Abstract

Super-resolution fluorescence microscopy is an important tool in biomedical research for its ability to discern features smaller than the diffraction limit. However, due to its difficult implementation and high cost, the super-resolution microscopy is not feasible in many applications. In this paper, we propose and demonstrate a saturation-based super-resolution fluorescence microscopy technique that can be easily implemented and requires neither additional hardware nor complex post-processing. The method is based on the principle of stepwise optical saturation (SOS), where M steps of raw fluorescence images are linearly combined to generate an image with a M-fold increase in resolution compared with conventional diffraction-limited images. For example, linearly combining (scaling and subtracting) two images obtained at regular powers extends the resolution by a factor of 1.4 beyond the diffraction limit. The resolution improvement in SOS microscopy is theoretically infinite but practically is limited by the signal-to-noise ratio. We perform simulations and experimentally demonstrate super-resolution microscopy with both one-photon (confocal) and multiphoton excitation fluorescence. We show that with the multiphoton modality, the SOS microscopy can provide super-resolution imaging deep in scattering samples.

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

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2017 (5)

2016 (4)

Y. Zhang, A. A. Khan, G. D. Vigil, and S. S. Howard, “Investigation of signal-to-noise ratio in frequency-domain multiphoton fluorescence lifetime imaging microscopy,” J. Opt. Soc. Am. A 33, B1–B11 (2016).
[Crossref]

P. D. Nallathamby, J. Hopf, L. E. Irimata, T. L. McGinnity, and R. K. Roeder, “Preparation of fluorescent Au-SiO2 core-shell nanoparticles and nanorods with tunable silica shell thickness and surface modification for immunotargeting,” J. Mater. Chem. B 4, 5418–5428 (2016).
[Crossref]

J. J. Field, K. A. Wernsing, S. R. Domingue, A. M. Allende Motz, K. F. DeLuca, D. H. Levi, J. G. DeLuca, M. D. Young, J. A. Squier, and R. A. Bartels, “Superresolved multiphoton microscopy with spatial frequency-modulated imaging,” Proc. Natl. Acad. Sci. USA 113, 6605–6610 (2016).
[Crossref] [PubMed]

N. S. Alexander, G. Palczewska, P. Stremplewski, M. Wojtkowski, T. S. Kern, and K. Palczewski, “Image registration and averaging of low laser power two-photon fluorescence images of mouse retina,” Biomed. Opt. Express 7, 2671–2691 (2016).
[Crossref] [PubMed]

2015 (3)

A. D. Nguyen, F. Duport, A. Bouwens, F. Vanholsbeeck, D. Egrise, G. Van Simaeys, P. Emplit, S. Goldman, and S.-P. Gorza, “3D super-resolved in vitro multiphoton microscopy by saturation of excitation,” Opt. Express 23, 22667–22675 (2015).
[Crossref] [PubMed]

P. D. Nallathamby, N. P. Mortensen, H. A. Palko, M. Malfatti, C. Smith, J. Sonnett, M. J. Doktycz, B. Gu, R. K. Roeder, W. Wang, and S. T. Retterer, “New surface radiolabeling schemes of super paramagnetic iron oxide nanoparticles (SPIONs) for biodistribution studies,” Nanoscale 7, 6545–6555 (2015).
[Crossref] [PubMed]

K. Yoshida, I. Nishidate, T. Ishizuka, S. Kawauchi, S. Sato, and M. Sato, “Multispectral imaging of absorption and scattering properties of in vivo exposed rat brain using a digital red-green-blue camera,” J. Biomed. Opt. 20, 051026 (2015).
[Crossref] [PubMed]

2014 (2)

2013 (3)

E. E. Hoover and J. A. Squier, “Advances in multiphoton microscopy technology,” Nat. Photonics 7, 93–101 (2013).
[Crossref] [PubMed]

C. Kuang, S. Li, W. Liu, X. Hao, Z. Gu, Y. Wang, J. Ge, H. Li, and X. Liu, “Breaking the diffraction barrier using fluorescence emission difference microscopy,” Sci. Rep. 3, 1441 (2013).
[Crossref] [PubMed]

W. Wang, P. D. Nallathamby, C. M. Foster, J. L. Morrell-Falvey, N. P. Mortensen, M. J. Doktycz, B. Gu, and S. T. Retterer, “Volume labeling with Alexa Fluor dyes and surface functionalization of highly sensitive fluorescent silica (SiO2) nanoparticles,” Nanoscale 5, 10369–10375 (2013).
[Crossref] [PubMed]

2011 (1)

E. Gatzogiannis, X. Zhu, Y.-T. Kao, and W. Min, “Observation of frequency-domain fluorescence anomalous phase advance due to dark-state hysteresis,” J. Phys. Chem. Lett. 2, 461–466 (2011).
[Crossref]

2009 (3)

T. Z. Veres, M. Shevchenko, G. Krasteva, E. Spies, F. Prenzler, S. Rochlitzer, T. Tschernig, N. Krug, W. Kummer, and A. Braun, “Dendritic cell-nerve clusters are sites of T cell proliferation in allergic airway inflammation,” Am. J. Pathol. 174, 808–817 (2009).
[Crossref] [PubMed]

J. Humpolíčková, A. Benda, and J. Enderlein, “Optical saturation as a versatile tool to enhance resolution in confocal microscopy,” Biophys. J. 97, 2623–2629 (2009).
[Crossref]

E. Rittweger, K. Y. Han, S. E. Irvine, C. Eggeling, and S. W. Hell, “STED microscopy reveals crystal colour centres with nanometric resolution,” Nat. Photonics 3, 144–147 (2009).
[Crossref]

2008 (1)

J. Vogelsang, R. Kasper, C. Steinhauer, B. Person, M. Heilemann, M. Sauer, and P. Tinnefeld, “A reducing and oxidizing system minimizes photobleaching and blinking of fluorescent dyes,” Angew. Chem. Int. Ed. 47, 5465–5469 (2008).
[Crossref]

2007 (2)

K. Fujita, M. Kobayashi, S. Kawano, M. Yamanaka, and S. Kawata, “High-resolution confocal microscopy by saturated excitation of fluorescence,” Phys. Rev. Lett. 99, 228105 (2007).
[Crossref]

S. W. Hell, “Far-field optical nanoscopy,” Science 316, 1153–1158 (2007).
[Crossref] [PubMed]

2006 (3)

E. Betzig, G. H. Patterson, R. Sougrat, O. W. Lindwasser, S. Olenych, J. S. Bonifacino, M. W. Davidson, J. Lippincott-Schwartz, and H. F. Hess, “Imaging intracellular fluorescent proteins at nanometer resolution,” Science 313, 1642–1645 (2006).
[Crossref] [PubMed]

M. J. Rust, M. Bates, and X. Zhuang, “Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM),” Nat. Methods 3, 793–796 (2006).
[Crossref] [PubMed]

R. M. Zucker, “Quality assessment of confocal microscopy slide based systems: Performance,” Cytom. Part A 69A, 659–676 (2006).
[Crossref]

2005 (4)

T. Bernas, J. P. Robinson, E. K. Asem, and B. Rajwa, “Loss of image quality in photobleaching during microscopic imaging of fluorescent probes bound to chromatin,” J. Biomed. Opt. 10, 064015 (2005).
[Crossref]

C. Eggeling, A. Volkmer, and C. A. M. Seidel, “Molecular photobleaching kinetics of rhodamine 6G by one- and two-photon induced confocal fluorescence microscopy,” ChemPhysChem. 6, 791–804 (2005).
[Crossref] [PubMed]

M. Hofmann, C. Eggeling, S. Jakobs, and S. W. Hell, “Breaking the diffraction barrier in fluorescence microscopy at low light intensities by using reversibly photoswitchable proteins,” Proc. Natl. Acad. Sci. USA 102, 17565–17569 (2005).
[Crossref] [PubMed]

M. G. L. Gustafsson, “Nonlinear structured-illumination microscopy: Wide-field fluorescence imaging with theoretically unlimited resolution,” Proc. Natl. Acad. Sci. USA 102, 13081–13086 (2005).
[Crossref] [PubMed]

2004 (1)

G. C. Cianci, J. Wu, and K. M. Berland, “Saturation modified point spread functions in two-photon microscopy,” Microsc. Res. Tech. 64, 135–141 (2004).
[Crossref] [PubMed]

2003 (2)

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21, 1369–1377 (2003).
[Crossref] [PubMed]

D. R. Larson, “Water-soluble quantum dots for multiphoton fluorescence imaging in vivo,” Science. 300, 1434–1436 (2003).
[Crossref] [PubMed]

2002 (1)

A. Egner, S. Jakobs, and S. W. Hell, “Fast 100-nm resolution three-dimensional microscope reveals structural plasticity of mitochondria in live yeast,” Proc. Natl. Acad. Sci. USA 99, 3370–3375 (2002).
[Crossref] [PubMed]

2000 (2)

M. G. L. Gustafsson, “Surpassing the lateral resolution limit by a factor of two using structured illumination microscopy,” J. Microsc. 198, 82–87 (2000).
[Crossref] [PubMed]

T. A. Klar, S. Jakobs, M. Dyba, A. Egner, and S. W. Hell, “Fluorescence microscopy with diffraction resolution barrier broken by stimulated emission,” Proc. Natl. Acad. Sci. USA 97, 8206–8210 (2000).
[Crossref] [PubMed]

1996 (1)

1994 (1)

1990 (1)

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248, 73–76 (1990).
[Crossref] [PubMed]

Ahmed, T.

Alexander, N. S.

Allende Motz, A. M.

J. J. Field, K. A. Wernsing, S. R. Domingue, A. M. Allende Motz, K. F. DeLuca, D. H. Levi, J. G. DeLuca, M. D. Young, J. A. Squier, and R. A. Bartels, “Superresolved multiphoton microscopy with spatial frequency-modulated imaging,” Proc. Natl. Acad. Sci. USA 113, 6605–6610 (2016).
[Crossref] [PubMed]

Asem, E. K.

T. Bernas, J. P. Robinson, E. K. Asem, and B. Rajwa, “Loss of image quality in photobleaching during microscopic imaging of fluorescent probes bound to chromatin,” J. Biomed. Opt. 10, 064015 (2005).
[Crossref]

Balzarotti, F.

F. Balzarotti, Y. Eilers, K. C. Gwosch, A. H. Gynnå, V. Westphal, F. D. Stefani, J. Elf, and S. W. Hell, “Nanometer resolution imaging and tracking of fluorescent molecules with minimal photon fluxes,” Science 355, 606–612 (2017).
[Crossref]

Bartels, R. A.

J. J. Field, K. A. Wernsing, S. R. Domingue, A. M. Allende Motz, K. F. DeLuca, D. H. Levi, J. G. DeLuca, M. D. Young, J. A. Squier, and R. A. Bartels, “Superresolved multiphoton microscopy with spatial frequency-modulated imaging,” Proc. Natl. Acad. Sci. USA 113, 6605–6610 (2016).
[Crossref] [PubMed]

Bates, M.

M. J. Rust, M. Bates, and X. Zhuang, “Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM),” Nat. Methods 3, 793–796 (2006).
[Crossref] [PubMed]

Benda, A.

J. Humpolíčková, A. Benda, and J. Enderlein, “Optical saturation as a versatile tool to enhance resolution in confocal microscopy,” Biophys. J. 97, 2623–2629 (2009).
[Crossref]

Benirschke, D.

Berland, K. M.

G. C. Cianci, J. Wu, and K. M. Berland, “Saturation modified point spread functions in two-photon microscopy,” Microsc. Res. Tech. 64, 135–141 (2004).
[Crossref] [PubMed]

Bernas, T.

T. Bernas, J. P. Robinson, E. K. Asem, and B. Rajwa, “Loss of image quality in photobleaching during microscopic imaging of fluorescent probes bound to chromatin,” J. Biomed. Opt. 10, 064015 (2005).
[Crossref]

Betzig, E.

E. Betzig, G. H. Patterson, R. Sougrat, O. W. Lindwasser, S. Olenych, J. S. Bonifacino, M. W. Davidson, J. Lippincott-Schwartz, and H. F. Hess, “Imaging intracellular fluorescent proteins at nanometer resolution,” Science 313, 1642–1645 (2006).
[Crossref] [PubMed]

Bonifacino, J. S.

E. Betzig, G. H. Patterson, R. Sougrat, O. W. Lindwasser, S. Olenych, J. S. Bonifacino, M. W. Davidson, J. Lippincott-Schwartz, and H. F. Hess, “Imaging intracellular fluorescent proteins at nanometer resolution,” Science 313, 1642–1645 (2006).
[Crossref] [PubMed]

Bouwens, A.

Braun, A.

T. Z. Veres, M. Shevchenko, G. Krasteva, E. Spies, F. Prenzler, S. Rochlitzer, T. Tschernig, N. Krug, W. Kummer, and A. Braun, “Dendritic cell-nerve clusters are sites of T cell proliferation in allergic airway inflammation,” Am. J. Pathol. 174, 808–817 (2009).
[Crossref] [PubMed]

Cao, L.

Chitnis, A.

Christensen, R.

Cianci, G. C.

G. C. Cianci, J. Wu, and K. M. Berland, “Saturation modified point spread functions in two-photon microscopy,” Microsc. Res. Tech. 64, 135–141 (2004).
[Crossref] [PubMed]

Davidson, M. W.

E. Betzig, G. H. Patterson, R. Sougrat, O. W. Lindwasser, S. Olenych, J. S. Bonifacino, M. W. Davidson, J. Lippincott-Schwartz, and H. F. Hess, “Imaging intracellular fluorescent proteins at nanometer resolution,” Science 313, 1642–1645 (2006).
[Crossref] [PubMed]

DeLuca, J. G.

J. J. Field, K. A. Wernsing, S. R. Domingue, A. M. Allende Motz, K. F. DeLuca, D. H. Levi, J. G. DeLuca, M. D. Young, J. A. Squier, and R. A. Bartels, “Superresolved multiphoton microscopy with spatial frequency-modulated imaging,” Proc. Natl. Acad. Sci. USA 113, 6605–6610 (2016).
[Crossref] [PubMed]

DeLuca, K. F.

J. J. Field, K. A. Wernsing, S. R. Domingue, A. M. Allende Motz, K. F. DeLuca, D. H. Levi, J. G. DeLuca, M. D. Young, J. A. Squier, and R. A. Bartels, “Superresolved multiphoton microscopy with spatial frequency-modulated imaging,” Proc. Natl. Acad. Sci. USA 113, 6605–6610 (2016).
[Crossref] [PubMed]

Denk, W.

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248, 73–76 (1990).
[Crossref] [PubMed]

Doi, A.

Doktycz, M. J.

P. D. Nallathamby, N. P. Mortensen, H. A. Palko, M. Malfatti, C. Smith, J. Sonnett, M. J. Doktycz, B. Gu, R. K. Roeder, W. Wang, and S. T. Retterer, “New surface radiolabeling schemes of super paramagnetic iron oxide nanoparticles (SPIONs) for biodistribution studies,” Nanoscale 7, 6545–6555 (2015).
[Crossref] [PubMed]

W. Wang, P. D. Nallathamby, C. M. Foster, J. L. Morrell-Falvey, N. P. Mortensen, M. J. Doktycz, B. Gu, and S. T. Retterer, “Volume labeling with Alexa Fluor dyes and surface functionalization of highly sensitive fluorescent silica (SiO2) nanoparticles,” Nanoscale 5, 10369–10375 (2013).
[Crossref] [PubMed]

Domingue, S. R.

J. J. Field, K. A. Wernsing, S. R. Domingue, A. M. Allende Motz, K. F. DeLuca, D. H. Levi, J. G. DeLuca, M. D. Young, J. A. Squier, and R. A. Bartels, “Superresolved multiphoton microscopy with spatial frequency-modulated imaging,” Proc. Natl. Acad. Sci. USA 113, 6605–6610 (2016).
[Crossref] [PubMed]

Duport, F.

Dyba, M.

T. A. Klar, S. Jakobs, M. Dyba, A. Egner, and S. W. Hell, “Fluorescence microscopy with diffraction resolution barrier broken by stimulated emission,” Proc. Natl. Acad. Sci. USA 97, 8206–8210 (2000).
[Crossref] [PubMed]

Eggeling, C.

E. Rittweger, K. Y. Han, S. E. Irvine, C. Eggeling, and S. W. Hell, “STED microscopy reveals crystal colour centres with nanometric resolution,” Nat. Photonics 3, 144–147 (2009).
[Crossref]

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Nguyen, A. D.

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Oketani, R.

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P. D. Nallathamby, J. Hopf, L. E. Irimata, T. L. McGinnity, and R. K. Roeder, “Preparation of fluorescent Au-SiO2 core-shell nanoparticles and nanorods with tunable silica shell thickness and surface modification for immunotargeting,” J. Mater. Chem. B 4, 5418–5428 (2016).
[Crossref]

P. D. Nallathamby, N. P. Mortensen, H. A. Palko, M. Malfatti, C. Smith, J. Sonnett, M. J. Doktycz, B. Gu, R. K. Roeder, W. Wang, and S. T. Retterer, “New surface radiolabeling schemes of super paramagnetic iron oxide nanoparticles (SPIONs) for biodistribution studies,” Nanoscale 7, 6545–6555 (2015).
[Crossref] [PubMed]

Rust, M. J.

M. J. Rust, M. Bates, and X. Zhuang, “Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM),” Nat. Methods 3, 793–796 (2006).
[Crossref] [PubMed]

Sato, M.

K. Yoshida, I. Nishidate, T. Ishizuka, S. Kawauchi, S. Sato, and M. Sato, “Multispectral imaging of absorption and scattering properties of in vivo exposed rat brain using a digital red-green-blue camera,” J. Biomed. Opt. 20, 051026 (2015).
[Crossref] [PubMed]

Sato, S.

K. Yoshida, I. Nishidate, T. Ishizuka, S. Kawauchi, S. Sato, and M. Sato, “Multispectral imaging of absorption and scattering properties of in vivo exposed rat brain using a digital red-green-blue camera,” J. Biomed. Opt. 20, 051026 (2015).
[Crossref] [PubMed]

Sauer, M.

J. Vogelsang, R. Kasper, C. Steinhauer, B. Person, M. Heilemann, M. Sauer, and P. Tinnefeld, “A reducing and oxidizing system minimizes photobleaching and blinking of fluorescent dyes,” Angew. Chem. Int. Ed. 47, 5465–5469 (2008).
[Crossref]

Seidel, C. A. M.

C. Eggeling, A. Volkmer, and C. A. M. Seidel, “Molecular photobleaching kinetics of rhodamine 6G by one- and two-photon induced confocal fluorescence microscopy,” ChemPhysChem. 6, 791–804 (2005).
[Crossref] [PubMed]

Shevchenko, M.

T. Z. Veres, M. Shevchenko, G. Krasteva, E. Spies, F. Prenzler, S. Rochlitzer, T. Tschernig, N. Krug, W. Kummer, and A. Braun, “Dendritic cell-nerve clusters are sites of T cell proliferation in allergic airway inflammation,” Am. J. Pathol. 174, 808–817 (2009).
[Crossref] [PubMed]

Shroff, H.

Smith, C.

P. D. Nallathamby, N. P. Mortensen, H. A. Palko, M. Malfatti, C. Smith, J. Sonnett, M. J. Doktycz, B. Gu, R. K. Roeder, W. Wang, and S. T. Retterer, “New surface radiolabeling schemes of super paramagnetic iron oxide nanoparticles (SPIONs) for biodistribution studies,” Nanoscale 7, 6545–6555 (2015).
[Crossref] [PubMed]

Smith, N. I.

R. Oketani, A. Doi, N. I. Smith, Y. Nawa, S. Kawata, and K. Fujita, “Saturated two-photon excitation fluorescence microscopy with core-ring illumination,” Opt. Lett. 42, 571 (2017).
[Crossref] [PubMed]

Y. Yonemaru, M. Yamanaka, N. I. Smith, S. Kawata, and K. Fujita, “Saturated excitation microscopy with optimized excitation modulation,” ChemPhysChem. 15, 743–749 (2014).
[Crossref] [PubMed]

Sonnett, J.

P. D. Nallathamby, N. P. Mortensen, H. A. Palko, M. Malfatti, C. Smith, J. Sonnett, M. J. Doktycz, B. Gu, R. K. Roeder, W. Wang, and S. T. Retterer, “New surface radiolabeling schemes of super paramagnetic iron oxide nanoparticles (SPIONs) for biodistribution studies,” Nanoscale 7, 6545–6555 (2015).
[Crossref] [PubMed]

Sougrat, R.

E. Betzig, G. H. Patterson, R. Sougrat, O. W. Lindwasser, S. Olenych, J. S. Bonifacino, M. W. Davidson, J. Lippincott-Schwartz, and H. F. Hess, “Imaging intracellular fluorescent proteins at nanometer resolution,” Science 313, 1642–1645 (2006).
[Crossref] [PubMed]

Spies, E.

T. Z. Veres, M. Shevchenko, G. Krasteva, E. Spies, F. Prenzler, S. Rochlitzer, T. Tschernig, N. Krug, W. Kummer, and A. Braun, “Dendritic cell-nerve clusters are sites of T cell proliferation in allergic airway inflammation,” Am. J. Pathol. 174, 808–817 (2009).
[Crossref] [PubMed]

Squier, J. A.

J. J. Field, K. A. Wernsing, S. R. Domingue, A. M. Allende Motz, K. F. DeLuca, D. H. Levi, J. G. DeLuca, M. D. Young, J. A. Squier, and R. A. Bartels, “Superresolved multiphoton microscopy with spatial frequency-modulated imaging,” Proc. Natl. Acad. Sci. USA 113, 6605–6610 (2016).
[Crossref] [PubMed]

E. E. Hoover and J. A. Squier, “Advances in multiphoton microscopy technology,” Nat. Photonics 7, 93–101 (2013).
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Stefani, F. D.

F. Balzarotti, Y. Eilers, K. C. Gwosch, A. H. Gynnå, V. Westphal, F. D. Stefani, J. Elf, and S. W. Hell, “Nanometer resolution imaging and tracking of fluorescent molecules with minimal photon fluxes,” Science 355, 606–612 (2017).
[Crossref]

Steinhauer, C.

J. Vogelsang, R. Kasper, C. Steinhauer, B. Person, M. Heilemann, M. Sauer, and P. Tinnefeld, “A reducing and oxidizing system minimizes photobleaching and blinking of fluorescent dyes,” Angew. Chem. Int. Ed. 47, 5465–5469 (2008).
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Stremplewski, P.

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W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248, 73–76 (1990).
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J. Vogelsang, R. Kasper, C. Steinhauer, B. Person, M. Heilemann, M. Sauer, and P. Tinnefeld, “A reducing and oxidizing system minimizes photobleaching and blinking of fluorescent dyes,” Angew. Chem. Int. Ed. 47, 5465–5469 (2008).
[Crossref]

Tschernig, T.

T. Z. Veres, M. Shevchenko, G. Krasteva, E. Spies, F. Prenzler, S. Rochlitzer, T. Tschernig, N. Krug, W. Kummer, and A. Braun, “Dendritic cell-nerve clusters are sites of T cell proliferation in allergic airway inflammation,” Am. J. Pathol. 174, 808–817 (2009).
[Crossref] [PubMed]

Van Simaeys, G.

Vanholsbeeck, F.

Veres, T. Z.

T. Z. Veres, M. Shevchenko, G. Krasteva, E. Spies, F. Prenzler, S. Rochlitzer, T. Tschernig, N. Krug, W. Kummer, and A. Braun, “Dendritic cell-nerve clusters are sites of T cell proliferation in allergic airway inflammation,” Am. J. Pathol. 174, 808–817 (2009).
[Crossref] [PubMed]

Vigil, G.

Vigil, G. D.

Vogelsang, J.

J. Vogelsang, R. Kasper, C. Steinhauer, B. Person, M. Heilemann, M. Sauer, and P. Tinnefeld, “A reducing and oxidizing system minimizes photobleaching and blinking of fluorescent dyes,” Angew. Chem. Int. Ed. 47, 5465–5469 (2008).
[Crossref]

Volkmer, A.

C. Eggeling, A. Volkmer, and C. A. M. Seidel, “Molecular photobleaching kinetics of rhodamine 6G by one- and two-photon induced confocal fluorescence microscopy,” ChemPhysChem. 6, 791–804 (2005).
[Crossref] [PubMed]

Wang, W.

P. D. Nallathamby, N. P. Mortensen, H. A. Palko, M. Malfatti, C. Smith, J. Sonnett, M. J. Doktycz, B. Gu, R. K. Roeder, W. Wang, and S. T. Retterer, “New surface radiolabeling schemes of super paramagnetic iron oxide nanoparticles (SPIONs) for biodistribution studies,” Nanoscale 7, 6545–6555 (2015).
[Crossref] [PubMed]

W. Wang, P. D. Nallathamby, C. M. Foster, J. L. Morrell-Falvey, N. P. Mortensen, M. J. Doktycz, B. Gu, and S. T. Retterer, “Volume labeling with Alexa Fluor dyes and surface functionalization of highly sensitive fluorescent silica (SiO2) nanoparticles,” Nanoscale 5, 10369–10375 (2013).
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Wang, Y.

C. Kuang, S. Li, W. Liu, X. Hao, Z. Gu, Y. Wang, J. Ge, H. Li, and X. Liu, “Breaking the diffraction barrier using fluorescence emission difference microscopy,” Sci. Rep. 3, 1441 (2013).
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W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21, 1369–1377 (2003).
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W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248, 73–76 (1990).
[Crossref] [PubMed]

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J. J. Field, K. A. Wernsing, S. R. Domingue, A. M. Allende Motz, K. F. DeLuca, D. H. Levi, J. G. DeLuca, M. D. Young, J. A. Squier, and R. A. Bartels, “Superresolved multiphoton microscopy with spatial frequency-modulated imaging,” Proc. Natl. Acad. Sci. USA 113, 6605–6610 (2016).
[Crossref] [PubMed]

Westphal, V.

F. Balzarotti, Y. Eilers, K. C. Gwosch, A. H. Gynnå, V. Westphal, F. D. Stefani, J. Elf, and S. W. Hell, “Nanometer resolution imaging and tracking of fluorescent molecules with minimal photon fluxes,” Science 355, 606–612 (2017).
[Crossref]

Wichmann, J.

Williams, R. M.

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21, 1369–1377 (2003).
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Wojtkowski, M.

Wu, J.

G. C. Cianci, J. Wu, and K. M. Berland, “Saturation modified point spread functions in two-photon microscopy,” Microsc. Res. Tech. 64, 135–141 (2004).
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Xu, C.

Yamanaka, M.

Y. Yonemaru, M. Yamanaka, N. I. Smith, S. Kawata, and K. Fujita, “Saturated excitation microscopy with optimized excitation modulation,” ChemPhysChem. 15, 743–749 (2014).
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K. Fujita, M. Kobayashi, S. Kawano, M. Yamanaka, and S. Kawata, “High-resolution confocal microscopy by saturated excitation of fluorescence,” Phys. Rev. Lett. 99, 228105 (2007).
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Y. Yonemaru, M. Yamanaka, N. I. Smith, S. Kawata, and K. Fujita, “Saturated excitation microscopy with optimized excitation modulation,” ChemPhysChem. 15, 743–749 (2014).
[Crossref] [PubMed]

York, A. G.

Yoshida, K.

K. Yoshida, I. Nishidate, T. Ishizuka, S. Kawauchi, S. Sato, and M. Sato, “Multispectral imaging of absorption and scattering properties of in vivo exposed rat brain using a digital red-green-blue camera,” J. Biomed. Opt. 20, 051026 (2015).
[Crossref] [PubMed]

Young, M. D.

J. J. Field, K. A. Wernsing, S. R. Domingue, A. M. Allende Motz, K. F. DeLuca, D. H. Levi, J. G. DeLuca, M. D. Young, J. A. Squier, and R. A. Bartels, “Superresolved multiphoton microscopy with spatial frequency-modulated imaging,” Proc. Natl. Acad. Sci. USA 113, 6605–6610 (2016).
[Crossref] [PubMed]

Zhang, Y.

Zhu, X.

E. Gatzogiannis, X. Zhu, Y.-T. Kao, and W. Min, “Observation of frequency-domain fluorescence anomalous phase advance due to dark-state hysteresis,” J. Phys. Chem. Lett. 2, 461–466 (2011).
[Crossref]

Zhuang, X.

M. J. Rust, M. Bates, and X. Zhuang, “Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM),” Nat. Methods 3, 793–796 (2006).
[Crossref] [PubMed]

Zipfel, W. R.

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21, 1369–1377 (2003).
[Crossref] [PubMed]

Zucker, R. M.

R. M. Zucker, “Quality assessment of confocal microscopy slide based systems: Performance,” Cytom. Part A 69A, 659–676 (2006).
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Am. J. Pathol. (1)

T. Z. Veres, M. Shevchenko, G. Krasteva, E. Spies, F. Prenzler, S. Rochlitzer, T. Tschernig, N. Krug, W. Kummer, and A. Braun, “Dendritic cell-nerve clusters are sites of T cell proliferation in allergic airway inflammation,” Am. J. Pathol. 174, 808–817 (2009).
[Crossref] [PubMed]

Angew. Chem. Int. Ed. (1)

J. Vogelsang, R. Kasper, C. Steinhauer, B. Person, M. Heilemann, M. Sauer, and P. Tinnefeld, “A reducing and oxidizing system minimizes photobleaching and blinking of fluorescent dyes,” Angew. Chem. Int. Ed. 47, 5465–5469 (2008).
[Crossref]

Biomed. Opt. Express (1)

Biophys. J. (1)

J. Humpolíčková, A. Benda, and J. Enderlein, “Optical saturation as a versatile tool to enhance resolution in confocal microscopy,” Biophys. J. 97, 2623–2629 (2009).
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ChemPhysChem. (2)

C. Eggeling, A. Volkmer, and C. A. M. Seidel, “Molecular photobleaching kinetics of rhodamine 6G by one- and two-photon induced confocal fluorescence microscopy,” ChemPhysChem. 6, 791–804 (2005).
[Crossref] [PubMed]

Y. Yonemaru, M. Yamanaka, N. I. Smith, S. Kawata, and K. Fujita, “Saturated excitation microscopy with optimized excitation modulation,” ChemPhysChem. 15, 743–749 (2014).
[Crossref] [PubMed]

Cytom. Part A (1)

R. M. Zucker, “Quality assessment of confocal microscopy slide based systems: Performance,” Cytom. Part A 69A, 659–676 (2006).
[Crossref]

J. Biomed. Opt. (2)

K. Yoshida, I. Nishidate, T. Ishizuka, S. Kawauchi, S. Sato, and M. Sato, “Multispectral imaging of absorption and scattering properties of in vivo exposed rat brain using a digital red-green-blue camera,” J. Biomed. Opt. 20, 051026 (2015).
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T. Bernas, J. P. Robinson, E. K. Asem, and B. Rajwa, “Loss of image quality in photobleaching during microscopic imaging of fluorescent probes bound to chromatin,” J. Biomed. Opt. 10, 064015 (2005).
[Crossref]

J. Mater. Chem. B (1)

P. D. Nallathamby, J. Hopf, L. E. Irimata, T. L. McGinnity, and R. K. Roeder, “Preparation of fluorescent Au-SiO2 core-shell nanoparticles and nanorods with tunable silica shell thickness and surface modification for immunotargeting,” J. Mater. Chem. B 4, 5418–5428 (2016).
[Crossref]

J. Microsc. (1)

M. G. L. Gustafsson, “Surpassing the lateral resolution limit by a factor of two using structured illumination microscopy,” J. Microsc. 198, 82–87 (2000).
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J. Opt. Soc. Am. A (2)

J. Opt. Soc. Am. B (1)

J. Phys. Chem. Lett. (1)

E. Gatzogiannis, X. Zhu, Y.-T. Kao, and W. Min, “Observation of frequency-domain fluorescence anomalous phase advance due to dark-state hysteresis,” J. Phys. Chem. Lett. 2, 461–466 (2011).
[Crossref]

Microsc. Res. Tech. (1)

G. C. Cianci, J. Wu, and K. M. Berland, “Saturation modified point spread functions in two-photon microscopy,” Microsc. Res. Tech. 64, 135–141 (2004).
[Crossref] [PubMed]

Nanoscale (2)

P. D. Nallathamby, N. P. Mortensen, H. A. Palko, M. Malfatti, C. Smith, J. Sonnett, M. J. Doktycz, B. Gu, R. K. Roeder, W. Wang, and S. T. Retterer, “New surface radiolabeling schemes of super paramagnetic iron oxide nanoparticles (SPIONs) for biodistribution studies,” Nanoscale 7, 6545–6555 (2015).
[Crossref] [PubMed]

W. Wang, P. D. Nallathamby, C. M. Foster, J. L. Morrell-Falvey, N. P. Mortensen, M. J. Doktycz, B. Gu, and S. T. Retterer, “Volume labeling with Alexa Fluor dyes and surface functionalization of highly sensitive fluorescent silica (SiO2) nanoparticles,” Nanoscale 5, 10369–10375 (2013).
[Crossref] [PubMed]

Nat. Biotechnol. (1)

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21, 1369–1377 (2003).
[Crossref] [PubMed]

Nat. Methods (1)

M. J. Rust, M. Bates, and X. Zhuang, “Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM),” Nat. Methods 3, 793–796 (2006).
[Crossref] [PubMed]

Nat. Photonics (3)

E. E. Hoover and J. A. Squier, “Advances in multiphoton microscopy technology,” Nat. Photonics 7, 93–101 (2013).
[Crossref] [PubMed]

S. Gigan, “Optical microscopy aims deep,” Nat. Photonics 11, 14–16 (2017).
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E. Rittweger, K. Y. Han, S. E. Irvine, C. Eggeling, and S. W. Hell, “STED microscopy reveals crystal colour centres with nanometric resolution,” Nat. Photonics 3, 144–147 (2009).
[Crossref]

Opt. Express (1)

Opt. Lett. (3)

Optica (1)

Phys. Rev. Lett. (1)

K. Fujita, M. Kobayashi, S. Kawano, M. Yamanaka, and S. Kawata, “High-resolution confocal microscopy by saturated excitation of fluorescence,” Phys. Rev. Lett. 99, 228105 (2007).
[Crossref]

Proc. Natl. Acad. Sci. USA (5)

A. Egner, S. Jakobs, and S. W. Hell, “Fast 100-nm resolution three-dimensional microscope reveals structural plasticity of mitochondria in live yeast,” Proc. Natl. Acad. Sci. USA 99, 3370–3375 (2002).
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J. J. Field, K. A. Wernsing, S. R. Domingue, A. M. Allende Motz, K. F. DeLuca, D. H. Levi, J. G. DeLuca, M. D. Young, J. A. Squier, and R. A. Bartels, “Superresolved multiphoton microscopy with spatial frequency-modulated imaging,” Proc. Natl. Acad. Sci. USA 113, 6605–6610 (2016).
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T. A. Klar, S. Jakobs, M. Dyba, A. Egner, and S. W. Hell, “Fluorescence microscopy with diffraction resolution barrier broken by stimulated emission,” Proc. Natl. Acad. Sci. USA 97, 8206–8210 (2000).
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M. Hofmann, C. Eggeling, S. Jakobs, and S. W. Hell, “Breaking the diffraction barrier in fluorescence microscopy at low light intensities by using reversibly photoswitchable proteins,” Proc. Natl. Acad. Sci. USA 102, 17565–17569 (2005).
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M. G. L. Gustafsson, “Nonlinear structured-illumination microscopy: Wide-field fluorescence imaging with theoretically unlimited resolution,” Proc. Natl. Acad. Sci. USA 102, 13081–13086 (2005).
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Sci. Rep. (1)

C. Kuang, S. Li, W. Liu, X. Hao, Z. Gu, Y. Wang, J. Ge, H. Li, and X. Liu, “Breaking the diffraction barrier using fluorescence emission difference microscopy,” Sci. Rep. 3, 1441 (2013).
[Crossref] [PubMed]

Science (4)

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248, 73–76 (1990).
[Crossref] [PubMed]

S. W. Hell, “Far-field optical nanoscopy,” Science 316, 1153–1158 (2007).
[Crossref] [PubMed]

F. Balzarotti, Y. Eilers, K. C. Gwosch, A. H. Gynnå, V. Westphal, F. D. Stefani, J. Elf, and S. W. Hell, “Nanometer resolution imaging and tracking of fluorescent molecules with minimal photon fluxes,” Science 355, 606–612 (2017).
[Crossref]

E. Betzig, G. H. Patterson, R. Sougrat, O. W. Lindwasser, S. Olenych, J. S. Bonifacino, M. W. Davidson, J. Lippincott-Schwartz, and H. F. Hess, “Imaging intracellular fluorescent proteins at nanometer resolution,” Science 313, 1642–1645 (2006).
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Science. (1)

D. R. Larson, “Water-soluble quantum dots for multiphoton fluorescence imaging in vivo,” Science. 300, 1434–1436 (2003).
[Crossref] [PubMed]

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Figures (12)

Fig. 1
Fig. 1 (a) Jablonski diagram of the two-level fluorophore model. (b) Simulated fluorescence-excitation relation for the 1PEF case showing the saturation behavior. (c) FWHM of 1PEF PSFs as a function of excitation irradiance.
Fig. 2
Fig. 2 Illustration of the principle of SOS microscopy from two-step to M-step.
Fig. 3
Fig. 3 PSFs of SOS microscopy from two-step to six-step for (a) 1PEF and (b) 2PEF, where diffraction-limited PSFs are also plotted for comparison.
Fig. 4
Fig. 4 Simulated SOS images of a two-dimensional artificial object. Scale bar: 500 nm.
Fig. 5
Fig. 5 Representative example of 2PEF two-step SOS with Alexa Fluor 488 phalloidin labeled F-actin in fixed bovine pulmonary artery endothelial (BPAE) cells. (a) The raw image of step1 with an MPM laser power of 3.45 mW. (b) The raw image of step2 with an MPM laser power of 3.60 mW. (c) The processed 2PEF two-step SOS image using the raw images in (a) and (b). Scale bar: 2 μm.
Fig. 6
Fig. 6 Experimental SOS images of RITC-SiO2-SiEDTA NPs in an agarose gel. The confocal (1PEF) (a) diffraction-limited and (b) two-step SOS images of the sample. (c) Intensity profiles (dots) with Gaussian fits (curves) along the yellow lines in (a) and (b). The multiphoton (2PEF) (d) diffraction-limited and (e) two-step SOS images of the sample. (f) Intensity profiles (dots) with Gaussian fits (curves) along the yellow lines in (d) and (e). Scale bar: 2 μm.
Fig. 7
Fig. 7 Experimental SOS images of the Alexa Fluor 488 phalloidin labeled F-actin in the biological test slide (fixed BPAE cells, FluoCells prepared slide #1, F36924). The confocal (1PEF) (a) diffraction-limited and (b) two-step SOS images. (c) Intensity profiles along the yellow lines in (a) and (b). The multiphoton (2PEF) (d) diffraction-limited and (e) two-step SOS images. (f) Intensity profiles along the yellow lines in (d) and (e). Scale bar: 2 μm.
Fig. 8
Fig. 8 Experimental SOS images of the Alexa Fluor 488 phalloidin labeled F-actin in the fixed cells (ECFCs) sample. The confocal (1PEF) (a) diffraction-limited and (b) two-step SOS images. (c) Intensity profiles along the yellow lines in (a) and (b). The multiphoton (2PEF) (d) diffraction-limited and (e) two-step SOS images. (f) Intensity profiles along the yellow lines in (d) and (e). Scale bar: 2 μm.
Fig. 9
Fig. 9 Experimental multiphoton (2PEF) SOS images of the RITC-SiO2-SiEDTA NPs in a scattering phantom mimicking a brain tissue at various depths. “0 μm” corresponds to the coverslip surface. The 2PEF diffraction-limited and two-step SOS images of the sample at depths of 0 μm, 25 μm, 50 μm, and 75 μm from the coverslip. Scale bar: 2 μm.
Fig. 10
Fig. 10 2PEF two-step SOS images of the biological test slide (Alexa Fluor 488 phalloidin labeled F-actin) with two-step excitation intensities of (a) I01=3.45 mW, I02=3.60 mW, (b) I01=3.45 mW, I02=4.57 mW, and (c) I01=3.45 mW, I02=8.99 mW. (d) Intensity profiles of a bright F-actin in (a–c) showing different pixel SNR performances. Scale bar: 2 μm.
Fig. 11
Fig. 11 SNR analysis of two-step SOS for 1PEF (a–d) and 2PEF (e–h) cases. Contour plots of (a,e) FWHM and (b,f) SNR for various excitation irradiances. Corresponding (c,g) optimal step1 irradiances and irradiance ratios of step2 and step1 and (d,h) optimal SNRs for a selected resolution (FWHM) goal.
Fig. 12
Fig. 12 (a) PSFs of two steps of images obtained at different excitation irradiances and their processed two-step SOS image for 1PEF fluorophores. (b) OTFs of corresponding PSFs in (a).

Tables (1)

Tables Icon

Table 1 Coefficients for the linear combination in SOS microscopy.

Equations (7)

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

d N 2 ( t ) d t = g p σ N ϕ N ( t ) ( N 0 N 2 ( t ) ) N 2 ( t ) τ .
d F ( t ) d t = K N 0 g p σ N γ N I N ( t ) ( g p σ N γ N I N ( t ) + 1 τ ) F ( t ) .
F = K N 0 τ g p σ N γ N I N 1 + τ g p σ N γ N I N .
F = K N 0 n = 1 ( 1 ) n + 1 τ n g p n σ N n γ n N I n N = K N 0 ( a I N a 2 I 2 N + a 3 I 3 N ) .
F i ( x ) = K N 0 ( a I 0 i N g N ( x ) a 2 I 0 i 2 N g 2 N ( x ) + a 3 I 0 i 3 N g 3 N ( x ) ) .
c B = ( 1 ) B 1 I 01 N I 0 B N j = 2 B 1 I 01 N I 0 j N I 0 j N I 0 B N .
SNR M SOS = μ M SOS σ M SOS = i = 1 M c i μ i i = 1 M c i 2 μ i .

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