[CrossRef]

A. Wax, C. Yang, V. Backman, K. Badizadegan, C. W. Boone, R. R. Dasari, and M. S. Feld, “Cellular organization and substructure measured using angle-resolved low-coherence interferometry,” Biophys. J. 82(4), 2256–2264 (2002).
[CrossRef] [PubMed]

2001 (1)

J. J. Tyson, K. Chen, and B. Novak, “Network dynamics and cell physiology,” Nat. Rev. Mol. Cell Biol. 2(12), 908–916 (2001).
[CrossRef] [PubMed]

2000 (2)

S. Yamada, D. Wirtz, and S. C. Kuo, “Mechanics of living cells measured by laser tracking microrheology,” Biophys. J. 78(4), 1736–1747 (2000).
[CrossRef] [PubMed]

T. Ichikawa, M. Yamada, D. Homma, R. J. Cherry, I. E. G. Morrison, and S. Kawato, “Digital fluorescence imaging of trafficking of endosomes containing low-density lipoprotein in brain astroglial cells,” Biochem. Biophys. Res. Commun. 269(1), 25–30 (2000).
[CrossRef] [PubMed]

1999 (1)

P. D. Kaplan, V. Trappe, and D. A. Weitz, “Light-scattering microscope,” Appl. Opt. 38(19), 4151–4157 (1999).
[CrossRef]

1998 (2)

A. Meller, R. Bar-Ziv, T. Tlusty, E. Moses, J. Stavans, and S. A. Safran, “Localized dynamic light scattering: a new approach to dynamic measurements in optical microscopy,” Biophys. J. 74(3), 1541–1548 (1998).
[CrossRef] [PubMed]

Y. Georgalis, E. B. Starikov, B. Hollenbach, R. Lurz, E. Scherzinger, W. Saenger, H. Lehrach, and E. E. Wanker, “Huntingtin aggregation monitored by dynamic light scattering,” Proc. Natl. Acad. Sci. U.S.A. 95(11), 6118–6121 (1998).
[CrossRef] [PubMed]

1997 (1)

R. B. Nicklas, “How cells get the right chromosomes,” Science 275(5300), 632–637 (1997).
[CrossRef] [PubMed]

1995 (1)

A. F. Fercher, C. K. Hitzenberger, G. Kamp, and S. Y. El-Zaiat, “Measurement of intraocular distances by backscattering spectral interferometry,” Opt. Commun. 117(1-2), 43–48 (1995).
[CrossRef]

1994 (1)

J. A. Izatt, M. R. Hee, G. M. Owen, E. A. Swanson, and J. G. Fujimoto, “Optical coherence microscopy in scattering media,” Opt. Lett. 19(8), 590–592 (1994).
[CrossRef] [PubMed]

1986 (1)

J. Peetermans, I. Nishio, S. T. Ohnishi, and T. Tanaka, “Light-scattering study of depolymerization kinetics of sickle hemoglobin polymers inside single erythrocytes,” Proc. Natl. Acad. Sci. U.S.A. 83(2), 352–356 (1986).
[CrossRef] [PubMed]

1985 (1)

I. Nishio, J. Peetermans, and T. Tanaka, “Microscope laser light scattering spectroscopy of single biological cells,” Cell Biophys. 7(2), 91–105 (1985).
[CrossRef] [PubMed]

1975 (1)

T. Tanaka and G. B. Benedek, “Observation of protein diffusivity in intact human and bovine lenses with application to cataract,” Invest. Ophthalmol. Vis. Sci. 14, 449–456 (1975).

1905 (1)

A. Einstein, “On the Motion – Required by the Molecular Kinetic Theory of Heat – of Small Particles Suspended in a Stationary Liquid,” Ann. Phys. 17, 549–560 (1905).
[CrossRef]

Akkin, T.

C. Joo, T. Akkin, B. Cense, B. H. Park, and J. F. de Boer, “Spectral-domain optical coherence phase microscopy for quantitative phase-contrast imaging,” Opt. Lett. 30(16), 2131–2133 (2005).
[CrossRef] [PubMed]

Andersson, C.

I. Itzkan, L. Qiu, H. Fang, M. M. Zaman, E. Vitkin, I. C. Ghiran, S. Salahuddin, M. Modell, C. Andersson, L. M. Kimerer, P. B. Cipolloni, K.-H. Lim, S. D. Freedman, I. Bigio, B. P. Sachs, E. B. Hanlon, and L. T. Perelman, “Confocal light absorption and scattering spectroscopic microscopy monitors organelles in live cells with no exogenous labels,” Proc. Natl. Acad. Sci. U.S.A. 104(44), 17255–17260 (2007).
[CrossRef] [PubMed]

Axelrod, D.

R. Dzakpasu and D. Axelrod, “Dynamic light scattering microscopy. A novel optical technique to image submicroscopic motions. I: theory,” Biophys. J. 87(2), 1279–1287 (2004).
[CrossRef] [PubMed]

R. Dzakpasu and D. Axelrod, “Dynamic light scattering microscopy. A novel optical technique to image submicroscopic motions. II: Experimental applications,” Biophys. J. 87(2), 1288–1297 (2004).
[CrossRef] [PubMed]

Backman, V.

A. Wax, C. Yang, V. Backman, K. Badizadegan, C. W. Boone, R. R. Dasari, and M. S. Feld, “Cellular organization and substructure measured using angle-resolved low-coherence interferometry,” Biophys. J. 82(4), 2256–2264 (2002).
[CrossRef] [PubMed]

Badizadegan, K.

W. Choi, C.-C. Yu, C. Fang-Yen, K. Badizadegan, R. R. Dasari, and M. S. Feld, “Field-based angle-resolved light-scattering study of single live cells,” Opt. Lett. 33(14), 1596–1598 (2008).
[CrossRef] [PubMed]

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods 4(9), 717–719 (2007).
[CrossRef] [PubMed]

A. Wax, C. Yang, V. Backman, K. Badizadegan, C. W. Boone, R. R. Dasari, and M. S. Feld, “Cellular organization and substructure measured using angle-resolved low-coherence interferometry,” Biophys. J. 82(4), 2256–2264 (2002).
[CrossRef] [PubMed]

Bar-Ziv, R.

A. Meller, R. Bar-Ziv, T. Tlusty, E. Moses, J. Stavans, and S. A. Safran, “Localized dynamic light scattering: a new approach to dynamic measurements in optical microscopy,” Biophys. J. 74(3), 1541–1548 (1998).
[CrossRef] [PubMed]

Benedek, G. B.

T. Tanaka and G. B. Benedek, “Observation of protein diffusivity in intact human and bovine lenses with application to cataract,” Invest. Ophthalmol. Vis. Sci. 14, 449–456 (1975).

Bigio, I.

I. Itzkan, L. Qiu, H. Fang, M. M. Zaman, E. Vitkin, I. C. Ghiran, S. Salahuddin, M. Modell, C. Andersson, L. M. Kimerer, P. B. Cipolloni, K.-H. Lim, S. D. Freedman, I. Bigio, B. P. Sachs, E. B. Hanlon, and L. T. Perelman, “Confocal light absorption and scattering spectroscopic microscopy monitors organelles in live cells with no exogenous labels,” Proc. Natl. Acad. Sci. U.S.A. 104(44), 17255–17260 (2007).
[CrossRef] [PubMed]

Boone, C. W.

A. Wax, C. Yang, V. Backman, K. Badizadegan, C. W. Boone, R. R. Dasari, and M. S. Feld, “Cellular organization and substructure measured using angle-resolved low-coherence interferometry,” Biophys. J. 82(4), 2256–2264 (2002).
[CrossRef] [PubMed]

Boppart, S. A.

H. Ding, F. Nguyen, S. A. Boppart, and G. Popescu, “Optical properties of tissues quantified by Fourier-transform light scattering,” Opt. Lett. 34(9), 1372–1374 (2009).
[CrossRef] [PubMed]

H. Ding, Z. Wang, F. Nguyen, S. A. Boppart, and G. Popescu, “Fourier transform light scattering of inhomogeneous and dynamic structures,” Phys. Rev. Lett. 101(23), 238102 (2008).
[CrossRef] [PubMed]

Bouma, B. E.

A. E. Desjardins, B. J. Vakoc, G. J. Tearney, and B. E. Bouma, “Backscattering spectroscopic contrast with angle-resolved optical coherence tomography,” Opt. Lett. 32(21), 3158–3160 (2007).
[CrossRef] [PubMed]

Bursac, P.

G. Lenormand, J. Chopin, P. Bursac, J. J. Fredberg, and J. P. Butler, “Directional memory and caged dynamics in cytoskeletal remodelling,” Biochem. Biophys. Res. Commun. 360(4), 797–801 (2007).
[CrossRef] [PubMed]

P. Bursac, G. Lenormand, B. Fabry, M. Oliver, D. A. Weitz, V. Viasnoff, J. P. Butler, and J. J. Fredberg, “Cytoskeletal remodelling and slow dynamics in the living cell,” Nat. Mater. 4(7), 557–561 (2005).
[CrossRef] [PubMed]

Butler, J. P.

G. Lenormand, J. Chopin, P. Bursac, J. J. Fredberg, and J. P. Butler, “Directional memory and caged dynamics in cytoskeletal remodelling,” Biochem. Biophys. Res. Commun. 360(4), 797–801 (2007).
[CrossRef] [PubMed]

L. Deng, X. Trepat, J. P. Butler, E. Millet, K. G. Morgan, D. A. Weitz, and J. J. Fredberg, “Fast and slow dynamics of the cytoskeleton,” Nat. Mater. 5(8), 636–640 (2006).
[CrossRef] [PubMed]

P. Bursac, G. Lenormand, B. Fabry, M. Oliver, D. A. Weitz, V. Viasnoff, J. P. Butler, and J. J. Fredberg, “Cytoskeletal remodelling and slow dynamics in the living cell,” Nat. Mater. 4(7), 557–561 (2005).
[CrossRef] [PubMed]

Cense, B.

C. Joo, T. Akkin, B. Cense, B. H. Park, and J. F. de Boer, “Spectral-domain optical coherence phase microscopy for quantitative phase-contrast imaging,” Opt. Lett. 30(16), 2131–2133 (2005).
[CrossRef] [PubMed]

Chen, K.

J. J. Tyson, K. Chen, and B. Novak, “Network dynamics and cell physiology,” Nat. Rev. Mol. Cell Biol. 2(12), 908–916 (2001).
[CrossRef] [PubMed]

Chen, Z.

S. Tang, C.-H. Sun, T. B. Krasieva, Z. Chen, and B. J. Tromberg, “Imaging subcellular scattering contrast by using combined optical coherence and multiphoton microscopy,” Opt. Lett. 32(5), 503–505 (2007).
[CrossRef] [PubMed]

Cherry, R. J.

T. Ichikawa, M. Yamada, D. Homma, R. J. Cherry, I. E. G. Morrison, and S. Kawato, “Digital fluorescence imaging of trafficking of endosomes containing low-density lipoprotein in brain astroglial cells,” Biochem. Biophys. Res. Commun. 269(1), 25–30 (2000).
[CrossRef] [PubMed]

Choi, W.

W. Choi, C.-C. Yu, C. Fang-Yen, K. Badizadegan, R. R. Dasari, and M. S. Feld, “Field-based angle-resolved light-scattering study of single live cells,” Opt. Lett. 33(14), 1596–1598 (2008).
[CrossRef] [PubMed]

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods 4(9), 717–719 (2007).
[CrossRef] [PubMed]

Choma, M. A.

M. A. Choma, A. K. Ellerbee, C. Yang, T. L. Creazzo, and J. A. Izatt, “Spectral-domain phase microscopy,” Opt. Lett. 30(10), 1162–1164 (2005).
[CrossRef] [PubMed]

Chopin, J.

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[CrossRef] [PubMed]

Popescu, G.

H. Ding, F. Nguyen, S. A. Boppart, and G. Popescu, “Optical properties of tissues quantified by Fourier-transform light scattering,” Opt. Lett. 34(9), 1372–1374 (2009).
[CrossRef] [PubMed]

H. Ding, Z. Wang, F. Nguyen, S. A. Boppart, and G. Popescu, “Fourier transform light scattering of inhomogeneous and dynamic structures,” Phys. Rev. Lett. 101(23), 238102 (2008).
[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]

Pyhtila, J. W.

J. W. Pyhtila and A. Wax, “Rapid, depth-resolved light scattering measurements using Fourier domain, angle-resolved low coherence interferometry,” Opt. Express 12(25), 6178–6183 (2004).
[CrossRef]

Qiu, L.

I. Itzkan, L. Qiu, H. Fang, M. M. Zaman, E. Vitkin, I. C. Ghiran, S. Salahuddin, M. Modell, C. Andersson, L. M. Kimerer, P. B. Cipolloni, K.-H. Lim, S. D. Freedman, I. Bigio, B. P. Sachs, E. B. Hanlon, and L. T. Perelman, “Confocal light absorption and scattering spectroscopic microscopy monitors organelles in live cells with no exogenous labels,” Proc. Natl. Acad. Sci. U.S.A. 104(44), 17255–17260 (2007).
[CrossRef] [PubMed]

Sachs, B. P.

I. Itzkan, L. Qiu, H. Fang, M. M. Zaman, E. Vitkin, I. C. Ghiran, S. Salahuddin, M. Modell, C. Andersson, L. M. Kimerer, P. B. Cipolloni, K.-H. Lim, S. D. Freedman, I. Bigio, B. P. Sachs, E. B. Hanlon, and L. T. Perelman, “Confocal light absorption and scattering spectroscopic microscopy monitors organelles in live cells with no exogenous labels,” Proc. Natl. Acad. Sci. U.S.A. 104(44), 17255–17260 (2007).
[CrossRef] [PubMed]

Saenger, W.

Y. Georgalis, E. B. Starikov, B. Hollenbach, R. Lurz, E. Scherzinger, W. Saenger, H. Lehrach, and E. E. Wanker, “Huntingtin aggregation monitored by dynamic light scattering,” Proc. Natl. Acad. Sci. U.S.A. 95(11), 6118–6121 (1998).
[CrossRef] [PubMed]

Safran, S. A.

A. Meller, R. Bar-Ziv, T. Tlusty, E. Moses, J. Stavans, and S. A. Safran, “Localized dynamic light scattering: a new approach to dynamic measurements in optical microscopy,” Biophys. J. 74(3), 1541–1548 (1998).
[CrossRef] [PubMed]

Salahuddin, S.

I. Itzkan, L. Qiu, H. Fang, M. M. Zaman, E. Vitkin, I. C. Ghiran, S. Salahuddin, M. Modell, C. Andersson, L. M. Kimerer, P. B. Cipolloni, K.-H. Lim, S. D. Freedman, I. Bigio, B. P. Sachs, E. B. Hanlon, and L. T. Perelman, “Confocal light absorption and scattering spectroscopic microscopy monitors organelles in live cells with no exogenous labels,” Proc. Natl. Acad. Sci. U.S.A. 104(44), 17255–17260 (2007).
[CrossRef] [PubMed]

Scherzinger, E.

Y. Georgalis, E. B. Starikov, B. Hollenbach, R. Lurz, E. Scherzinger, W. Saenger, H. Lehrach, and E. E. Wanker, “Huntingtin aggregation monitored by dynamic light scattering,” Proc. Natl. Acad. Sci. U.S.A. 95(11), 6118–6121 (1998).
[CrossRef] [PubMed]

Singh, R. P.

R. P. Singh, V. K. Jaiswal, and V. K. Jain, “Study of smoke aerosols under a controlled environment by using dynamic light scattering,” Appl. Opt. 45(10), 2217–2221 (2006).
[CrossRef] [PubMed]

Starikov, E. B.

Y. Georgalis, E. B. Starikov, B. Hollenbach, R. Lurz, E. Scherzinger, W. Saenger, H. Lehrach, and E. E. Wanker, “Huntingtin aggregation monitored by dynamic light scattering,” Proc. Natl. Acad. Sci. U.S.A. 95(11), 6118–6121 (1998).
[CrossRef] [PubMed]

Stavans, J.

A. Meller, R. Bar-Ziv, T. Tlusty, E. Moses, J. Stavans, and S. A. Safran, “Localized dynamic light scattering: a new approach to dynamic measurements in optical microscopy,” Biophys. J. 74(3), 1541–1548 (1998).
[CrossRef] [PubMed]

Sun, C.-H.

S. Tang, C.-H. Sun, T. B. Krasieva, Z. Chen, and B. J. Tromberg, “Imaging subcellular scattering contrast by using combined optical coherence and multiphoton microscopy,” Opt. Lett. 32(5), 503–505 (2007).
[CrossRef] [PubMed]

Suresh, S.

J. Li, G. Lykotrafitis, M. Dao, and S. Suresh, “Cytoskeletal dynamics of human erythrocyte,” Proc. Natl. Acad. Sci. U.S.A. 104(12), 4937–4942 (2007).
[CrossRef] [PubMed]

Swanson, E. A.

J. A. Izatt, M. R. Hee, G. M. Owen, E. A. Swanson, and J. G. Fujimoto, “Optical coherence microscopy in scattering media,” Opt. Lett. 19(8), 590–592 (1994).
[CrossRef] [PubMed]

Tanaka, T.

J. Peetermans, I. Nishio, S. T. Ohnishi, and T. Tanaka, “Light-scattering study of depolymerization kinetics of sickle hemoglobin polymers inside single erythrocytes,” Proc. Natl. Acad. Sci. U.S.A. 83(2), 352–356 (1986).
[CrossRef] [PubMed]

I. Nishio, J. Peetermans, and T. Tanaka, “Microscope laser light scattering spectroscopy of single biological cells,” Cell Biophys. 7(2), 91–105 (1985).
[CrossRef] [PubMed]

T. Tanaka and G. B. Benedek, “Observation of protein diffusivity in intact human and bovine lenses with application to cataract,” Invest. Ophthalmol. Vis. Sci. 14, 449–456 (1975).

Tang, S.

S. Tang, C.-H. Sun, T. B. Krasieva, Z. Chen, and B. J. Tromberg, “Imaging subcellular scattering contrast by using combined optical coherence and multiphoton microscopy,” Opt. Lett. 32(5), 503–505 (2007).
[CrossRef] [PubMed]

Tearney, G. J.

A. E. Desjardins, B. J. Vakoc, G. J. Tearney, and B. E. Bouma, “Backscattering spectroscopic contrast with angle-resolved optical coherence tomography,” Opt. Lett. 32(21), 3158–3160 (2007).
[CrossRef] [PubMed]

Tlusty, T.

A. Meller, R. Bar-Ziv, T. Tlusty, E. Moses, J. Stavans, and S. A. Safran, “Localized dynamic light scattering: a new approach to dynamic measurements in optical microscopy,” Biophys. J. 74(3), 1541–1548 (1998).
[CrossRef] [PubMed]

Trappe, V.

P. D. Kaplan, V. Trappe, and D. A. Weitz, “Light-scattering microscope,” Appl. Opt. 38(19), 4151–4157 (1999).
[CrossRef]

Trepat, X.

L. Deng, X. Trepat, J. P. Butler, E. Millet, K. G. Morgan, D. A. Weitz, and J. J. Fredberg, “Fast and slow dynamics of the cytoskeleton,” Nat. Mater. 5(8), 636–640 (2006).
[CrossRef] [PubMed]

Tromberg, B. J.

S. Tang, C.-H. Sun, T. B. Krasieva, Z. Chen, and B. J. Tromberg, “Imaging subcellular scattering contrast by using combined optical coherence and multiphoton microscopy,” Opt. Lett. 32(5), 503–505 (2007).
[CrossRef] [PubMed]

Tyson, J. J.

J. J. Tyson, K. Chen, and B. Novak, “Network dynamics and cell physiology,” Nat. Rev. Mol. Cell Biol. 2(12), 908–916 (2001).
[CrossRef] [PubMed]

Vakoc, B. J.

A. E. Desjardins, B. J. Vakoc, G. J. Tearney, and B. E. Bouma, “Backscattering spectroscopic contrast with angle-resolved optical coherence tomography,” Opt. Lett. 32(21), 3158–3160 (2007).
[CrossRef] [PubMed]

Van Citters, K. M.

K. M. Van Citters, B. D. Hoffman, G. Massiera, and J. C. Crocker, “The role of F-actin and myosin in epithelial cell rheology,” Biophys. J. 91(10), 3946–3956 (2006).
[CrossRef] [PubMed]

Viasnoff, V.

P. Bursac, G. Lenormand, B. Fabry, M. Oliver, D. A. Weitz, V. Viasnoff, J. P. Butler, and J. J. Fredberg, “Cytoskeletal remodelling and slow dynamics in the living cell,” Nat. Mater. 4(7), 557–561 (2005).
[CrossRef] [PubMed]

Vitkin, E.

I. Itzkan, L. Qiu, H. Fang, M. M. Zaman, E. Vitkin, I. C. Ghiran, S. Salahuddin, M. Modell, C. Andersson, L. M. Kimerer, P. B. Cipolloni, K.-H. Lim, S. D. Freedman, I. Bigio, B. P. Sachs, E. B. Hanlon, and L. T. Perelman, “Confocal light absorption and scattering spectroscopic microscopy monitors organelles in live cells with no exogenous labels,” Proc. Natl. Acad. Sci. U.S.A. 104(44), 17255–17260 (2007).
[CrossRef] [PubMed]

Wang, Z.

H. Ding, Z. Wang, F. Nguyen, S. A. Boppart, and G. Popescu, “Fourier transform light scattering of inhomogeneous and dynamic structures,” Phys. Rev. Lett. 101(23), 238102 (2008).
[CrossRef] [PubMed]

Wanker, E. E.

Y. Georgalis, E. B. Starikov, B. Hollenbach, R. Lurz, E. Scherzinger, W. Saenger, H. Lehrach, and E. E. Wanker, “Huntingtin aggregation monitored by dynamic light scattering,” Proc. Natl. Acad. Sci. U.S.A. 95(11), 6118–6121 (1998).
[CrossRef] [PubMed]

Wax, A.

J. W. Pyhtila and A. Wax, “Rapid, depth-resolved light scattering measurements using Fourier domain, angle-resolved low coherence interferometry,” Opt. Express 12(25), 6178–6183 (2004).
[CrossRef]

A. Wax, C. Yang, V. Backman, K. Badizadegan, C. W. Boone, R. R. Dasari, and M. S. Feld, “Cellular organization and substructure measured using angle-resolved low-coherence interferometry,” Biophys. J. 82(4), 2256–2264 (2002).
[CrossRef] [PubMed]

Weitz, D. A.

L. Deng, X. Trepat, J. P. Butler, E. Millet, K. G. Morgan, D. A. Weitz, and J. J. Fredberg, “Fast and slow dynamics of the cytoskeleton,” Nat. Mater. 5(8), 636–640 (2006).
[CrossRef] [PubMed]

P. Bursac, G. Lenormand, B. Fabry, M. Oliver, D. A. Weitz, V. Viasnoff, J. P. Butler, and J. J. Fredberg, “Cytoskeletal remodelling and slow dynamics in the living cell,” Nat. Mater. 4(7), 557–561 (2005).
[CrossRef] [PubMed]

P. D. Kaplan, V. Trappe, and D. A. Weitz, “Light-scattering microscope,” Appl. Opt. 38(19), 4151–4157 (1999).
[CrossRef]

Wirtz, D.

S. Yamada, D. Wirtz, and S. C. Kuo, “Mechanics of living cells measured by laser tracking microrheology,” Biophys. J. 78(4), 1736–1747 (2000).
[CrossRef] [PubMed]

Wu, D. D.

R. P. Kulkarni, D. D. Wu, M. E. Davis, and S. E. Fraser, “Quantitating intracellular transport of polyplexes by spatio-temporal image correlation spectroscopy,” Proc. Natl. Acad. Sci. U.S.A. 102(21), 7523–7528 (2005).
[CrossRef] [PubMed]

Yamada, M.

T. Ichikawa, M. Yamada, D. Homma, R. J. Cherry, I. E. G. Morrison, and S. Kawato, “Digital fluorescence imaging of trafficking of endosomes containing low-density lipoprotein in brain astroglial cells,” Biochem. Biophys. Res. Commun. 269(1), 25–30 (2000).
[CrossRef] [PubMed]

Yamada, S.

S. Yamada, D. Wirtz, and S. C. Kuo, “Mechanics of living cells measured by laser tracking microrheology,” Biophys. J. 78(4), 1736–1747 (2000).
[CrossRef] [PubMed]

Yang, C.

M. A. Choma, A. K. Ellerbee, C. Yang, T. L. Creazzo, and J. A. Izatt, “Spectral-domain phase microscopy,” Opt. Lett. 30(10), 1162–1164 (2005).
[CrossRef] [PubMed]

A. Wax, C. Yang, V. Backman, K. Badizadegan, C. W. Boone, R. R. Dasari, and M. S. Feld, “Cellular organization and substructure measured using angle-resolved low-coherence interferometry,” Biophys. J. 82(4), 2256–2264 (2002).
[CrossRef] [PubMed]

Yazdanfar, S.

S. Yazdanfar and J. A. Izatt, “Self-referenced Doppler optical coherence tomography,” Opt. Lett. 27(23), 2085–2087 (2002).
[CrossRef]

Yu, C.-C.

W. Choi, C.-C. Yu, C. Fang-Yen, K. Badizadegan, R. R. Dasari, and M. S. Feld, “Field-based angle-resolved light-scattering study of single live cells,” Opt. Lett. 33(14), 1596–1598 (2008).
[CrossRef] [PubMed]

Zaman, M. M.

I. Itzkan, L. Qiu, H. Fang, M. M. Zaman, E. Vitkin, I. C. Ghiran, S. Salahuddin, M. Modell, C. Andersson, L. M. Kimerer, P. B. Cipolloni, K.-H. Lim, S. D. Freedman, I. Bigio, B. P. Sachs, E. B. Hanlon, and L. T. Perelman, “Confocal light absorption and scattering spectroscopic microscopy monitors organelles in live cells with no exogenous labels,” Proc. Natl. Acad. Sci. U.S.A. 104(44), 17255–17260 (2007).
[CrossRef] [PubMed]

Ann. Phys. (1)

A. Einstein, “On the Motion – Required by the Molecular Kinetic Theory of Heat – of Small Particles Suspended in a Stationary Liquid,” Ann. Phys. 17, 549–560 (1905).
[CrossRef]

Appl. Opt. (2)

R. P. Singh, V. K. Jaiswal, and V. K. Jain, “Study of smoke aerosols under a controlled environment by using dynamic light scattering,” Appl. Opt. 45(10), 2217–2221 (2006).
[CrossRef] [PubMed]

P. D. Kaplan, V. Trappe, and D. A. Weitz, “Light-scattering microscope,” Appl. Opt. 38(19), 4151–4157 (1999).
[CrossRef]

Biochem. Biophys. Res. Commun. (2)

G. Lenormand, J. Chopin, P. Bursac, J. J. Fredberg, and J. P. Butler, “Directional memory and caged dynamics in cytoskeletal remodelling,” Biochem. Biophys. Res. Commun. 360(4), 797–801 (2007).
[CrossRef] [PubMed]

T. Ichikawa, M. Yamada, D. Homma, R. J. Cherry, I. E. G. Morrison, and S. Kawato, “Digital fluorescence imaging of trafficking of endosomes containing low-density lipoprotein in brain astroglial cells,” Biochem. Biophys. Res. Commun. 269(1), 25–30 (2000).
[CrossRef] [PubMed]

Biophys. J. (6)

A. Wax, C. Yang, V. Backman, K. Badizadegan, C. W. Boone, R. R. Dasari, and M. S. Feld, “Cellular organization and substructure measured using angle-resolved low-coherence interferometry,” Biophys. J. 82(4), 2256–2264 (2002).
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[CrossRef] [PubMed]

A. Meller, R. Bar-Ziv, T. Tlusty, E. Moses, J. Stavans, and S. A. Safran, “Localized dynamic light scattering: a new approach to dynamic measurements in optical microscopy,” Biophys. J. 74(3), 1541–1548 (1998).
[CrossRef] [PubMed]

S. Yamada, D. Wirtz, and S. C. Kuo, “Mechanics of living cells measured by laser tracking microrheology,” Biophys. J. 78(4), 1736–1747 (2000).
[CrossRef] [PubMed]

K. M. Van Citters, B. D. Hoffman, G. Massiera, and J. C. Crocker, “The role of F-actin and myosin in epithelial cell rheology,” Biophys. J. 91(10), 3946–3956 (2006).
[CrossRef] [PubMed]

Cell Biophys. (1)

I. Nishio, J. Peetermans, and T. Tanaka, “Microscope laser light scattering spectroscopy of single biological cells,” Cell Biophys. 7(2), 91–105 (1985).
[CrossRef] [PubMed]

Invest. Ophthalmol. Vis. Sci. (1)

T. Tanaka and G. B. Benedek, “Observation of protein diffusivity in intact human and bovine lenses with application to cataract,” Invest. Ophthalmol. Vis. Sci. 14, 449–456 (1975).

Nat. Mater. (2)

L. Deng, X. Trepat, J. P. Butler, E. Millet, K. G. Morgan, D. A. Weitz, and J. J. Fredberg, “Fast and slow dynamics of the cytoskeleton,” Nat. Mater. 5(8), 636–640 (2006).
[CrossRef] [PubMed]

P. Bursac, G. Lenormand, B. Fabry, M. Oliver, D. A. Weitz, V. Viasnoff, J. P. Butler, and J. J. Fredberg, “Cytoskeletal remodelling and slow dynamics in the living cell,” Nat. Mater. 4(7), 557–561 (2005).
[CrossRef] [PubMed]

Nat. Methods (1)

W. Choi, C. Fang-Yen, K. Badizadegan, S. Oh, N. Lue, R. R. Dasari, and M. S. Feld, “Tomographic phase microscopy,” Nat. Methods 4(9), 717–719 (2007).
[CrossRef] [PubMed]

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

J. J. Tyson, K. Chen, and B. Novak, “Network dynamics and cell physiology,” Nat. Rev. Mol. Cell Biol. 2(12), 908–916 (2001).
[CrossRef] [PubMed]

Opt. Commun. (1)

A. F. Fercher, C. K. Hitzenberger, G. Kamp, and S. Y. El-Zaiat, “Measurement of intraocular distances by backscattering spectral interferometry,” Opt. Commun. 117(1-2), 43–48 (1995).
[CrossRef]

Opt. Express (1)

J. W. Pyhtila and A. Wax, “Rapid, depth-resolved light scattering measurements using Fourier domain, angle-resolved low coherence interferometry,” Opt. Express 12(25), 6178–6183 (2004).
[CrossRef]

Opt. Lett. (9)

A. E. Desjardins, B. J. Vakoc, G. J. Tearney, and B. E. Bouma, “Backscattering spectroscopic contrast with angle-resolved optical coherence tomography,” Opt. Lett. 32(21), 3158–3160 (2007).
[CrossRef] [PubMed]

S. Yazdanfar and J. A. Izatt, “Self-referenced Doppler optical coherence tomography,” Opt. Lett. 27(23), 2085–2087 (2002).
[CrossRef]

S. Tang, C.-H. Sun, T. B. Krasieva, Z. Chen, and B. J. Tromberg, “Imaging subcellular scattering contrast by using combined optical coherence and multiphoton microscopy,” Opt. Lett. 32(5), 503–505 (2007).
[CrossRef] [PubMed]

J. A. Izatt, M. R. Hee, G. M. Owen, E. A. Swanson, and J. G. Fujimoto, “Optical coherence microscopy in scattering media,” Opt. Lett. 19(8), 590–592 (1994).
[CrossRef] [PubMed]

W. Choi, C.-C. Yu, C. Fang-Yen, K. Badizadegan, R. R. Dasari, and M. S. Feld, “Field-based angle-resolved light-scattering study of single live cells,” Opt. Lett. 33(14), 1596–1598 (2008).
[CrossRef] [PubMed]

H. Ding, F. Nguyen, S. A. Boppart, and G. Popescu, “Optical properties of tissues quantified by Fourier-transform light scattering,” Opt. Lett. 34(9), 1372–1374 (2009).
[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]

C. Joo, T. Akkin, B. Cense, B. H. Park, and J. F. de Boer, “Spectral-domain optical coherence phase microscopy for quantitative phase-contrast imaging,” Opt. Lett. 30(16), 2131–2133 (2005).
[CrossRef] [PubMed]

M. A. Choma, A. K. Ellerbee, C. Yang, T. L. Creazzo, and J. A. Izatt, “Spectral-domain phase microscopy,” Opt. Lett. 30(10), 1162–1164 (2005).
[CrossRef] [PubMed]

Phys. Rev. Lett. (1)

H. Ding, Z. Wang, F. Nguyen, S. A. Boppart, and G. Popescu, “Fourier transform light scattering of inhomogeneous and dynamic structures,” Phys. Rev. Lett. 101(23), 238102 (2008).
[CrossRef] [PubMed]

Proc. Natl. Acad. Sci. U.S.A. (5)

I. Itzkan, L. Qiu, H. Fang, M. M. Zaman, E. Vitkin, I. C. Ghiran, S. Salahuddin, M. Modell, C. Andersson, L. M. Kimerer, P. B. Cipolloni, K.-H. Lim, S. D. Freedman, I. Bigio, B. P. Sachs, E. B. Hanlon, and L. T. Perelman, “Confocal light absorption and scattering spectroscopic microscopy monitors organelles in live cells with no exogenous labels,” Proc. Natl. Acad. Sci. U.S.A. 104(44), 17255–17260 (2007).
[CrossRef] [PubMed]

J. Li, G. Lykotrafitis, M. Dao, and S. Suresh, “Cytoskeletal dynamics of human erythrocyte,” Proc. Natl. Acad. Sci. U.S.A. 104(12), 4937–4942 (2007).
[CrossRef] [PubMed]

R. P. Kulkarni, D. D. Wu, M. E. Davis, and S. E. Fraser, “Quantitating intracellular transport of polyplexes by spatio-temporal image correlation spectroscopy,” Proc. Natl. Acad. Sci. U.S.A. 102(21), 7523–7528 (2005).
[CrossRef] [PubMed]

Y. Georgalis, E. B. Starikov, B. Hollenbach, R. Lurz, E. Scherzinger, W. Saenger, H. Lehrach, and E. E. Wanker, “Huntingtin aggregation monitored by dynamic light scattering,” Proc. Natl. Acad. Sci. U.S.A. 95(11), 6118–6121 (1998).
[CrossRef] [PubMed]

J. Peetermans, I. Nishio, S. T. Ohnishi, and T. Tanaka, “Light-scattering study of depolymerization kinetics of sickle hemoglobin polymers inside single erythrocytes,” Proc. Natl. Acad. Sci. U.S.A. 83(2), 352–356 (1986).
[CrossRef] [PubMed]

Science (1)

R. B. Nicklas, “How cells get the right chromosomes,” Science 275(5300), 632–637 (1997).
[CrossRef] [PubMed]

Other (5)

B. J. Berne, and R. Pecora, Dynamic Light Scattering: With Applications to Chemistry, Biology, and Physics (John Wiley, New York, 1976).

W. Brown, Dynamic Light Scattering: The Method and Some Applications (Clarendon Press, Oxford, 1993).

C. Joo and J. F. de Boer are preparing a manuscript to be called “Theory for field-based dynamic light scattering microscopy.”

Liposyn II Intravenous Fat Emulsion, Hospira Inc., http://www.hospira.com/Files/TPN_Liposyn_II.pdf .

T. Wilson, Confocal Microscopy (Academic Press, 1990).

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Figures (5)

Fig. 1
Fig. 1

Top: SD-OCPM detection scheme. SD-OCPM uses the light back-reflected from the bottom surface of a coverslip as a reference to ensure the phase stability in measuring amplitude and phase of sample light scattered from the focal volume. Bottom: A broadband light source illuminates a fiber-based common-path interferometer. The light coupled to the sample arm is delivered to a specimen via an integrated laser-scanning inverted microscope. The backscattered light is re-coupled to the fiber for the subsequent interference spectrum measurement at the detection arm.

Fig. 2
Fig. 2

(a) Measured amplitude and phase fluctuation of the interference between the reflected light from the top and bottom surfaces of a coverslip. The phase stability was measured as ~~9.8 × 10−3 rad at the measured SNR of ~37.5 dB. (b-d) Magnitude of the autocorrelation function, MSD, and TAD. The high stability of SD-OCPM produced a flat correlation with a value of ~1. The mean MSD and TAD were found as ~4.5 × 10−7 μm2 and ~5.4 × 10−9 μm, respectively.

Fig. 3
Fig. 3

F-DLS measurement for emulsion particles undergoing Brownian (black dot) and directional (green and blue dots) motion. The volume flow rates of 80 μL/min and 160 μL/min were used for the flow experiments. (a) SD-OCPM depth-resolved intensity distribution. The peak indicated by the red dot represents the interference between the light scattered from the emulsion particles inside the focal volume and the light reflected from the bottom surface of a coverslip. (b) Magnitudes of complex autocorrelation functions for the emulsion particles in Brownian and directional motion. The correlation function for the higher volume flow rate exhibits a shorter time constant. (c) MSDs: The power-law fits to MSDs found the exponents as ~1.04 for the particles in Brownian motion, and as ~1.07 and ~1.10 for the flow cases, respectively. The measured diffusion coefficient for the particles in Brownian motion (~0.99 μm2/sec) agreed with the predicted value (~1.07 μm2/sec) to within ~7%. (d) TADs calculated by the phase information of the complex autocorrelation functions. The static measurement exhibited no net time-averaged displacement, while the flow measurements showed linear behaviors with average velocities of –6.4 μm/sec (Q = 80 μL/min) and –12.5 μm/sec (Q = 160 μL/min), which agreed to the predicted values to within ~16% and ~20%, respectively.

Fig. 4
Fig. 4

F-DLS applied to monitoring intracellular dynamics of OVCAR-5 cells. (a) Representative amplitude image of the cells at a depth of ~3.4 μm above the top surface of the collagen-I coated coverslip. Highly scattering intracellular structures such as mitochondria and cytoskeleton may account for the observed image contrast. The scale bar denotes 10 μm. (b) Measured amplitude and phase fluctuation recorded at the position indicated in (a). (c-d) Summary of F-DLS analysis: averages of log-transformed MSDs and magnitudes of TADs (N = 62). The intracellular dynamics is shown to vary dramatically from random to directional processes at ~0.01 sec. The inset in (d) is the log-log plot of TAD for better visualization of the short timescale. The thickening of the average TAD profile is due to the large standard errors on the long timescales. (e-f) Averages of log-transformed MSDs and the magnitudes of TADs for the fixed cells (N = 47). The fixed cells exhibit significantly different diffusive characteristics with no directional transport. The error bar represents ± SE, and is included in (c-f).

Fig. 5
Fig. 5

Summarized F-DLS results for control (N = 62), Colchicine-treated (N = 57) and ATP-depleted (N = 68) OVCAR-5 cells. (a) Averages of log-transformed MSDs. (b-c) The mean exponents on the short timescale did not show a remarkable difference (*: p<0.5), but on the long timescale, the mean exponents for the control, Colchicine and ATP-depleted cells were 0.73, 0.54, and 0.38, respectively (****: p<0.0005). The error bar represents ± SE. (d) TADs: Most control cells exhibited directed motion as evident from the linear TAD profiles, whereas the Colchicine-treated and ATP-depleted cells showed randomized behaviors. (e) Velocity correlation coefficient as a function of time-delay, Δτ, averaged over all the measurements in each condition. The shorter time constants for Colchicine-treated and ATP-depleted cells indicate significant disruption of directional intracellular dynamics. The correlation diagrams at Δτ = 0.5 sec (inset) demonstrate the transition from correlated to randomized motion for Colchicine-treated and ATP-depleted cells.

Equations (4)

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R ( τ ) = F ( t + τ ) F * ( t ) F ( t ) F * ( t ) ,
R ( τ ) ~ exp ( γ D Q 2 m σ 2 ( τ ) ) exp ( i γ T μ ( τ ) Q m ) .
μ ( τ ) = tan 1 [ Im ( R ( τ ) ) / Re ( R ( τ ) ) ] γ T Q m ,
M S D ( τ ) = σ 2 ( τ ) + μ 2 ( τ ) = ln ( R ( τ ) R * ( τ ) ) 2 γ D Q m 2 + [ tan 1 [ Im ( R ( τ ) ) / Re ( R ( τ ) ) ] γ T Q m ] 2 .

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