Abstract

Label-free imaging of rapidly moving, sub-diffraction sized structures has important applications in both biology and material science, as it removes the limitations associated with fluorescence tagging. However, unlabeled nanoscale particles in suspension are difficult to image due to their transparency and fast Brownian motion. Here we describe a novel interferometric imaging technique referred to as Magnified Image Spatial Spectrum (MISS) microscopy, which overcomes these challenges. The MISS microscope provides quantitative phase information and enables dynamic light scattering investigations with an overall optical path length sensitivity of 0.95 nm at 833 frames per second acquisition rate. Using spatiotemporal filtering, we find that the sensitivity can be further pushed down to 10−3-10−2 nm. We demonstrate the instrument’s capability through colloidal nanoparticle sizing down to 20 nm diameter and measurements of live neuron membrane dynamics. MISS microscopy is implemented as an upgrade module to an existing microscope, which converts it into a powerful light scattering instrument. Thus, we anticipate that MISS will be adopted broadly for both material and life sciences applications.

© 2018 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

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2017 (5)

T. H. Nguyen, M. E. Kandel, M. Rubessa, M. B. Wheeler, and G. Popescu, “Gradient light interference microscopy for 3D imaging of unlabeled specimens,” Nat. Commun. 8(1), 210 (2017).
[Crossref] [PubMed]

M. E. Kandel, K. W. Teng, P. R. Selvin, and G. Popescu, “Label-Free Imaging of Single Microtubule Dynamics Using Spatial Light Interference Microscopy,” ACS Nano 11(1), 647–655 (2017).
[Crossref] [PubMed]

H. Majeed, S. Sridharan, M. Mir, L. Ma, E. Min, W. Jung, and G. Popescu, “Quantitative phase imaging for medical diagnosis,” J. Biophotonics 10(2), 177–205 (2017).
[Crossref] [PubMed]

W. J. Eldridge, Z. A. Steelman, B. Loomis, and A. Wax, “Optical Phase Measurements of Disorder Strength Link Microstructure to Cell Stiffness,” Biophys. J. 112(4), 692–702 (2017).
[Crossref] [PubMed]

M. E. Kandel, S. Sridharan, J. Liang, Z. Luo, K. Han, V. Macias, A. Shah, R. Patel, K. Tangella, A. Kajdacsy-Balla, G. Guzman, and G. Popescu, “Label-free tissue scanner for colorectal cancer screening,” J. Biomed. Opt. 22(6), 66016 (2017).
[Crossref] [PubMed]

2016 (3)

Z. Jia, R. Ikeda, J. Ling, V. Viatchenko-Karpinski, and J. G. Gu, “Regulation of Piezo2 Mechanotransduction by Static Plasma Membrane Tension in Primary Afferent Neurons,” J. Biol. Chem. 291(17), 9087–9104 (2016).
[Crossref] [PubMed]

P. Hosseini, R. Zhou, Y.-H. Kim, C. Peres, A. Diaspro, C. Kuang, Z. Yaqoob, and P. T. C. So, “Pushing phase and amplitude sensitivity limits in interferometric microscopy,” Opt. Lett. 41(7), 1656–1659 (2016).
[Crossref] [PubMed]

J. O. Arroyo and P. Kukura, “Non-fluorescent schemes for single-molecule detection, imaging and spectroscopy,” Nat. Photonics 10(1), 11–17 (2016).
[Crossref]

2015 (5)

H. Park, S.-H. Hong, K. Kim, S.-H. Cho, W.-J. Lee, Y. Kim, S.-E. Lee, and Y. Park, “Characterizations of individual mouse red blood cells parasitized by Babesia microti using 3-D holographic microscopy,” Sci. Rep. 5(1), 10827 (2015).
[Crossref] [PubMed]

H. Majeed, M. E. Kandel, K. Han, Z. Luo, V. Macias, K. Tangella, A. Balla, and G. Popescu, “Breast cancer diagnosis using spatial light interference microscopy,” J. Biomed. Opt. 20(11), 111210 (2015).
[Crossref] [PubMed]

S. Sridharan, V. Macias, K. Tangella, A. Kajdacsy-Balla, and G. Popescu, “Prediction of Prostate Cancer Recurrence Using Quantitative Phase Imaging,” Sci. Rep. 5(1), 9976 (2015).
[Crossref] [PubMed]

S. Uttam, H. V. Pham, J. LaFace, B. Leibowitz, J. Yu, R. E. Brand, D. J. Hartman, and Y. Liu, “Early Prediction of Cancer Progression by Depth-Resolved Nanoscale Mapping of Nuclear Architecture from Unstained Tissue Specimens,” Cancer Res. 75(22), 4718–4727 (2015).
[Crossref] [PubMed]

A. El Hady and B. B. Machta, “Mechanical surface waves accompany action potential propagation,” Nat. Commun. 6(1), 6697 (2015).
[Crossref] [PubMed]

2014 (8)

C. Edwards, B. Bhaduri, B. G. Griffin, L. L. Goddard, and G. Popescu, “Epi-illumination diffraction phase microscopy with white light,” Opt. Lett. 39(21), 6162–6165 (2014).
[Crossref] [PubMed]

Y. Kim, H. Shim, K. Kim, H. Park, S. Jang, and Y. Park, “Profiling individual human red blood cells using common-path diffraction optical tomography,” Sci. Rep. 4(1), 6659 (2014).
[Crossref] [PubMed]

V. Bianco, F. Merola, L. Miccio, P. Memmolo, O. Gennari, M. Paturzo, P. A. Netti, and P. Ferraro, “Imaging adherent cells in the microfluidic channel hidden by flowing RBCs as occluding objects by a holographic method,” Lab Chip 14(14), 2499–2504 (2014).
[Crossref] [PubMed]

P. Memmolo, L. Miccio, F. Merola, O. Gennari, P. A. Netti, and P. Ferraro, “3D morphometry of red blood cells by digital holography,” Cytometry A 85(12), 1030–1036 (2014).
[Crossref] [PubMed]

Y. Bishitz, H. Gabai, P. Girshovitz, and N. T. Shaked, “Optical-mechanical signatures of cancer cells based on fluctuation profiles measured by interferometry,” J. Biophotonics 7(8), 624–630 (2014).
[Crossref] [PubMed]

B. Bhaduri, C. Edwards, H. Pham, R. Zhou, T. H. Nguyen, L. L. Goddard, and G. Popescu, “Diffraction phase microscopy: principles and applications in materials and life sciences,” Adv. Opt. Photonics 6(1), 57–119 (2014).
[Crossref]

M. Mir, T. Kim, A. Majumder, M. Xiang, R. Wang, S. C. Liu, M. U. Gillette, S. Stice, and G. Popescu, “Label-Free Characterization of Emerging Human Neuronal Networks,” Sci. Rep. 4(1), 4434 (2014).
[Crossref] [PubMed]

T. Kim, R. J. Zhou, M. Mir, S. D. Babacan, P. S. Carney, L. L. Goddard, and G. Popescu, “White-light diffraction tomography of unlabeled live cells,” Nat. Photonics 8(3), 256–263 (2014).
[Crossref]

2013 (3)

K. L. Cooper, S. Oh, Y. Sung, R. R. Dasari, M. W. Kirschner, and C. J. Tabin, “Multiple phases of chondrocyte enlargement underlie differences in skeletal proportions,” Nature 495(7441), 375–378 (2013).
[Crossref] [PubMed]

R. Zhou, C. Edwards, A. Arbabi, G. Popescu, and L. L. Goddard, “Detecting 20 nm Wide Defects in Large Area Nanopatterns Using Optical Interferometric Microscopy,” Nano Lett. 13(8), 3716–3721 (2013).
[Crossref] [PubMed]

B. Pontes, Y. Ayala, A. C. Fonseca, L. F. Romão, R. F. Amaral, L. T. Salgado, F. R. Lima, M. Farina, N. B. Viana, V. Moura-Neto, and H. M. Nussenzveig, “Membrane elastic properties and cell function,” PLoS One 8(7), e67708 (2013).
[Crossref] [PubMed]

2012 (5)

B. Bhaduri, H. Pham, M. Mir, and G. Popescu, “Diffraction phase microscopy with white light,” Opt. Lett. 37(6), 1094–1096 (2012).
[Crossref] [PubMed]

C. Edwards, A. Arbabi, G. Popescu, and L. L. Goddard, “Optically monitoring and controlling nanoscale topography during semiconductor etching,” Light Sci. Appl. 1(9), e30 (2012).
[Crossref]

G. W. John, “Improved nano-particle tracking analysis,” Meas. Sci. Technol. 23(6), 065605 (2012).
[Crossref]

R. Wang, L. Lei, Y. Wang, A. J. Levine, and G. Popescu, “Dispersion-Relation Fluorescence Spectroscopy,” Phys. Rev. Lett. 109(18), 188104 (2012).
[Crossref] [PubMed]

B. Bhaduri and G. Popescu, “Derivative method for phase retrieval in off-axis quantitative phase imaging,” Opt. Lett. 37(11), 1868–1870 (2012).
[Crossref] [PubMed]

2011 (6)

Z. Wang, L. Millet, M. Mir, H. Ding, S. Unarunotai, J. Rogers, M. U. Gillette, and G. Popescu, “Spatial light interference microscopy (SLIM),” Opt. Express 19(2), 1016–1026 (2011).
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B. Kemper, A. Vollmer, C. E. Rommel, J. Schnekenburger, and G. von Bally, “Simplified approach for quantitative digital holographic phase contrast imaging of living cells,” J. Biomed. Opt. 16(2), 026014 (2011).
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Z. Wang, K. Tangella, A. Balla, and G. Popescu, “Tissue refractive index as marker of disease,” J. Biomed. Opt. 16(11), 116017 (2011).
[Crossref] [PubMed]

M. Mir, Z. Wang, Z. Shen, M. Bednarz, R. Bashir, I. Golding, S. G. Prasanth, and G. Popescu, “Optical measurement of cycle-dependent cell growth,” Proc. Natl. Acad. Sci. U.S.A. 108(32), 13124–13129 (2011).
[Crossref] [PubMed]

R. Wang, Z. Wang, L. Millet, M. U. Gillette, A. J. Levine, and G. Popescu, “Dispersion-relation phase spectroscopy of intracellular transport,” Opt. Express 19(21), 20571–20579 (2011).
[Crossref] [PubMed]

R. Wang, Z. Wang, L. Millet, M. U. Gillette, A. J. Levine, and G. Popescu, “Dispersion-Relation Phase Spectroscopy of Intracellular Transport,” Opt. Express 19(21), 20571–20579 (2011).
[Crossref] [PubMed]

2010 (7)

X. Michalet, “Mean Square Displacement Analysis of Single-Particle Trajectories with Localization Error: Brownian Motion in an Isotropic Medium,” Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 82(4), 041914 (2010).
[Crossref] [PubMed]

Y. Park, C. A. Best, T. Auth, N. S. Gov, S. A. Safran, G. Popescu, S. Suresh, and M. S. Feld, “Metabolic remodeling of the human red blood cell membrane,” Proc. Natl. Acad. Sci. U.S.A. 107(4), 1289–1294 (2010).
[Crossref] [PubMed]

Y. Park, C. A. Best, K. Badizadegan, R. R. Dasari, M. S. Feld, T. Kuriabova, M. L. Henle, A. J. Levine, and G. Popescu, “Measurement of red blood cell mechanics during morphological changes,” Proc. Natl. Acad. Sci. U.S.A. 107(15), 6731–6736 (2010).
[Crossref] [PubMed]

L. Xiao, Y. Qiao, Y. He, and E. S. Yeung, “Three Dimensional Orientational Imaging of Nanoparticles with Darkfield Microscopy,” Anal. Chem. 82(12), 5268–5274 (2010).
[Crossref] [PubMed]

Y. Park, C. A. Best, K. Badizadegan, R. R. Dasari, M. S. Feld, T. Kuriabova, M. L. Henle, A. J. Levine, and G. Popescu, “Measurement of red blood cell mechanics during morphological changes,” Proc. Natl. Acad. Sci. U.S.A. 107(15), 6731–6736 (2010).
[Crossref] [PubMed]

M. Mir, H. Ding, Z. Wang, J. Reedy, K. Tangella, and G. Popescu, “Blood screening using diffraction phase cytometry,” J. Biomed. Opt. 15(2), 027016 (2010).
[Crossref] [PubMed]

P. Wang, R. K. Bista, W. E. Khalbuss, W. Qiu, S. Uttam, K. Staton, L. Zhang, T. A. Brentnall, R. E. Brand, and Y. Liu, “Nanoscale nuclear architecture for cancer diagnosis beyond pathology via spatial-domain low-coherence quantitative phase microscopy,” J. Biomed. Opt. 15(6), 066028 (2010).
[Crossref] [PubMed]

2008 (1)

Y. Park, M. Diez-Silva, G. Popescu, G. Lykotrafitis, W. Choi, M. S. Feld, and S. Suresh, “Refractive index maps and membrane dynamics of human red blood cells parasitized by Plasmodium falciparum,” Proc. Natl. Acad. Sci. U.S.A. 105(37), 13730–13735 (2008).
[Crossref] [PubMed]

2007 (4)

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]

T. S. Ralston, D. L. Marks, P. S. Carney, and S. A. Boppart, “Interferometric synthetic aperture microscopy,” Nat. Phys. 3(2), 129–134 (2007).
[Crossref] [PubMed]

R. A. Hoebe, C. H. Van Oven, T. W. Gadella, P. B. Dhonukshe, C. J. F. Van Noorden, and E. M. M. Manders, “Controlled light-exposure microscopy reduces photobleaching and phototoxicity in fluorescence live-cell imaging,” Nat. Biotechnol. 25(2), 249–253 (2007).
[Crossref] [PubMed]

T. Biederer and P. Scheiffele, “Mixed-culture assays for analyzing neuronal synapse formation,” Nat. Protoc. 2(3), 670–676 (2007).
[Crossref] [PubMed]

2006 (3)

2005 (1)

S. Suresh, J. Spatz, J. P. Mills, A. Micoulet, M. Dao, C. T. Lim, M. Beil, and T. Seufferlein, “Connections between single-cell biomechanics and human disease states: gastrointestinal cancer and malaria,” Acta Biomater. 1(1), 15–30 (2005).
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2003 (2)

N. Gov, A. G. Zilman, and S. Safran, “Cytoskeleton Confinement and Tension of Red Blood Cell Membranes,” Phys. Rev. Lett. 90(22), 228101 (2003).
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J. Lippincott-Schwartz, N. Altan-Bonnet, and G. H. Patterson, “Photobleaching and photoactivation: following protein dynamics in living cells,” Nat. Cell Biol. 5(Suppl), S7–S14 (2003).
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2000 (1)

M. Atature, A. V. Sergienko, B. E. Saleh, and M. C. Teich, “Dispersion-independent high-visibility quantum interference in ultrafast parametric down-conversion,” Phys. Rev. Lett. 84(4), 618–621 (2000).
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1999 (2)

W. I. Goldburg, “Dynamic light scattering,” Am. J. Phys. 67(12), 1152–1160 (1999).
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G. Ghosh, “Dispersion-equation coefficients for the refractive index and birefringence of calcite and quartz crystals,” Opt. Commun. 163(1-3), 95–102 (1999).
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1998 (1)

J. Prost, J.-B. Manneville, and R. Bruinsma, “Fluctuation-magnification of non-equilibrium membranes near a wall,” Eur. Phys. J. B 1(4), 465–480 (1998).
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1995 (1)

G. A. Dunn and D. Zicha, “Dynamics Of Fibroblast Spreading,” J. Cell Sci. 108(Pt 3), 1239–1249 (1995).
[PubMed]

1994 (1)

D. E. Discher, N. Mohandas, and E. A. Evans, “Molecular maps of red cell deformation: hidden elasticity and in situ connectivity,” Science 266(5187), 1032–1035 (1994).
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1984 (1)

H. Engelhardt, H. Gaub, and E. Sackmann, “Viscoelastic properties of erythrocyte membranes in high-frequency electric fields,” Nature 307(5949), 378–380 (1984).
[Crossref] [PubMed]

1982 (1)

1962 (1)

1953 (1)

R. Barer, “Determination of dry mass, thickness, solid and water concentration in living cells,” Nature 172(4389), 1097–1098 (1953).
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1905 (1)

A. Einstein, “Investigations on the theory of the Brownian movement,” Ann. Phys. 17, 549 (1905).
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Altan-Bonnet, N.

J. Lippincott-Schwartz, N. Altan-Bonnet, and G. H. Patterson, “Photobleaching and photoactivation: following protein dynamics in living cells,” Nat. Cell Biol. 5(Suppl), S7–S14 (2003).
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Amaral, R. F.

B. Pontes, Y. Ayala, A. C. Fonseca, L. F. Romão, R. F. Amaral, L. T. Salgado, F. R. Lima, M. Farina, N. B. Viana, V. Moura-Neto, and H. M. Nussenzveig, “Membrane elastic properties and cell function,” PLoS One 8(7), e67708 (2013).
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Arbabi, A.

R. Zhou, C. Edwards, A. Arbabi, G. Popescu, and L. L. Goddard, “Detecting 20 nm Wide Defects in Large Area Nanopatterns Using Optical Interferometric Microscopy,” Nano Lett. 13(8), 3716–3721 (2013).
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C. Edwards, A. Arbabi, G. Popescu, and L. L. Goddard, “Optically monitoring and controlling nanoscale topography during semiconductor etching,” Light Sci. Appl. 1(9), e30 (2012).
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Arroyo, J. O.

J. O. Arroyo and P. Kukura, “Non-fluorescent schemes for single-molecule detection, imaging and spectroscopy,” Nat. Photonics 10(1), 11–17 (2016).
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Atature, M.

M. Atature, A. V. Sergienko, B. E. Saleh, and M. C. Teich, “Dispersion-independent high-visibility quantum interference in ultrafast parametric down-conversion,” Phys. Rev. Lett. 84(4), 618–621 (2000).
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Auth, T.

Y. Park, C. A. Best, T. Auth, N. S. Gov, S. A. Safran, G. Popescu, S. Suresh, and M. S. Feld, “Metabolic remodeling of the human red blood cell membrane,” Proc. Natl. Acad. Sci. U.S.A. 107(4), 1289–1294 (2010).
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Ayala, Y.

B. Pontes, Y. Ayala, A. C. Fonseca, L. F. Romão, R. F. Amaral, L. T. Salgado, F. R. Lima, M. Farina, N. B. Viana, V. Moura-Neto, and H. M. Nussenzveig, “Membrane elastic properties and cell function,” PLoS One 8(7), e67708 (2013).
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Babacan, S. D.

T. Kim, R. J. Zhou, M. Mir, S. D. Babacan, P. S. Carney, L. L. Goddard, and G. Popescu, “White-light diffraction tomography of unlabeled live cells,” Nat. Photonics 8(3), 256–263 (2014).
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Badizadegan, K.

Y. Park, C. A. Best, K. Badizadegan, R. R. Dasari, M. S. Feld, T. Kuriabova, M. L. Henle, A. J. Levine, and G. Popescu, “Measurement of red blood cell mechanics during morphological changes,” Proc. Natl. Acad. Sci. U.S.A. 107(15), 6731–6736 (2010).
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Y. Park, C. A. Best, K. Badizadegan, R. R. Dasari, M. S. Feld, T. Kuriabova, M. L. Henle, A. J. Levine, and G. Popescu, “Measurement of red blood cell mechanics during morphological changes,” Proc. Natl. Acad. Sci. U.S.A. 107(15), 6731–6736 (2010).
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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).
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G. Popescu, T. Ikeda, K. Goda, C. A. Best-Popescu, M. Laposata, S. Manley, R. R. Dasari, K. Badizadegan, and M. S. Feld, “Optical measurement of cell membrane tension,” Phys. Rev. Lett. 97(21), 218101 (2006).
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Balla, A.

H. Majeed, M. E. Kandel, K. Han, Z. Luo, V. Macias, K. Tangella, A. Balla, and G. Popescu, “Breast cancer diagnosis using spatial light interference microscopy,” J. Biomed. Opt. 20(11), 111210 (2015).
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Z. Wang, K. Tangella, A. Balla, and G. Popescu, “Tissue refractive index as marker of disease,” J. Biomed. Opt. 16(11), 116017 (2011).
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Barer, R.

R. Barer, “Determination of dry mass, thickness, solid and water concentration in living cells,” Nature 172(4389), 1097–1098 (1953).
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Bashir, R.

M. Mir, Z. Wang, Z. Shen, M. Bednarz, R. Bashir, I. Golding, S. G. Prasanth, and G. Popescu, “Optical measurement of cycle-dependent cell growth,” Proc. Natl. Acad. Sci. U.S.A. 108(32), 13124–13129 (2011).
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Bednarz, M.

M. Mir, Z. Wang, Z. Shen, M. Bednarz, R. Bashir, I. Golding, S. G. Prasanth, and G. Popescu, “Optical measurement of cycle-dependent cell growth,” Proc. Natl. Acad. Sci. U.S.A. 108(32), 13124–13129 (2011).
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Beil, M.

S. Suresh, J. Spatz, J. P. Mills, A. Micoulet, M. Dao, C. T. Lim, M. Beil, and T. Seufferlein, “Connections between single-cell biomechanics and human disease states: gastrointestinal cancer and malaria,” Acta Biomater. 1(1), 15–30 (2005).
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Best, C. A.

Y. Park, C. A. Best, K. Badizadegan, R. R. Dasari, M. S. Feld, T. Kuriabova, M. L. Henle, A. J. Levine, and G. Popescu, “Measurement of red blood cell mechanics during morphological changes,” Proc. Natl. Acad. Sci. U.S.A. 107(15), 6731–6736 (2010).
[Crossref] [PubMed]

Y. Park, C. A. Best, T. Auth, N. S. Gov, S. A. Safran, G. Popescu, S. Suresh, and M. S. Feld, “Metabolic remodeling of the human red blood cell membrane,” Proc. Natl. Acad. Sci. U.S.A. 107(4), 1289–1294 (2010).
[Crossref] [PubMed]

Y. Park, C. A. Best, K. Badizadegan, R. R. Dasari, M. S. Feld, T. Kuriabova, M. L. Henle, A. J. Levine, and G. Popescu, “Measurement of red blood cell mechanics during morphological changes,” Proc. Natl. Acad. Sci. U.S.A. 107(15), 6731–6736 (2010).
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Best-Popescu, C. A.

G. Popescu, T. Ikeda, K. Goda, C. A. Best-Popescu, M. Laposata, S. Manley, R. R. Dasari, K. Badizadegan, and M. S. Feld, “Optical measurement of cell membrane tension,” Phys. Rev. Lett. 97(21), 218101 (2006).
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Bhaduri, B.

Bianco, V.

V. Bianco, F. Merola, L. Miccio, P. Memmolo, O. Gennari, M. Paturzo, P. A. Netti, and P. Ferraro, “Imaging adherent cells in the microfluidic channel hidden by flowing RBCs as occluding objects by a holographic method,” Lab Chip 14(14), 2499–2504 (2014).
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Biederer, T.

T. Biederer and P. Scheiffele, “Mixed-culture assays for analyzing neuronal synapse formation,” Nat. Protoc. 2(3), 670–676 (2007).
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Bishitz, Y.

Y. Bishitz, H. Gabai, P. Girshovitz, and N. T. Shaked, “Optical-mechanical signatures of cancer cells based on fluctuation profiles measured by interferometry,” J. Biophotonics 7(8), 624–630 (2014).
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P. Wang, R. K. Bista, W. E. Khalbuss, W. Qiu, S. Uttam, K. Staton, L. Zhang, T. A. Brentnall, R. E. Brand, and Y. Liu, “Nanoscale nuclear architecture for cancer diagnosis beyond pathology via spatial-domain low-coherence quantitative phase microscopy,” J. Biomed. Opt. 15(6), 066028 (2010).
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Boppart, S. A.

T. S. Ralston, D. L. Marks, P. S. Carney, and S. A. Boppart, “Interferometric synthetic aperture microscopy,” Nat. Phys. 3(2), 129–134 (2007).
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S. Uttam, H. V. Pham, J. LaFace, B. Leibowitz, J. Yu, R. E. Brand, D. J. Hartman, and Y. Liu, “Early Prediction of Cancer Progression by Depth-Resolved Nanoscale Mapping of Nuclear Architecture from Unstained Tissue Specimens,” Cancer Res. 75(22), 4718–4727 (2015).
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P. Wang, R. K. Bista, W. E. Khalbuss, W. Qiu, S. Uttam, K. Staton, L. Zhang, T. A. Brentnall, R. E. Brand, and Y. Liu, “Nanoscale nuclear architecture for cancer diagnosis beyond pathology via spatial-domain low-coherence quantitative phase microscopy,” J. Biomed. Opt. 15(6), 066028 (2010).
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Brentnall, T. A.

P. Wang, R. K. Bista, W. E. Khalbuss, W. Qiu, S. Uttam, K. Staton, L. Zhang, T. A. Brentnall, R. E. Brand, and Y. Liu, “Nanoscale nuclear architecture for cancer diagnosis beyond pathology via spatial-domain low-coherence quantitative phase microscopy,” J. Biomed. Opt. 15(6), 066028 (2010).
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Bruinsma, R.

J. Prost, J.-B. Manneville, and R. Bruinsma, “Fluctuation-magnification of non-equilibrium membranes near a wall,” Eur. Phys. J. B 1(4), 465–480 (1998).
[Crossref]

Carney, P. S.

T. Kim, R. J. Zhou, M. Mir, S. D. Babacan, P. S. Carney, L. L. Goddard, and G. Popescu, “White-light diffraction tomography of unlabeled live cells,” Nat. Photonics 8(3), 256–263 (2014).
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T. S. Ralston, D. L. Marks, P. S. Carney, and S. A. Boppart, “Interferometric synthetic aperture microscopy,” Nat. Phys. 3(2), 129–134 (2007).
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Cho, S.-H.

H. Park, S.-H. Hong, K. Kim, S.-H. Cho, W.-J. Lee, Y. Kim, S.-E. Lee, and Y. Park, “Characterizations of individual mouse red blood cells parasitized by Babesia microti using 3-D holographic microscopy,” Sci. Rep. 5(1), 10827 (2015).
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Choi, W.

Y. Park, M. Diez-Silva, G. Popescu, G. Lykotrafitis, W. Choi, M. S. Feld, and S. Suresh, “Refractive index maps and membrane dynamics of human red blood cells parasitized by Plasmodium falciparum,” Proc. Natl. Acad. Sci. U.S.A. 105(37), 13730–13735 (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).
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Colomb, T.

Cooper, K. L.

K. L. Cooper, S. Oh, Y. Sung, R. R. Dasari, M. W. Kirschner, and C. J. Tabin, “Multiple phases of chondrocyte enlargement underlie differences in skeletal proportions,” Nature 495(7441), 375–378 (2013).
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S. Suresh, J. Spatz, J. P. Mills, A. Micoulet, M. Dao, C. T. Lim, M. Beil, and T. Seufferlein, “Connections between single-cell biomechanics and human disease states: gastrointestinal cancer and malaria,” Acta Biomater. 1(1), 15–30 (2005).
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K. L. Cooper, S. Oh, Y. Sung, R. R. Dasari, M. W. Kirschner, and C. J. Tabin, “Multiple phases of chondrocyte enlargement underlie differences in skeletal proportions,” Nature 495(7441), 375–378 (2013).
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Y. Park, C. A. Best, K. Badizadegan, R. R. Dasari, M. S. Feld, T. Kuriabova, M. L. Henle, A. J. Levine, and G. Popescu, “Measurement of red blood cell mechanics during morphological changes,” Proc. Natl. Acad. Sci. U.S.A. 107(15), 6731–6736 (2010).
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Y. Park, C. A. Best, K. Badizadegan, R. R. Dasari, M. S. Feld, T. Kuriabova, M. L. Henle, A. J. Levine, and G. Popescu, “Measurement of red blood cell mechanics during morphological changes,” Proc. Natl. Acad. Sci. U.S.A. 107(15), 6731–6736 (2010).
[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).
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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).
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Dhonukshe, P. B.

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Diez-Silva, M.

Y. Park, M. Diez-Silva, G. Popescu, G. Lykotrafitis, W. Choi, M. S. Feld, and S. Suresh, “Refractive index maps and membrane dynamics of human red blood cells parasitized by Plasmodium falciparum,” Proc. Natl. Acad. Sci. U.S.A. 105(37), 13730–13735 (2008).
[Crossref] [PubMed]

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Z. Wang, L. Millet, M. Mir, H. Ding, S. Unarunotai, J. Rogers, M. U. Gillette, and G. Popescu, “Spatial light interference microscopy (SLIM),” Opt. Express 19(2), 1016–1026 (2011).
[Crossref] [PubMed]

M. Mir, H. Ding, Z. Wang, J. Reedy, K. Tangella, and G. Popescu, “Blood screening using diffraction phase cytometry,” J. Biomed. Opt. 15(2), 027016 (2010).
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D. E. Discher, N. Mohandas, and E. A. Evans, “Molecular maps of red cell deformation: hidden elasticity and in situ connectivity,” Science 266(5187), 1032–1035 (1994).
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G. A. Dunn and D. Zicha, “Dynamics Of Fibroblast Spreading,” J. Cell Sci. 108(Pt 3), 1239–1249 (1995).
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C. Edwards, B. Bhaduri, B. G. Griffin, L. L. Goddard, and G. Popescu, “Epi-illumination diffraction phase microscopy with white light,” Opt. Lett. 39(21), 6162–6165 (2014).
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B. Bhaduri, C. Edwards, H. Pham, R. Zhou, T. H. Nguyen, L. L. Goddard, and G. Popescu, “Diffraction phase microscopy: principles and applications in materials and life sciences,” Adv. Opt. Photonics 6(1), 57–119 (2014).
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R. Zhou, C. Edwards, A. Arbabi, G. Popescu, and L. L. Goddard, “Detecting 20 nm Wide Defects in Large Area Nanopatterns Using Optical Interferometric Microscopy,” Nano Lett. 13(8), 3716–3721 (2013).
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C. Edwards, A. Arbabi, G. Popescu, and L. L. Goddard, “Optically monitoring and controlling nanoscale topography during semiconductor etching,” Light Sci. Appl. 1(9), e30 (2012).
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A. Einstein, “Investigations on the theory of the Brownian movement,” Ann. Phys. 17, 549 (1905).
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W. J. Eldridge, Z. A. Steelman, B. Loomis, and A. Wax, “Optical Phase Measurements of Disorder Strength Link Microstructure to Cell Stiffness,” Biophys. J. 112(4), 692–702 (2017).
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H. Engelhardt, H. Gaub, and E. Sackmann, “Viscoelastic properties of erythrocyte membranes in high-frequency electric fields,” Nature 307(5949), 378–380 (1984).
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D. E. Discher, N. Mohandas, and E. A. Evans, “Molecular maps of red cell deformation: hidden elasticity and in situ connectivity,” Science 266(5187), 1032–1035 (1994).
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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. Methods 4(9), 717–719 (2007).
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B. Pontes, Y. Ayala, A. C. Fonseca, L. F. Romão, R. F. Amaral, L. T. Salgado, F. R. Lima, M. Farina, N. B. Viana, V. Moura-Neto, and H. M. Nussenzveig, “Membrane elastic properties and cell function,” PLoS One 8(7), e67708 (2013).
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Feld, M. S.

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Figures (8)

Fig. 1
Fig. 1 MISS microscope. f1 = 60 mm, f2 = 150 mm, f3 = 0.3 mm. L3 and L2 form a 4-f system that magnifies the Fourier transform of the zero-order by a factor of 500. For the L3-L2 imaging system, image formation at both high and low spatial frequencies is shown to illustrate the magnification process.
Fig. 2
Fig. 2 (a) A 1024 x 1024 raw image of 40 µm wide square quartz pillar obtained using the MISS system (b) The Fourier transform of the raw image. Color bar is in log base 10 arbitrary units. (c) Height map obtained from the reconstructed phase map with color bar in nm. (d) Histogram of the pillar height map. The separation between the peak means corresponds to the measured pillar height.
Fig. 3
Fig. 3 Analysis of spatiotemporal stability of the MISS microscopy system. (a) A 256 x 1500 pixels no-sample OPD image with color bar in nm. (b) The histogram of the noise OPD stack acquired at 833 fps. (c) Plot showing the noise content at each spatial and temporal frequency component along three different planes in 3d frequency space. Color bar is in log scale with units of n m 2 (rad/μm) 2 (rad/s) . (d) Band-pass filtering over the spatio-temporal bands shown in (c) results in noise values 2-3 orders of magnitude less than the total noise of 0.95 nm.
Fig. 4
Fig. 4 Particle sizing results for 1 ��m polystyrene particles using dispersion relation spectroscopy (DPS). (a) A representative phase image from the 512 frame stack (color bar in radians). (b) The temporal standard deviation map of OPD computed for the stack (color bar in nm) (c) 2d plot of temporal bandwidth à versus wave vector q=( q x , q y ).(d) Profile obtained by radial averaging of 2d plot in (c). Fitting a second order polynomial to the curve allows the determination of the diffusion coefficientD, as indicated.
Fig. 5
Fig. 5 (a, b, c, d) DPS analysis results for 4 different particle sizes in water, as indicated. (e) Fitting a first-order polynomial to the log10 (D) vs log10 (p = 2r) data verifies that the measurement follows the Stokes-Einstein equation. Each data-point is the mean and each error-bar the standard-deviation of 20 experiments.
Fig. 6
Fig. 6 Measurement of neuron membrane dynamics and surface tension σ before and after high K+ stimulation. (a-b) Fluorescence images of a neuron before and after stimulation, respectively. The enhanced fluorescence signal after stimulation reports on the intracellular Ca+2 ion concentration. (c-d) Representative phase images of the neuron. (e-f) Temporal standard deviation of the OPD time-lapse overlaid over the corresponding phase image. (g) DPS analysis on four different cells before high K+ stimulation. Linear fitting of the average dispersion curve yields the mean surface tension σof the neuron membrane. (h) Dispersion curve for a no-sample, i.e., background (BG) region. (i) DPS analysis on the same four cells after high K+ stimulation. Linear fitting of the average dispersion curve was used to extract mean surface tension σof the neuron membrane.
Fig. 7
Fig. 7 (a) and (b) Average raw intensity images obtained for MISS and DPM, respectively, by temporally averaging 1024 frames. (c) Histograms of the intensity images in (a) and (b). Fitting a mixture of two normal distributions to the bimodal histograms show a greater separation between the peaks in MISS than in DPM.
Fig. 8
Fig. 8 Temporal standard deviation of OPD maps for (a) 300 nm (b) 100 nm (c) 50 nm and (d) 20 nm colloidal nanoparticle solutions. Scale bar: 5 µm. The same map for 1 ��m colloidal particles is shown in Fig. 4(b).

Equations (5)

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D= k B T 6πηr
Γ=Δvq+D q 2 .
Γ=D q 2 .
Γ=[ κ q 3 +σq+ γ q ] 1 4η
Γ= ω 2 P(ω)dω P(ω)dω = | ωϕ(ω) | 2 dω P(ω)dω = | dϕ(t) dt | 2 dt |ϕ(t) | 2 dt .

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