Abstract

Quantitative phase imaging (QPI) is an important tool in biomedicine that allows for the microscopic investigation of live cells and other thin, transparent samples. Importantly, this technology yields access to the cellular and sub-cellular structure and activity at nanometer scales without labels or dyes. Despite this unparalleled ability, QPI’s restriction to relatively thin samples severely hinders its versatility and overall utility in biomedicine. Here we overcome this significant limitation of QPI to enable the same rich level of quantitative detail in thick scattering samples. We achieve this by first illuminating the sample in an epi-mode configuration and using multiple scattering within the sample—a hindrance to conventional transmission imaging used in QPI—as a source of transmissive illumination from within. Second, we quantify phase via deconvolution by modeling the transfer function of the system based on the ensemble average angular distribution of light illuminating the sample at the focal plane. This technique packages the quantitative, real-time sub-cellular imaging capabilities of QPI into a flexible configuration, opening the door for truly non-invasive, label-free, tomographic quantitative phase imaging of unaltered thick, scattering specimens. Images of controlled scattering phantoms, blood in collection bags, cerebral organoids and freshly excised whole mouse brains are presented to validate the approach.

© 2019 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

Full Article  |  PDF Article
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References

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2019 (1)

S. Liu, Z. Deng, J. Li, J. Wang, N. Huang, R. Cui, Q. Zhang, J. Mei, W. Zhou, C. Zhang, Q. Ye, and J. Tian, “Measurement of the refractive index of whole blood and its components for a continuous spectral region,” J. Biomed. Opt. 24, 1 (2019).

2018 (4)

2017 (3)

2016 (4)

H. Lu, J. Chung, X. Ou, and C. Yang, “Quantitative phase imaging and complex field reconstruction by pupil modulation differential phase contrast,” Opt. Express 24, 25345 (2016).
[Crossref] [PubMed]

N. Ji, J. Freeman, and S. L. Smith, “Technologies for imaging neural activity in large volumes,” Nat. Neurosci. 19, 1154–1164 (2016).
[Crossref] [PubMed]

E. L. Jackson and H. Lu, “Three-dimensional models for studying development and disease: moving on from organisms to organs-on-a-chip and organoids,” Integr. Biol. 8, 672–683 (2016).
[Crossref]

X. Qian, H. N. Nguyen, M. M. Song, C. Hadiono, S. C. Ogden, C. Hammack, B. Yao, G. R. Hamersky, F. Jacob, C. Zhong, K.-J. Yoon, W. Jeang, L. Lin, Y. Li, J. Thakor, D. A. Berg, C. Zhang, E. Kang, M. Chickering, D. Nauen, C.-Y. Ho, Z. Wen, K. M. Christian, P.-Y. Shi, B. J. Maher, H. Wu, P. Jin, H. Tang, H. Song, and G.-l. Ming, “Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure,” Cell 165, 1238–1254 (2016).
[Crossref] [PubMed]

2015 (2)

J. Mariani, G. Coppola, P. Zhang, A. Abyzov, L. Provini, L. Tomasini, M. Amenduni, A. Szekely, D. Palejev, M. Wilson, M. Gerstein, E. L. Grigorenko, K. Chawarska, K. A. Pelphrey, J. R. Howe, and F. M. Vaccarino, “FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders,” Cell 162, 375–390 (2015).
[Crossref] [PubMed]

L. Tian and L. Waller, “Quantitative differential phase contrast imaging in an LED array microscope,” Opt. Express 23, 11394 (2015).
[Crossref] [PubMed]

2014 (4)

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]

J. David Giese, T. N. Ford, and J. Mertz, “Fast volumetric phase-gradient imaging in thick samples,” Opt. Express 22, 1152 (2014).
[Crossref] [PubMed]

M. A. Lancaster and J. A. Knoblich, “Organogenesis in a dish: Modeling development and disease using organoid technologies,” Science 345, 1247125 (2014).
[Crossref] [PubMed]

J. Mertz, A. Gasecka, A. Daradich, I. Davison, and D. Coté, “Phase-gradient contrast in thick tissue with a scanning microscope,” Biomed. Opt. Express 5, 407 (2014).
[Crossref] [PubMed]

2013 (2)

T. Bart, M. Boo, S. Balabanova, Y. Fischer, G. Nicoloso, L. Foeken, M. Oudshoorn, J. Passweg, A. Tichelli, V. Kindler, J. Kurtzberg, T. Price, D. Regan, E. J. Shpall, and R. Schwabe, “Impact of selection of cord blood units from the united states and swiss registries on the cost of banking operations,” Transfus. Medicine Hemotherapy 40(1), 14–20 (2013).
[Crossref]

M. Gao, X. Huang, P. Yang, and G. W. Kattawar, “Angular distribution of diffuse reflectance from incoherent multiple scattering in turbid media,” Appl. Opt. 52, 5869 (2013).
[Crossref] [PubMed]

2012 (2)

M. Mir, B. Bhaduri, R. Wang, R. Zhu, and G. Popescu, “Quantitative Phase Imaging,” Prog. Opt. 57, 133–217 (2012).
[Crossref]

T. N. Ford, K. K. Chu, and J. Mertz, “Phase-gradient microscopy in thick tissue with oblique back-illumination,” Nat. Methods 9, 1195–1197 (2012).
[Crossref] [PubMed]

2011 (1)

D. B. Kim-Shapiro, J. Lee, and M. T. Gladwin, “Storage lesion: role of red blood cell breakdown,” Transfusion 51, 844–851 (2011).
[Crossref] [PubMed]

2009 (2)

2008 (2)

2007 (2)

M. Meinke, G. Müller, J. Helfmann, and M. Friebel, “Empirical model functions to calculate hematocrit-dependent optical properties of human blood,” Appl. Opt. 46, 1742 (2007).
[Crossref] [PubMed]

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

2006 (1)

A. J. North, “Seeing is believing? A beginners’ guide to practical pitfalls in image acquisition,” The J. Cell Biol. 172, 9–18 (2006).
[Crossref]

2004 (1)

M. R. Arnison, K. G. Larkin, C. J. R. Sheppard, N. I. Smith, and C. J. Cogswell, “Linear phase imaging using differential interference contrast microscopy,” J. Microsc. 214, 7–12 (2004).
[Crossref] [PubMed]

2002 (2)

A. N. Yaroslavsky, P. C. Schulze, I. V. Yaroslavsky, R. Schober, F. Ulrich, and H. J. Schwarzmaier, “Optical properties of selected native and coagulated human brain tissues in vitro in the visible and near infrared spectral range,” Phys. Medicine Biol. 47, 2059–2073 (2002).
[Crossref]

S. González and Z. Tannous, “Real-time, in vivo confocal reflectance microscopy of basal cell carcinoma,” J. Am. Acad. Dermatol. 47, 869–874 (2002).
[Crossref] [PubMed]

1999 (1)

W. M. White, M. Rajadhyaksha, S. González, R. L. Fabian, and R. R. Anderson, “Noninvasive Imaging of Human Oral Mucosa in Vivo by Confocal Reflectance Microscopy,” Laryngoscope 109, 1709–1717 (1999).
[Crossref] [PubMed]

1997 (1)

1991 (1)

D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, and C. A. Puliafito, “Optical coherence tomography,” Sci. (New York, N.Y.) 254, 1178–1181 (1991).
[Crossref]

1985 (1)

1984 (1)

D. K. Hamilton and C. J. R. Sheppard, “Differential phase contrast in scanning optical microscopy,” J. Microsc. 133, 27–39 (1984).
[Crossref]

1981 (1)

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

1978 (1)

C. Sheppard and T. Wilson, “Image Formation in Scanning Microscopes with Partially Coherent Source and Detector,” Opt. Acta Int. J. Opt. 25, 315–325 (1978).
[Crossref]

1977 (2)

C. Sheppard and A. Choudhury, “Image Formation in the Scanning Microscope,” Opt. Acta Int. J. Opt. 24, 1051–1073 (1977).
[Crossref]

G. Wahba, “Practical Approximate Solutions to Linear Operator Equations when the Data are Noisy,” SIAM J. Numer. Analysis 14, 651–667 (1977).
[Crossref]

1972 (1)

E. Evans and Y.-C. Fung, “Improved measurements of the erythrocyte geometry,” Microvasc. Res. 4, 335–347 (1972).
[Crossref] [PubMed]

1955 (1)

F. Zernike, “How I discovered phase contrast,” Science 121, 345–349 (1955).
[Crossref] [PubMed]

1953 (1)

H. H. Hopkins, “On the Diffraction Theory of Optical Images,” Proc. Royal Soc. A Math. Phys. Eng. Sci. 217, 408–432 (1953).
[Crossref]

Abyzov, A.

J. Mariani, G. Coppola, P. Zhang, A. Abyzov, L. Provini, L. Tomasini, M. Amenduni, A. Szekely, D. Palejev, M. Wilson, M. Gerstein, E. L. Grigorenko, K. Chawarska, K. A. Pelphrey, J. R. Howe, and F. M. Vaccarino, “FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders,” Cell 162, 375–390 (2015).
[Crossref] [PubMed]

Amenduni, M.

J. Mariani, G. Coppola, P. Zhang, A. Abyzov, L. Provini, L. Tomasini, M. Amenduni, A. Szekely, D. Palejev, M. Wilson, M. Gerstein, E. L. Grigorenko, K. Chawarska, K. A. Pelphrey, J. R. Howe, and F. M. Vaccarino, “FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders,” Cell 162, 375–390 (2015).
[Crossref] [PubMed]

Anderson, R. R.

W. M. White, M. Rajadhyaksha, S. González, R. L. Fabian, and R. R. Anderson, “Noninvasive Imaging of Human Oral Mucosa in Vivo by Confocal Reflectance Microscopy,” Laryngoscope 109, 1709–1717 (1999).
[Crossref] [PubMed]

Arikkath, J.

T. H. Nguyen, M. Kandel, H. M. Shakir, C. Best-Popescu, J. Arikkath, M. N. Do, and G. Popescu, “Halo-free Phase Contrast Microscopy,” Nat. Publ. Group (2017).

Arnison, M. R.

M. R. Arnison, K. G. Larkin, C. J. R. Sheppard, N. I. Smith, and C. J. Cogswell, “Linear phase imaging using differential interference contrast microscopy,” J. Microsc. 214, 7–12 (2004).
[Crossref] [PubMed]

Balabanova, S.

T. Bart, M. Boo, S. Balabanova, Y. Fischer, G. Nicoloso, L. Foeken, M. Oudshoorn, J. Passweg, A. Tichelli, V. Kindler, J. Kurtzberg, T. Price, D. Regan, E. J. Shpall, and R. Schwabe, “Impact of selection of cord blood units from the united states and swiss registries on the cost of banking operations,” Transfus. Medicine Hemotherapy 40(1), 14–20 (2013).
[Crossref]

Bart, T.

T. Bart, M. Boo, S. Balabanova, Y. Fischer, G. Nicoloso, L. Foeken, M. Oudshoorn, J. Passweg, A. Tichelli, V. Kindler, J. Kurtzberg, T. Price, D. Regan, E. J. Shpall, and R. Schwabe, “Impact of selection of cord blood units from the united states and swiss registries on the cost of banking operations,” Transfus. Medicine Hemotherapy 40(1), 14–20 (2013).
[Crossref]

Bass, M.

M. Bass, C. DeCusatis, J. Enoch, V. Lakshminarayanan, G. Li, C. Macdonald, V. Mahajan, and E. Van Stryland, Handbook of Optics, Third Edition Volume I: Geometrical and Physical Optics, Polarized Light, Components and Instruments(Set) (McGraw-Hill, Inc., 2010), 3rd ed.

Berg, D. A.

X. Qian, H. N. Nguyen, M. M. Song, C. Hadiono, S. C. Ogden, C. Hammack, B. Yao, G. R. Hamersky, F. Jacob, C. Zhong, K.-J. Yoon, W. Jeang, L. Lin, Y. Li, J. Thakor, D. A. Berg, C. Zhang, E. Kang, M. Chickering, D. Nauen, C.-Y. Ho, Z. Wen, K. M. Christian, P.-Y. Shi, B. J. Maher, H. Wu, P. Jin, H. Tang, H. Song, and G.-l. Ming, “Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure,” Cell 165, 1238–1254 (2016).
[Crossref] [PubMed]

Bertero, M.

M. Bertero and P. Boccacci, Introduction to inverse problems in imaging (Institute of Physics Pub, 1998).
[Crossref]

Best-Popescu, C.

T. H. Nguyen, M. Kandel, H. M. Shakir, C. Best-Popescu, J. Arikkath, M. N. Do, and G. Popescu, “Halo-free Phase Contrast Microscopy,” Nat. Publ. Group (2017).

Bhaduri, B.

M. Mir, B. Bhaduri, R. Wang, R. Zhu, and G. Popescu, “Quantitative Phase Imaging,” Prog. Opt. 57, 133–217 (2012).
[Crossref]

Bhatia, A. B.

M. Born, E. Wolf, A. B. Bhatia, P. C. Clemmow, D. Gabor, A. R. Stokes, A. M. Taylor, P. A. Wayman, and W. L. Wilcock, Principles of Optics (Cambridge University Press, Cambridge, 1999).
[Crossref]

Boas, D. A.

Boccacci, P.

M. Bertero and P. Boccacci, Introduction to inverse problems in imaging (Institute of Physics Pub, 1998).
[Crossref]

Boo, M.

T. Bart, M. Boo, S. Balabanova, Y. Fischer, G. Nicoloso, L. Foeken, M. Oudshoorn, J. Passweg, A. Tichelli, V. Kindler, J. Kurtzberg, T. Price, D. Regan, E. J. Shpall, and R. Schwabe, “Impact of selection of cord blood units from the united states and swiss registries on the cost of banking operations,” Transfus. Medicine Hemotherapy 40(1), 14–20 (2013).
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J. Mariani, G. Coppola, P. Zhang, A. Abyzov, L. Provini, L. Tomasini, M. Amenduni, A. Szekely, D. Palejev, M. Wilson, M. Gerstein, E. L. Grigorenko, K. Chawarska, K. A. Pelphrey, J. R. Howe, and F. M. Vaccarino, “FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders,” Cell 162, 375–390 (2015).
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Van Stryland, E.

M. Bass, C. DeCusatis, J. Enoch, V. Lakshminarayanan, G. Li, C. Macdonald, V. Mahajan, and E. Van Stryland, Handbook of Optics, Third Edition Volume I: Geometrical and Physical Optics, Polarized Light, Components and Instruments(Set) (McGraw-Hill, Inc., 2010), 3rd ed.

Vera, M. U.

Wahba, G.

G. Wahba, “Practical Approximate Solutions to Linear Operator Equations when the Data are Noisy,” SIAM J. Numer. Analysis 14, 651–667 (1977).
[Crossref]

Waller, L.

Wang, J.

S. Liu, Z. Deng, J. Li, J. Wang, N. Huang, R. Cui, Q. Zhang, J. Mei, W. Zhou, C. Zhang, Q. Ye, and J. Tian, “Measurement of the refractive index of whole blood and its components for a continuous spectral region,” J. Biomed. Opt. 24, 1 (2019).

Wang, R.

M. Mir, B. Bhaduri, R. Wang, R. Zhu, and G. Popescu, “Quantitative Phase Imaging,” Prog. Opt. 57, 133–217 (2012).
[Crossref]

Wayman, P. A.

M. Born, E. Wolf, A. B. Bhatia, P. C. Clemmow, D. Gabor, A. R. Stokes, A. M. Taylor, P. A. Wayman, and W. L. Wilcock, Principles of Optics (Cambridge University Press, Cambridge, 1999).
[Crossref]

Wen, Z.

X. Qian, H. N. Nguyen, M. M. Song, C. Hadiono, S. C. Ogden, C. Hammack, B. Yao, G. R. Hamersky, F. Jacob, C. Zhong, K.-J. Yoon, W. Jeang, L. Lin, Y. Li, J. Thakor, D. A. Berg, C. Zhang, E. Kang, M. Chickering, D. Nauen, C.-Y. Ho, Z. Wen, K. M. Christian, P.-Y. Shi, B. J. Maher, H. Wu, P. Jin, H. Tang, H. Song, and G.-l. Ming, “Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure,” Cell 165, 1238–1254 (2016).
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Wheeler, M. B.

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, 210 (2017).
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White, W. M.

W. M. White, M. Rajadhyaksha, S. González, R. L. Fabian, and R. R. Anderson, “Noninvasive Imaging of Human Oral Mucosa in Vivo by Confocal Reflectance Microscopy,” Laryngoscope 109, 1709–1717 (1999).
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Wilcock, W. L.

M. Born, E. Wolf, A. B. Bhatia, P. C. Clemmow, D. Gabor, A. R. Stokes, A. M. Taylor, P. A. Wayman, and W. L. Wilcock, Principles of Optics (Cambridge University Press, Cambridge, 1999).
[Crossref]

Wilson, M.

J. Mariani, G. Coppola, P. Zhang, A. Abyzov, L. Provini, L. Tomasini, M. Amenduni, A. Szekely, D. Palejev, M. Wilson, M. Gerstein, E. L. Grigorenko, K. Chawarska, K. A. Pelphrey, J. R. Howe, and F. M. Vaccarino, “FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders,” Cell 162, 375–390 (2015).
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Wilson, T.

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

C. Sheppard and T. Wilson, “Image Formation in Scanning Microscopes with Partially Coherent Source and Detector,” Opt. Acta Int. J. Opt. 25, 315–325 (1978).
[Crossref]

Wolf, E.

M. Born, E. Wolf, A. B. Bhatia, P. C. Clemmow, D. Gabor, A. R. Stokes, A. M. Taylor, P. A. Wayman, and W. L. Wilcock, Principles of Optics (Cambridge University Press, Cambridge, 1999).
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Wu, H.

X. Qian, H. N. Nguyen, M. M. Song, C. Hadiono, S. C. Ogden, C. Hammack, B. Yao, G. R. Hamersky, F. Jacob, C. Zhong, K.-J. Yoon, W. Jeang, L. Lin, Y. Li, J. Thakor, D. A. Berg, C. Zhang, E. Kang, M. Chickering, D. Nauen, C.-Y. Ho, Z. Wen, K. M. Christian, P.-Y. Shi, B. J. Maher, H. Wu, P. Jin, H. Tang, H. Song, and G.-l. Ming, “Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure,” Cell 165, 1238–1254 (2016).
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Yang, C.

Yang, P.

Yao, B.

X. Qian, H. N. Nguyen, M. M. Song, C. Hadiono, S. C. Ogden, C. Hammack, B. Yao, G. R. Hamersky, F. Jacob, C. Zhong, K.-J. Yoon, W. Jeang, L. Lin, Y. Li, J. Thakor, D. A. Berg, C. Zhang, E. Kang, M. Chickering, D. Nauen, C.-Y. Ho, Z. Wen, K. M. Christian, P.-Y. Shi, B. J. Maher, H. Wu, P. Jin, H. Tang, H. Song, and G.-l. Ming, “Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure,” Cell 165, 1238–1254 (2016).
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Yaroslavsky, A. N.

A. N. Yaroslavsky, P. C. Schulze, I. V. Yaroslavsky, R. Schober, F. Ulrich, and H. J. Schwarzmaier, “Optical properties of selected native and coagulated human brain tissues in vitro in the visible and near infrared spectral range,” Phys. Medicine Biol. 47, 2059–2073 (2002).
[Crossref]

Yaroslavsky, I. V.

A. N. Yaroslavsky, P. C. Schulze, I. V. Yaroslavsky, R. Schober, F. Ulrich, and H. J. Schwarzmaier, “Optical properties of selected native and coagulated human brain tissues in vitro in the visible and near infrared spectral range,” Phys. Medicine Biol. 47, 2059–2073 (2002).
[Crossref]

Ye, Q.

S. Liu, Z. Deng, J. Li, J. Wang, N. Huang, R. Cui, Q. Zhang, J. Mei, W. Zhou, C. Zhang, Q. Ye, and J. Tian, “Measurement of the refractive index of whole blood and its components for a continuous spectral region,” J. Biomed. Opt. 24, 1 (2019).

Yoon, K.-J.

X. Qian, H. N. Nguyen, M. M. Song, C. Hadiono, S. C. Ogden, C. Hammack, B. Yao, G. R. Hamersky, F. Jacob, C. Zhong, K.-J. Yoon, W. Jeang, L. Lin, Y. Li, J. Thakor, D. A. Berg, C. Zhang, E. Kang, M. Chickering, D. Nauen, C.-Y. Ho, Z. Wen, K. M. Christian, P.-Y. Shi, B. J. Maher, H. Wu, P. Jin, H. Tang, H. Song, and G.-l. Ming, “Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure,” Cell 165, 1238–1254 (2016).
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F. Zernike, “How I discovered phase contrast,” Science 121, 345–349 (1955).
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Zhang, C.

S. Liu, Z. Deng, J. Li, J. Wang, N. Huang, R. Cui, Q. Zhang, J. Mei, W. Zhou, C. Zhang, Q. Ye, and J. Tian, “Measurement of the refractive index of whole blood and its components for a continuous spectral region,” J. Biomed. Opt. 24, 1 (2019).

X. Qian, H. N. Nguyen, M. M. Song, C. Hadiono, S. C. Ogden, C. Hammack, B. Yao, G. R. Hamersky, F. Jacob, C. Zhong, K.-J. Yoon, W. Jeang, L. Lin, Y. Li, J. Thakor, D. A. Berg, C. Zhang, E. Kang, M. Chickering, D. Nauen, C.-Y. Ho, Z. Wen, K. M. Christian, P.-Y. Shi, B. J. Maher, H. Wu, P. Jin, H. Tang, H. Song, and G.-l. Ming, “Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure,” Cell 165, 1238–1254 (2016).
[Crossref] [PubMed]

Zhang, J.

Zhang, P.

J. Mariani, G. Coppola, P. Zhang, A. Abyzov, L. Provini, L. Tomasini, M. Amenduni, A. Szekely, D. Palejev, M. Wilson, M. Gerstein, E. L. Grigorenko, K. Chawarska, K. A. Pelphrey, J. R. Howe, and F. M. Vaccarino, “FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders,” Cell 162, 375–390 (2015).
[Crossref] [PubMed]

Zhang, Q.

S. Liu, Z. Deng, J. Li, J. Wang, N. Huang, R. Cui, Q. Zhang, J. Mei, W. Zhou, C. Zhang, Q. Ye, and J. Tian, “Measurement of the refractive index of whole blood and its components for a continuous spectral region,” J. Biomed. Opt. 24, 1 (2019).

Zhong, C.

X. Qian, H. N. Nguyen, M. M. Song, C. Hadiono, S. C. Ogden, C. Hammack, B. Yao, G. R. Hamersky, F. Jacob, C. Zhong, K.-J. Yoon, W. Jeang, L. Lin, Y. Li, J. Thakor, D. A. Berg, C. Zhang, E. Kang, M. Chickering, D. Nauen, C.-Y. Ho, Z. Wen, K. M. Christian, P.-Y. Shi, B. J. Maher, H. Wu, P. Jin, H. Tang, H. Song, and G.-l. Ming, “Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure,” Cell 165, 1238–1254 (2016).
[Crossref] [PubMed]

Zhou, W.

S. Liu, Z. Deng, J. Li, J. Wang, N. Huang, R. Cui, Q. Zhang, J. Mei, W. Zhou, C. Zhang, Q. Ye, and J. Tian, “Measurement of the refractive index of whole blood and its components for a continuous spectral region,” J. Biomed. Opt. 24, 1 (2019).

Zhu, R.

M. Mir, B. Bhaduri, R. Wang, R. Zhu, and G. Popescu, “Quantitative Phase Imaging,” Prog. Opt. 57, 133–217 (2012).
[Crossref]

Zuo, C.

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[Crossref] [PubMed]

X. Qian, H. N. Nguyen, M. M. Song, C. Hadiono, S. C. Ogden, C. Hammack, B. Yao, G. R. Hamersky, F. Jacob, C. Zhong, K.-J. Yoon, W. Jeang, L. Lin, Y. Li, J. Thakor, D. A. Berg, C. Zhang, E. Kang, M. Chickering, D. Nauen, C.-Y. Ho, Z. Wen, K. M. Christian, P.-Y. Shi, B. J. Maher, H. Wu, P. Jin, H. Tang, H. Song, and G.-l. Ming, “Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure,” Cell 165, 1238–1254 (2016).
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Figures (6)

Fig. 1
Fig. 1 (a) Diagram of qOBM assembly. Four LEDs, two red (630 nm) and two green (530 nm), sequentially illuminate the target from some distance off axis and at some angle (45° in this work), and an image is produced with an inverted microscope. (b) Top-down view of imaging apparatus indicating the entry positions of the four LEDs. (c) Representative photon visitation in the source-detector plane. (d) Example angular distribution overlaid on a unit sphere, which is smoothed and projected onto a flat surface to produce (e) the effective source distribution in spatial frequency space. (f) The effective optical transfer function of the difference image.
Fig. 2
Fig. 2 Representative images of unsectioned mouse cortex in a diagram demonstrating the qOBM process. (a,b) Red and green captured images. (c,d) DPC images produced from left and right illumination, representing images formed with conventional OBM. (e,f) Images of quantitative phase produced from only an individual pair of LED illuminations. Note the lack of structured detail in one dimension. (g) Final qOBM image produced as a composite of of the deconvolved DPC images from two orthogonal dimensions. Note the high level of detail, allowing for the detection of subtle features not present in either individual illumination. The scale bars in all images represent 25 μm.
Fig. 3
Fig. 3 (a) Relief depiction of qOBM image of lithography target. (b) Cross-section of phase image through the top 6 letters (blue) with actual height overlaid (black dashed). (c) qOBM image of several 2μm polystyrene beads immersed in a well of oil beneath an intralipid scattering phantom. (c inset) Phase reconstruction from simulated image of a 2μm polystyrene bead in oil. (d) The average height from cross-sections of 20 imaged beads (blue, standard deviation shaded), overlaid with the simulated phase recovery (orange), and ideal height (black dashed).
Fig. 4
Fig. 4 (a) Sterile bag with diluted blood (b) qOBM image of blood cells in the bag from a patient with sickle-cell disease (b inset) Profile of n=20 healthy RBCs from the same image (blue), simulated RBC (red) and ideal (dashed black). (c) Relief image showing optical volume differences in blood cell contents.
Fig. 5
Fig. 5 (a) Maximum-intensity projection of a 60 μm vertical stack of qOBM images of blood vessel in unsectioned mouse cortex. (b) Representative images from the stack (lateral dimensions are 250μm x 250μm). (c) Blood vessel, with red blood cells and nearby brain cells in unsectioned cortex. Color bar above c applies to c and e. (d) Descending capillary, axons, and myelin nodes from coronal section. Color bar above d applies to d and f. (e) Neuron soma with internal structures visible from unsectioned cortex. (f) Axonal projections from white matter in coronal section.
Fig. 6
Fig. 6 Sequential depth sections of 26 day-old cerebral organoid. Total field of view is shown in the bottom row, and selected regions are enlarged above. Depth is indicated above each enlarged region. (a,b) Depict neuroblasts and immature neurons before they have developed characteristic axonal or dendritic processes. (c,d) Mature neurons with characteristic shape with internal cell contents discernible within the soma. (e) The characteristic “rosette” shape formed by neural progenitor cells that develop and grow radially. Scale bar is 100μm.

Equations (29)

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

I DPC = I L I R I L + I R
I ( r ) = | 1 { P ( f ) { o ( x ) 1 { E ( u ) } } } | 2
I ( r ) = S ( u ) | P ( f ) [ o ( x ) e i 2 π ( f u ) x d 2 x ] e i 2 π ( f r ) d 2 f | 2 d 2 u
I ( r ) = O ( m ) O * ( n ) C ( m , n ) exp ( i 2 π ( r ( m n ) ) ) d 2 m d 2 n
C ( m , n ) = S ( u ) P ( m + u ) P * ( n + u ) d 2 u
o ( x ) = exp ( μ ( x ) + i ϕ ( x ) ) 1 μ ( x ) + i ϕ ( x )
O ( m ) = δ ( m ) M ( m ) + i Φ ( m )
O ( m ) O * ( n ) δ ( m ) δ ( n ) [ M ( m ) δ ( n ) + M * ( n ) δ ( m ) ] + i [ Φ ( m ) δ ( n ) Φ * ( n ) δ ( m ) ]
C Δ ( m ) = [ S ( u ) P ( m + u ) P * ( u ) d 2 u S ( u ) P ( m + u ) P * ( u ) d 2 u ]
I DPC ( r ) = 1 { C Δ ( m ) C ( 0 , 0 ) i Φ ( m ) } = Im { c δ ( r ) } * ϕ ( r ) C ( 0 , 0 )
ϕ = 1 { k λ 0 λ k I ˜ DPC k C DPC * k | C D P C | 2 + α }
α = argmin { V ( α ) } , with
V ( α ) = ( A f g ) 2 Trace [ I A ( α ) ] 2
I ( r ) = | E ( u ) o ( x ) P ( f ) e i 2 π ( u x ) e i 2 π ( x f ) e i 2 π ( f r ) d 2 u d 2 x d 2 f | 2 .
I ( r ) = S ( u ) | P ( f ) o ( x ) e i 2 π [ ( f u ) x + f r ] d 2 x d 2 f | 2 d 2 u
I ( r ) = S ( u ) | P ( m + u ) [ o ( x ) e i 2 π ( m x ) d 2 x ] e i 2 π ( f r ) d 2 f | 2 d 2 u = S ( u ) | P ( m + u ) O ( m ) e i 2 π ( ( m + u ) r ) d 2 m | 2 d 2 u .
I ( r ) = O ( m ) O * ( n ) [ S ( u ) P ( m + u ) P * ( n + u ) d 2 u ] e i 2 π ( ( m n ) r ) d 2 m d 2 n .
I ( r ) = O ( m ) O * ( m q ) C ( m , m q ) e i 2 π ( q r ) d 2 m d 2 r .
I ˜ ( q ) = O ( m ) O * ( m q ) C ( m , m q ) d 2 m ,
O ( m ) O * ( n ) = δ ( m ) δ ( n ) = [ M ( m ) δ ( n ) + M * ( n ) δ ( m ) ] + i [ Φ ( m ) δ ( n ) Φ * ( n ) δ ( m ) ] + i [ M ( m ) Φ * ( n ) M * ( n ) Φ ( m ) ] + M ( m ) M * ( n ) + Φ ( m ) Φ * ( n ) .
I ˜ ( q ) = δ ( q ) C ( 0 , q ) [ M ( q ) C ( q , 0 ) + M * ( q ) C ( 0 , q ) ] + i [ Φ ( q ) C ( q , 0 ) Φ * ( q ) C ( 0 , q ) ] .
C Δ ( q ) = [ S ( u ) S ( u ) ] P ( u + q ) P * ( u ) d 2 u , and
C Σ ( q ) = [ S ( u ) + S ( u ) ] P ( u + q ) P * ( u ) d 2 u ,
I ˜ Δ ( q ) = C Δ ( q ) δ ( q ) C Δ ( q ) [ M ( q ) M * ( q ) ] + i C Δ ( q ) [ Φ ( q ) + Φ * ( q ) ]
I ˜ Σ ( q ) = C Σ ( q ) δ ( q ) C Σ ( q ) [ M ( q ) + M * ( q ) ] + i C Σ ( q ) [ Φ ( q ) Φ * ( q ) ] .
I Δ ( r ) = 2 i c δ ( r ) * ϕ ( r ) .
I Σ ( r ) = 2 C ( 0 , 0 ) 2 c σ ( r ) * μ ( r ) ,
I DPC ( r ) = i c δ ( r ) * ϕ ( r ) C ( 0 , 0 ) c σ ( r ) * μ ( r ) i c δ ( r ) * ϕ ( r ) C ( 0 , 0 ) .
C DPC ( q ) = i [ S ( u ) S ( u ) ] P ( u + q ) P * ( u ) d 2 u S ( u ) P ( u ) P * ( u ) d 2 u .

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