Abstract

Label-free imaging approaches seek to simplify and augment histopathologic assessment by replacing the current practice of staining by dyes to visualize tissue morphology with quantitative optical measurements. Quantitative phase imaging (QPI) operates with visible/UV light and thus provides a resolution matched to current practice. Here we introduce and demonstrate confocal QPI for label-free imaging of tissue sections and assess its utility for manual histopathologic inspection. Imaging cancerous and normal adjacent human breast and prostate, we show that tissue structural organization can be resolved with high spatial detail comparable to conventional hematoxylin and eosin (H&E) stains. Our confocal QPI images are found to be free of halo, solving this common problem in QPI. We further describe a virtual imaging system based on finite-difference time-domain (FDTD) calculations and combine it with numerical tissue phantoms to quantitatively show the absence of halo and the improved clarity in resolving subcellular features with confocal QPI compared to wide-field QPI. Confocal QPI bears the potential to become a common tool for label-free disease diagnosis, while the presented FDTD method provides a flexible platform to evaluate the diagnostic potential of QPI methods.

© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

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2020 (1)

Y. N. Nygate, M. Levi, S. K. Mirsky, N. A. Turko, M. Rubin, I. Barnea, G. Dardikman-Yoffe, M. Haifler, A. Shalev, and N. T. Shaked, “Holographic virtual staining of individual biological cells,” Proc. Natl. Acad. Sci. USA 117, 9223–9231 (2020).
[Crossref]

2019 (2)

2018 (4)

H. Majeed, T. H. Nguyen, M. E. Kandel, A. Kajdacsy-Balla, and G. Popescu, “Label-free quantitative evaluation of breast tissue using spatial light interference microscopy (SLIM),” Sci. Rep. 8, 6875 (2018).
[Crossref]

Y. Rivenson, Y. Zhang, H. Günaydın, D. Teng, and A. Ozcan, “Phase recovery and holographic image reconstruction using deep learning in neural networks,” Light Sci. Appl. 7, 17141 (2018).
[Crossref]

I. Y. Yanina, E. N. Lazareva, and V. V. Tuchin, “Refractive index of adipose tissue and lipid droplet measured in wide spectral and temperature ranges,” Appl. Opt. 57, 4839–4848 (2018).
[Crossref]

Y. Park, C. Depeursinge, and G. Popescu, “Quantitative phase imaging in biomedicine,” Nat. Photonics 12, 578–589 (2018).
[Crossref]

2017 (3)

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

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, 066016 (2017).
[Crossref]

S. Chowdhury, W. J. Eldridge, A. Wax, and J. A. Izatt, “Structured illumination multimodal 3D-resolved quantitative phase and fluorescence sub-diffraction microscopy,” Biomed. Opt. Express 8, 2496–2518 (2017).
[Crossref]

2016 (4)

B. Titze and C. Genoud, “Volume scanning electron microscopy for imaging biological ultrastructure: volume scanning electron microscopy,” Biol. Cell 108, 307–323 (2016).
[Crossref]

P. Y. Liu, L. K. Chin, W. Ser, H. F. Chen, C.-M. Hsieh, C.-H. Lee, K.-B. Sung, T. C. Ayi, P. H. Yap, B. Liedberg, K. Wang, T. Bourouina, and Y. Leprince-Wang, “Cell refractive index for cell biology and disease diagnosis: past, present and future,” Lab Chip 16, 634–644 (2016).
[Crossref]

C. Liu, S. Knitter, Z. Cong, I. Sencan, H. Cao, and M. A. Choma, “High-speed line-field confocal holographic microscope for quantitative phase imaging,” Opt. Express 24, 9251–9265 (2016).
[Crossref]

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, 1656–1659 (2016).
[Crossref]

2015 (5)

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, 111210 (2015).
[Crossref]

S. Sridharan, V. Macias, K. Tangella, A. Kajdacsy-Balla, and G. Popescu, “Prediction of prostate cancer recurrence using quantitative phase imaging,” Sci. Rep. 5, 9976 (2015).
[Crossref]

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, 4718–4727 (2015).
[Crossref]

A. Kremer, S. Lippens, S. Bartunkova, B. Asselbergh, C. Blanpain, M. Fendrych, A. Goossens, M. Holt, S. Janssens, M. Krols, J.-C. Larsimont, C. McGUIRE, M. Nowack, X. Saelens, A. Schertel, B. Schepens, M. Slezak, V. Timmerman, C. Theunis, R. Van Brempt, Y. Visser, and C. Guérin, “Developing 3D SEM in a broad biological context: 3D SEM,” J. Microsc. 259, 80–96 (2015).
[Crossref]

S. Chowdhury, W. J. Eldridge, A. Wax, and J. A. Izatt, “Spatial frequency-domain multiplexed microscopy for simultaneous, single-camera, one-shot, fluorescent, and quantitative-phase imaging,” Opt. Lett. 40, 4839–4842 (2015).
[Crossref]

2014 (9)

B. Deutsch, M. Schnell, R. Hillenbrand, and P. S. Carney, “Synthetic optical holography with nonlinear-phase reference,” Opt. Express 22, 26621–26634 (2014).
[Crossref]

M. Schnell, P. S. Carney, and R. Hillenbrand, “Synthetic optical holography for rapid nanoimaging,” Nat. Commun. 5, 3499 (2014).
[Crossref]

M. Schnell, M. J. Perez-Roldan, P. S. Carney, and R. Hillenbrand, “Quantitative confocal phase imaging by synthetic optical holography,” Opt. Express 22, 15267–15276 (2014).
[Crossref]

C. Liu, S. Marchesini, and M. K. Kim, “Quantitative phase-contrast confocal microscope,” Opt. Express 22, 17830–17839 (2014).
[Crossref]

P. Marquet, C. Depeursinge, and P. J. Magistretti, “Review of quantitative phase-digital holographic microscopy: promising novel imaging technique to resolve neuronal network activity and identify cellular biomarkers of psychiatric disorders,” Neurophotonics 1, 020901 (2014).
[Crossref]

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. Photon. 6, 57–119 (2014).
[Crossref]

M. J. Baker, J. Trevisan, P. Bassan, R. Bhargava, H. J. Butler, K. M. Dorling, P. R. Fielden, S. W. Fogarty, N. J. Fullwood, K. A. Heys, C. Hughes, P. Lasch, P. L. Martin-Hirsch, B. Obinaju, G. D. Sockalingum, J. Sulé-Suso, R. J. Strong, M. J. Walsh, B. R. Wood, P. Gardner, and F. L. Martin, “Using Fourier transform IR spectroscopy to analyze biological materials,” Nat. Protoc. 9, 1771–1791 (2014).
[Crossref]

C. Edwards, B. Bhaduri, T. Nguyen, B. G. Griffin, H. Pham, T. Kim, G. Popescu, and L. L. Goddard, “Effects of spatial coherence in diffraction phase microscopy,” Opt. Express 22, 5133–5146 (2014).
[Crossref]

T. H. Nguyen, C. Edwards, L. L. Goddard, and G. Popescu, “Quantitative phase imaging with partially coherent illumination,” Opt. Lett. 39, 5511–5514 (2014).
[Crossref]

2013 (3)

K. Lee, K. Kim, J. Jung, J. Heo, S. Cho, S. Lee, G. Chang, Y. Jo, H. Park, and Y. Park, “Quantitative phase imaging techniques for the study of cell pathophysiology: from principles to applications,” Sensors 13, 4170–4191 (2013).
[Crossref]

Y. Cotte, F. Toy, P. Jourdain, N. Pavillon, D. Boss, P. Magistretti, P. Marquet, and C. Depeursinge, “Marker-free phase nanoscopy,” Nat. Photonics 7, 113–117 (2013).
[Crossref]

A. S. Goy, M. Unser, and D. Psaltis, “Multiple contrast metrics from the measurements of a digital confocal microscope,” Biomed. Opt. Express 4, 001091 (2013).
[Crossref]

2012 (2)

2011 (4)

2010 (1)

2009 (1)

2008 (4)

2006 (2)

2005 (3)

2004 (1)

2001 (1)

G. G. Fattinger and P. T. Tikka, “Modified Mach–Zender laser interferometer for probing bulk acoustic waves,” Appl. Phys. Lett. 79, 290–292 (2001).
[Crossref]

2000 (1)

1999 (1)

1994 (1)

1993 (1)

Y. Clermont, L. Xia, A. Rambourg, J. D. Turner, and L. Hermo, “Structure of the Golgi apparatus in stimulated and nonstimulated acinar cells of mammary glands of the rat,” Anat. Rec. 237, 308–317 (1993).
[Crossref]

1986 (1)

1981 (2)

G. E. Sommargren, “Optical heterodyne profilometry,” Appl. Opt. 20, 610–618 (1981).
[Crossref]

T. Wilson and C. J. R. Sheppard, “The halo effect of image processing by spatial frequency filtering,” Optik 59, 19–23 (1981).

Abbas, A. K.

V. Kumar and A. K. Abbas, and J. C. Aster, eds., Robbins and Cotran Pathologic Basis of Disease, 9th ed. (Elsevier/Saunders, 2015).

Akkin, T.

Amitrano, A. M.

Asselbergh, B.

A. Kremer, S. Lippens, S. Bartunkova, B. Asselbergh, C. Blanpain, M. Fendrych, A. Goossens, M. Holt, S. Janssens, M. Krols, J.-C. Larsimont, C. McGUIRE, M. Nowack, X. Saelens, A. Schertel, B. Schepens, M. Slezak, V. Timmerman, C. Theunis, R. Van Brempt, Y. Visser, and C. Guérin, “Developing 3D SEM in a broad biological context: 3D SEM,” J. Microsc. 259, 80–96 (2015).
[Crossref]

Ayi, T. C.

P. Y. Liu, L. K. Chin, W. Ser, H. F. Chen, C.-M. Hsieh, C.-H. Lee, K.-B. Sung, T. C. Ayi, P. H. Yap, B. Liedberg, K. Wang, T. Bourouina, and Y. Leprince-Wang, “Cell refractive index for cell biology and disease diagnosis: past, present and future,” Lab Chip 16, 634–644 (2016).
[Crossref]

Backman, V.

I. R. Çapoğlu, J. D. Rogers, A. Taflove, and V. Backman, “The microscope in a computer: image synthesis from three-dimensional full-vector solutions of Maxwell’s equations at the nanometer scale,” in Progress in Optics, E. Wolf, ed. (Elsevier, 2012), Vol. 57.

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Sridharan, S.

H. Majeed, S. Sridharan, M. Mir, L. Ma, E. Min, W. Jung, and G. Popescu, “Quantitative phase imaging for medical diagnosis,” J. Biophoton. 10, 177–205 (2017).
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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, 066016 (2017).
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S. Sridharan, V. Macias, K. Tangella, A. Kajdacsy-Balla, and G. Popescu, “Prediction of prostate cancer recurrence using quantitative phase imaging,” Sci. Rep. 5, 9976 (2015).
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M. J. Baker, J. Trevisan, P. Bassan, R. Bhargava, H. J. Butler, K. M. Dorling, P. R. Fielden, S. W. Fogarty, N. J. Fullwood, K. A. Heys, C. Hughes, P. Lasch, P. L. Martin-Hirsch, B. Obinaju, G. D. Sockalingum, J. Sulé-Suso, R. J. Strong, M. J. Walsh, B. R. Wood, P. Gardner, and F. L. Martin, “Using Fourier transform IR spectroscopy to analyze biological materials,” Nat. Protoc. 9, 1771–1791 (2014).
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M. J. Baker, J. Trevisan, P. Bassan, R. Bhargava, H. J. Butler, K. M. Dorling, P. R. Fielden, S. W. Fogarty, N. J. Fullwood, K. A. Heys, C. Hughes, P. Lasch, P. L. Martin-Hirsch, B. Obinaju, G. D. Sockalingum, J. Sulé-Suso, R. J. Strong, M. J. Walsh, B. R. Wood, P. Gardner, and F. L. Martin, “Using Fourier transform IR spectroscopy to analyze biological materials,” Nat. Protoc. 9, 1771–1791 (2014).
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P. Y. Liu, L. K. Chin, W. Ser, H. F. Chen, C.-M. Hsieh, C.-H. Lee, K.-B. Sung, T. C. Ayi, P. H. Yap, B. Liedberg, K. Wang, T. Bourouina, and Y. Leprince-Wang, “Cell refractive index for cell biology and disease diagnosis: past, present and future,” Lab Chip 16, 634–644 (2016).
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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, 066016 (2017).
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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, 111210 (2015).
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S. Sridharan, V. Macias, K. Tangella, A. Kajdacsy-Balla, and G. Popescu, “Prediction of prostate cancer recurrence using quantitative phase imaging,” Sci. Rep. 5, 9976 (2015).
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Z. Wang, G. Popescu, K. V. Tangella, and A. Balla, “Tissue refractive index as marker of disease,” J. Biomed. Opt. 16, 116017 (2011).
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Y. Rivenson, Y. Zhang, H. Günaydın, D. Teng, and A. Ozcan, “Phase recovery and holographic image reconstruction using deep learning in neural networks,” Light Sci. Appl. 7, 17141 (2018).
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A. Kremer, S. Lippens, S. Bartunkova, B. Asselbergh, C. Blanpain, M. Fendrych, A. Goossens, M. Holt, S. Janssens, M. Krols, J.-C. Larsimont, C. McGUIRE, M. Nowack, X. Saelens, A. Schertel, B. Schepens, M. Slezak, V. Timmerman, C. Theunis, R. Van Brempt, Y. Visser, and C. Guérin, “Developing 3D SEM in a broad biological context: 3D SEM,” J. Microsc. 259, 80–96 (2015).
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G. G. Fattinger and P. T. Tikka, “Modified Mach–Zender laser interferometer for probing bulk acoustic waves,” Appl. Phys. Lett. 79, 290–292 (2001).
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J. V. Knuuttila, P. T. Tikka, and M. M. Salomaa, “Scanning Michelson interferometer for imaging surface acoustic wave fields,” Opt. Lett. 25, 613–615 (2000).
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A. Kremer, S. Lippens, S. Bartunkova, B. Asselbergh, C. Blanpain, M. Fendrych, A. Goossens, M. Holt, S. Janssens, M. Krols, J.-C. Larsimont, C. McGUIRE, M. Nowack, X. Saelens, A. Schertel, B. Schepens, M. Slezak, V. Timmerman, C. Theunis, R. Van Brempt, Y. Visser, and C. Guérin, “Developing 3D SEM in a broad biological context: 3D SEM,” J. Microsc. 259, 80–96 (2015).
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B. Titze and C. Genoud, “Volume scanning electron microscopy for imaging biological ultrastructure: volume scanning electron microscopy,” Biol. Cell 108, 307–323 (2016).
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Y. Cotte, F. Toy, P. Jourdain, N. Pavillon, D. Boss, P. Magistretti, P. Marquet, and C. Depeursinge, “Marker-free phase nanoscopy,” Nat. Photonics 7, 113–117 (2013).
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M. J. Baker, J. Trevisan, P. Bassan, R. Bhargava, H. J. Butler, K. M. Dorling, P. R. Fielden, S. W. Fogarty, N. J. Fullwood, K. A. Heys, C. Hughes, P. Lasch, P. L. Martin-Hirsch, B. Obinaju, G. D. Sockalingum, J. Sulé-Suso, R. J. Strong, M. J. Walsh, B. R. Wood, P. Gardner, and F. L. Martin, “Using Fourier transform IR spectroscopy to analyze biological materials,” Nat. Protoc. 9, 1771–1791 (2014).
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Y. N. Nygate, M. Levi, S. K. Mirsky, N. A. Turko, M. Rubin, I. Barnea, G. Dardikman-Yoffe, M. Haifler, A. Shalev, and N. T. Shaked, “Holographic virtual staining of individual biological cells,” Proc. Natl. Acad. Sci. USA 117, 9223–9231 (2020).
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Y. Clermont, L. Xia, A. Rambourg, J. D. Turner, and L. Hermo, “Structure of the Golgi apparatus in stimulated and nonstimulated acinar cells of mammary glands of the rat,” Anat. Rec. 237, 308–317 (1993).
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A. S. Goy, M. Unser, and D. Psaltis, “Multiple contrast metrics from the measurements of a digital confocal microscope,” Biomed. Opt. Express 4, 001091 (2013).
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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, 4718–4727 (2015).
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A. Kremer, S. Lippens, S. Bartunkova, B. Asselbergh, C. Blanpain, M. Fendrych, A. Goossens, M. Holt, S. Janssens, M. Krols, J.-C. Larsimont, C. McGUIRE, M. Nowack, X. Saelens, A. Schertel, B. Schepens, M. Slezak, V. Timmerman, C. Theunis, R. Van Brempt, Y. Visser, and C. Guérin, “Developing 3D SEM in a broad biological context: 3D SEM,” J. Microsc. 259, 80–96 (2015).
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Visser, Y.

A. Kremer, S. Lippens, S. Bartunkova, B. Asselbergh, C. Blanpain, M. Fendrych, A. Goossens, M. Holt, S. Janssens, M. Krols, J.-C. Larsimont, C. McGUIRE, M. Nowack, X. Saelens, A. Schertel, B. Schepens, M. Slezak, V. Timmerman, C. Theunis, R. Van Brempt, Y. Visser, and C. Guérin, “Developing 3D SEM in a broad biological context: 3D SEM,” J. Microsc. 259, 80–96 (2015).
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Walker, S. A.

Walsh, M. J.

M. J. Baker, J. Trevisan, P. Bassan, R. Bhargava, H. J. Butler, K. M. Dorling, P. R. Fielden, S. W. Fogarty, N. J. Fullwood, K. A. Heys, C. Hughes, P. Lasch, P. L. Martin-Hirsch, B. Obinaju, G. D. Sockalingum, J. Sulé-Suso, R. J. Strong, M. J. Walsh, B. R. Wood, P. Gardner, and F. L. Martin, “Using Fourier transform IR spectroscopy to analyze biological materials,” Nat. Protoc. 9, 1771–1791 (2014).
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P. Y. Liu, L. K. Chin, W. Ser, H. F. Chen, C.-M. Hsieh, C.-H. Lee, K.-B. Sung, T. C. Ayi, P. H. Yap, B. Liedberg, K. Wang, T. Bourouina, and Y. Leprince-Wang, “Cell refractive index for cell biology and disease diagnosis: past, present and future,” Lab Chip 16, 634–644 (2016).
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Wang, P.

Wang, Z.

Z. Wang, G. Popescu, K. V. Tangella, and A. Balla, “Tissue refractive index as marker of disease,” J. Biomed. Opt. 16, 116017 (2011).
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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, 1016–1026 (2011).
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T. Wilson and C. J. R. Sheppard, “The halo effect of image processing by spatial frequency filtering,” Optik 59, 19–23 (1981).

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M. J. Baker, J. Trevisan, P. Bassan, R. Bhargava, H. J. Butler, K. M. Dorling, P. R. Fielden, S. W. Fogarty, N. J. Fullwood, K. A. Heys, C. Hughes, P. Lasch, P. L. Martin-Hirsch, B. Obinaju, G. D. Sockalingum, J. Sulé-Suso, R. J. Strong, M. J. Walsh, B. R. Wood, P. Gardner, and F. L. Martin, “Using Fourier transform IR spectroscopy to analyze biological materials,” Nat. Protoc. 9, 1771–1791 (2014).
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Y. Rivenson, Y. Wu, and A. Ozcan, “Deep learning in holography and coherent imaging,” Light Sci. Appl. 8, 85 (2019).
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Xia, L.

Y. Clermont, L. Xia, A. Rambourg, J. D. Turner, and L. Hermo, “Structure of the Golgi apparatus in stimulated and nonstimulated acinar cells of mammary glands of the rat,” Anat. Rec. 237, 308–317 (1993).
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Yang, C.

Yang, T. D.

Yanina, I. Y.

Yao, B.

Yap, P. H.

P. Y. Liu, L. K. Chin, W. Ser, H. F. Chen, C.-M. Hsieh, C.-H. Lee, K.-B. Sung, T. C. Ayi, P. H. Yap, B. Liedberg, K. Wang, T. Bourouina, and Y. Leprince-Wang, “Cell refractive index for cell biology and disease diagnosis: past, present and future,” Lab Chip 16, 634–644 (2016).
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Yaqoob, Z.

Yu, J.

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, 4718–4727 (2015).
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Yu, L.

Zhang, Y.

Y. Rivenson, Y. Zhang, H. Günaydın, D. Teng, and A. Ozcan, “Phase recovery and holographic image reconstruction using deep learning in neural networks,” Light Sci. Appl. 7, 17141 (2018).
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Zhou, R.

Zhuo, Y.

Adv. Opt. Photon. (1)

Am. J. Physiol. Cell Physiol. (1)

G. Popescu, Y. Park, N. Lue, C. Best-Popescu, L. Deflores, R. R. Dasari, M. S. Feld, and K. Badizadegan, “Optical imaging of cell mass and growth dynamics,” Am. J. Physiol. Cell Physiol. 295, C538–C544 (2008).
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Anat. Rec. (1)

Y. Clermont, L. Xia, A. Rambourg, J. D. Turner, and L. Hermo, “Structure of the Golgi apparatus in stimulated and nonstimulated acinar cells of mammary glands of the rat,” Anat. Rec. 237, 308–317 (1993).
[Crossref]

Appl. Opt. (5)

Appl. Phys. Lett. (1)

G. G. Fattinger and P. T. Tikka, “Modified Mach–Zender laser interferometer for probing bulk acoustic waves,” Appl. Phys. Lett. 79, 290–292 (2001).
[Crossref]

Biol. Cell (1)

B. Titze and C. Genoud, “Volume scanning electron microscopy for imaging biological ultrastructure: volume scanning electron microscopy,” Biol. Cell 108, 307–323 (2016).
[Crossref]

Biomed. Opt. Express (2)

S. Chowdhury, W. J. Eldridge, A. Wax, and J. A. Izatt, “Structured illumination multimodal 3D-resolved quantitative phase and fluorescence sub-diffraction microscopy,” Biomed. Opt. Express 8, 2496–2518 (2017).
[Crossref]

A. S. Goy, M. Unser, and D. Psaltis, “Multiple contrast metrics from the measurements of a digital confocal microscope,” Biomed. Opt. Express 4, 001091 (2013).
[Crossref]

Cancer Res. (1)

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, 4718–4727 (2015).
[Crossref]

J. Biomed. Opt. (3)

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, 066016 (2017).
[Crossref]

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, 111210 (2015).
[Crossref]

Z. Wang, G. Popescu, K. V. Tangella, and A. Balla, “Tissue refractive index as marker of disease,” J. Biomed. Opt. 16, 116017 (2011).
[Crossref]

J. Biophoton. (1)

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

J. Microsc. (1)

A. Kremer, S. Lippens, S. Bartunkova, B. Asselbergh, C. Blanpain, M. Fendrych, A. Goossens, M. Holt, S. Janssens, M. Krols, J.-C. Larsimont, C. McGUIRE, M. Nowack, X. Saelens, A. Schertel, B. Schepens, M. Slezak, V. Timmerman, C. Theunis, R. Van Brempt, Y. Visser, and C. Guérin, “Developing 3D SEM in a broad biological context: 3D SEM,” J. Microsc. 259, 80–96 (2015).
[Crossref]

Lab Chip (1)

P. Y. Liu, L. K. Chin, W. Ser, H. F. Chen, C.-M. Hsieh, C.-H. Lee, K.-B. Sung, T. C. Ayi, P. H. Yap, B. Liedberg, K. Wang, T. Bourouina, and Y. Leprince-Wang, “Cell refractive index for cell biology and disease diagnosis: past, present and future,” Lab Chip 16, 634–644 (2016).
[Crossref]

Light Sci. Appl. (2)

Y. Rivenson, Y. Zhang, H. Günaydın, D. Teng, and A. Ozcan, “Phase recovery and holographic image reconstruction using deep learning in neural networks,” Light Sci. Appl. 7, 17141 (2018).
[Crossref]

Y. Rivenson, Y. Wu, and A. Ozcan, “Deep learning in holography and coherent imaging,” Light Sci. Appl. 8, 85 (2019).
[Crossref]

Nat. Commun. (1)

M. Schnell, P. S. Carney, and R. Hillenbrand, “Synthetic optical holography for rapid nanoimaging,” Nat. Commun. 5, 3499 (2014).
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Nat. Photonics (2)

Y. Park, C. Depeursinge, and G. Popescu, “Quantitative phase imaging in biomedicine,” Nat. Photonics 12, 578–589 (2018).
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Y. Cotte, F. Toy, P. Jourdain, N. Pavillon, D. Boss, P. Magistretti, P. Marquet, and C. Depeursinge, “Marker-free phase nanoscopy,” Nat. Photonics 7, 113–117 (2013).
[Crossref]

Nat. Protoc. (1)

M. J. Baker, J. Trevisan, P. Bassan, R. Bhargava, H. J. Butler, K. M. Dorling, P. R. Fielden, S. W. Fogarty, N. J. Fullwood, K. A. Heys, C. Hughes, P. Lasch, P. L. Martin-Hirsch, B. Obinaju, G. D. Sockalingum, J. Sulé-Suso, R. J. Strong, M. J. Walsh, B. R. Wood, P. Gardner, and F. L. Martin, “Using Fourier transform IR spectroscopy to analyze biological materials,” Nat. Protoc. 9, 1771–1791 (2014).
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Neurophotonics (1)

P. Marquet, C. Depeursinge, and P. J. Magistretti, “Review of quantitative phase-digital holographic microscopy: promising novel imaging technique to resolve neuronal network activity and identify cellular biomarkers of psychiatric disorders,” Neurophotonics 1, 020901 (2014).
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Opt. Express (11)

S. Bernet, A. Jesacher, S. Fürhapter, C. Maurer, and M. Ritsch-Marte, “Quantitative imaging of complex samples by spiral phase contrast microscopy,” Opt. Express 14, 3792–3805 (2006).
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C. J. Mann, L. Yu, C.-M. Lo, and M. K. Kim, “High-resolution quantitative phase-contrast microscopy by digital holography,” Opt. Express 13, 8693–8698 (2005).
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C. Maurer, A. Jesacher, S. Bernet, and M. Ritsch-Marte, “Phase contrast microscopy with full numerical aperture illumination,” Opt. Express 16, 19821–19829 (2008).
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C. Edwards, B. Bhaduri, T. Nguyen, B. G. Griffin, H. Pham, T. Kim, G. Popescu, and L. L. Goddard, “Effects of spatial coherence in diffraction phase microscopy,” Opt. Express 22, 5133–5146 (2014).
[Crossref]

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, 1016–1026 (2011).
[Crossref]

M. Schnell, M. J. Perez-Roldan, P. S. Carney, and R. Hillenbrand, “Quantitative confocal phase imaging by synthetic optical holography,” Opt. Express 22, 15267–15276 (2014).
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C. Liu, S. Marchesini, and M. K. Kim, “Quantitative phase-contrast confocal microscope,” Opt. Express 22, 17830–17839 (2014).
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C. Liu, S. Knitter, Z. Cong, I. Sencan, H. Cao, and M. A. Choma, “High-speed line-field confocal holographic microscope for quantitative phase imaging,” Opt. Express 24, 9251–9265 (2016).
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B. Deutsch, M. Schnell, R. Hillenbrand, and P. S. Carney, “Synthetic optical holography with nonlinear-phase reference,” Opt. Express 22, 26621–26634 (2014).
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A. S. Goy and D. Psaltis, “Digital confocal microscope,” Opt. Express 20, 22720–22727 (2012).
[Crossref]

Y. Park, G. Popescu, K. Badizadegan, R. R. Dasari, and M. S. Feld, “Diffraction phase and fluorescence microscopy,” Opt. Express 14, 8263–8268 (2006).
[Crossref]

Opt. Lett. (15)

S. Chowdhury, W. J. Eldridge, A. Wax, and J. A. Izatt, “Spatial frequency-domain multiplexed microscopy for simultaneous, single-camera, one-shot, fluorescent, and quantitative-phase imaging,” Opt. Lett. 40, 4839–4842 (2015).
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J. S. Maier, S. A. Walker, S. Fantini, M. A. Franceschini, and E. Gratton, “Possible correlation between blood glucose concentration and the reduced scattering coefficient of tissues in the near infrared,” Opt. Lett. 19, 2062–2064 (1994).
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P. Gao, B. Yao, I. Harder, N. Lindlein, and F. J. Torcal-Milla, “Phase-shifting Zernike phase contrast microscopy for quantitative phase measurement,” Opt. Lett. 36, 4305–4307 (2011).
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Y. Choi, T. D. Yang, K. J. Lee, and W. Choi, “Full-field and single-shot quantitative phase microscopy using dynamic speckle illumination,” Opt. Lett. 36, 2465–2467 (2011).
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B. Bhaduri, H. Pham, M. Mir, and G. Popescu, “Diffraction phase microscopy with white light,” Opt. Lett. 37, 1094–1096 (2012).
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P. Wang, R. Bista, R. Bhargava, R. E. Brand, and Y. Liu, “Spatial-domain low-coherence quantitative phase microscopy for cancer diagnosis,” Opt. Lett. 35, 2840–2842 (2010).
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T. H. Nguyen, C. Edwards, L. L. Goddard, and G. Popescu, “Quantitative phase imaging with partially coherent illumination,” Opt. Lett. 39, 5511–5514 (2014).
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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, 1656–1659 (2016).
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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, 2131–2133 (2005).
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M. A. Choma, A. K. Ellerbee, C. Yang, T. L. Creazzo, and J. A. Izatt, “Spectral-domain phase microscopy,” Opt. Lett. 30, 1162–1164 (2005).
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N. Lue, W. Choi, K. Badizadegan, R. R. Dasari, M. S. Feld, and G. Popescu, “Confocal diffraction phase microscopy of live cells,” Opt. Lett. 33, 2074–2076 (2008).
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J. V. Knuuttila, P. T. Tikka, and M. M. Salomaa, “Scanning Michelson interferometer for imaging surface acoustic wave fields,” Opt. Lett. 25, 613–615 (2000).
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G. Popescu, L. P. Deflores, J. C. Vaughan, K. Badizadegan, H. Iwai, R. R. Dasari, and M. S. Feld, “Fourier phase microscopy for investigation of biological structures and dynamics,” Opt. Lett. 29, 2503–2505 (2004).
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N. T. Shaked, M. T. Rinehart, and A. Wax, “Dual-interference-channel quantitative-phase microscopy of live cell dynamics,” Opt. Lett. 34, 767–769 (2009).
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Optik (1)

T. Wilson and C. J. R. Sheppard, “The halo effect of image processing by spatial frequency filtering,” Optik 59, 19–23 (1981).

Proc. Natl. Acad. Sci. USA (1)

Y. N. Nygate, M. Levi, S. K. Mirsky, N. A. Turko, M. Rubin, I. Barnea, G. Dardikman-Yoffe, M. Haifler, A. Shalev, and N. T. Shaked, “Holographic virtual staining of individual biological cells,” Proc. Natl. Acad. Sci. USA 117, 9223–9231 (2020).
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Sci. Rep. (2)

H. Majeed, T. H. Nguyen, M. E. Kandel, A. Kajdacsy-Balla, and G. Popescu, “Label-free quantitative evaluation of breast tissue using spatial light interference microscopy (SLIM),” Sci. Rep. 8, 6875 (2018).
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S. Sridharan, V. Macias, K. Tangella, A. Kajdacsy-Balla, and G. Popescu, “Prediction of prostate cancer recurrence using quantitative phase imaging,” Sci. Rep. 5, 9976 (2015).
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Sensors (1)

K. Lee, K. Kim, J. Jung, J. Heo, S. Cho, S. Lee, G. Chang, Y. Jo, H. Park, and Y. Park, “Quantitative phase imaging techniques for the study of cell pathophysiology: from principles to applications,” Sensors 13, 4170–4191 (2013).
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Supplementary Material (1)

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Figures (5)

Fig. 1.
Fig. 1. Performance prediction of an idealized confocal QPI microscope and comparison to wide-field QPI methods. (a) Virtual imaging system based on FDTD describing transmission-mode confocal QPI. (b) Virtual wide-field QPI. (c) Equally spaced plane waves describing Köhler illumination. (d)–(f) Synthesized quantitative phase images of a phase-object resolution test target at wavelength $\lambda = 561\;{\rm nm}$ for confocal QPI (${{\rm NA}_{{\rm cond}}} = {{\rm NA}_{{\rm obj}}} = 0.8$), traditional wide-field QPI, and common-path wide-field QPI (${{\rm NA}_{{\rm cond}}} = 0.09$ and ${{\rm NA}_{{\rm obj}}} = 0.8$). (g), (h) Vertical line profiles across the square of group 9 and the bars of group 10, respectively, as indicated by the arrows in (d)–(f). PML, perfectly matched layer boundary; Bloch, Bloch periodic boundary.
Fig. 2.
Fig. 2. Calculated phase contrast for numerical tissue section models. (a) High-resolution 2D refractive index model adopted from ultrastructural electron microscopy data on breast. (b) Calculated phase images illustrate improved spatial resolution and absence of ringing artifacts with confocal QPI (${{\rm NA}_{{\rm cond}}} = 0.09$ and ${{\rm NA}_{{\rm obj}}} = 0.8$). (c) Large area, low resolution model of breast tissue constructed from the data in Fig. 3. (d) Calculated phase images illustrate the effect of halo on image contrast that appears with common-path wide-field QPI (${{\rm NA}_{{\rm cond}}} = 0.045$ and ${{\rm NA}_{{\rm obj}}} = 0.4$). Common-path WF phase data were offset by ${+}0.1$ and ${+}0.5$ rad in (b) and (d).
Fig. 3.
Fig. 3. Confocal phase imaging of tissue sections mounted on reflective glass slides with sinusoidal-wave synthetic optical holography. (a) Schematic. (b) Example hologram and (c) digital zoom. (d) Fourier transform of the hologram. (e), (f) Reconstructed amplitude and phase images. Scale bar is 50 µm.
Fig. 4.
Fig. 4. Confocal phase images of (a)–(d) normal adjacent breast and (e)–(h) histologic specimen corresponding to phase. Confocal phase imaging of (i)–(l) invasive ductal carcinoma and (m)–(p) corresponding H&E image. Scale bar applies to entire column (core-level, medium zoom, high zoom setting). Numerical aperture (NA): 0.40 (confocal phase), 0.75 (H&E).
Fig. 5.
Fig. 5. Confocal phase images of (a), (b) cancer adjacent prostate and (c), (d) corresponding H&E image. Confocal phase imaging of (e), (f) adenocarcinoma lesion in prostate and (g), (h) corresponding H&E image. Numerical aperture (NA): 0.40 (confocal phase), 0.75 (H&E).

Equations (3)

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I Δ φ C F ( x , y ) = n = x , y , z | E n O B J ( x , y ) + e i Δ φ E n R E F | 2 ,
I Δ φ W F ( x , y ) = s x , s y n = x , y , z | E n , s x , s y O B J ( x , y ) + e i Δ φ E n , s x , s y R E F ( x , y ) | 2 ,
φ = a t a n 2 ( I 90 I 270 , I 0 I 180 ) ,