Abstract

The uneven illumination of a Gaussian profile makes quantitative analysis highly challenging in laser-based wide-field fluorescence microscopy. Here we present flat-field illumination (FFI) where the Gaussian beam is reshaped into a uniform flat-top profile using a high-precision refractive optical component. The long working distance and high spatial coherence of FFI allows us to accomplish uniform epi and TIRF illumination for multi-color single-molecule imaging. In addition, high-throughput borderless imaging is demonstrated with minimal image overlap.

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

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References

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2017 (4)

G. Pegoraro and T. Misteli, “High-throughput imaging for the discovery of cellular mechanisms of disease,” Trends Genet. 33(9), 604–615 (2017).
[Crossref] [PubMed]

J. C. Caicedo, S. Cooper, F. Heigwer, S. Warchal, P. Qiu, C. Molnar, A. S. Vasilevich, J. D. Barry, H. S. Bansal, O. Kraus, M. Wawer, L. Paavolainen, M. D. Herrmann, M. Rohban, J. Hung, H. Hennig, J. Concannon, I. Smith, P. A. Clemons, S. Singh, P. Rees, P. Horvath, R. G. Linington, and A. E. Carpenter, “Data-analysis strategies for image-based cell profiling,” Nat. Methods 14(9), 849–863 (2017).
[Crossref] [PubMed]

G. Je, B. Croop, S. Basu, J. Tang, K. Y. Han, and Y.-S. Kim, “Endogenous alpha-synuclein protein analysis from human brain tissues using single-molecule pull-down assay,” Anal. Chem. 89(24), 13044–13048 (2017).
[Crossref] [PubMed]

J. Tang, Y. Sun, S. Pang, and K. Y. Han, “Spatially encoded fast single-molecule fluorescence spectroscopy with full field-of-view,” Sci. Rep. 7(1), 10945 (2017).
[Crossref] [PubMed]

2016 (6)

K. Kwakwa, A. Savell, T. Davies, I. Munro, S. Parrinello, M. A. Purbhoo, C. Dunsby, M. A. A. Neil, and P. M. W. French, “easySTORM: a robust, lower-cost approach to localisation and TIRF microscopy,” J. Biophotonics 9(9), 948–957 (2016).
[Crossref] [PubMed]

A. Möhl and U. Fuchs, “Exploring the unlimited possibilities of modular aspheric Gauss to top-hat beam shaping,” Adv. Opt. Technol. 5, 201–210 (2016).

M. F. Juette, D. S. Terry, M. R. Wasserman, R. B. Altman, Z. Zhou, H. Zhao, and S. C. Blanchard, “Single-molecule imaging of non-equilibrium molecular ensembles on the millisecond timescale,” Nat. Methods 13(4), 341–344 (2016).
[Crossref] [PubMed]

J. Deschamps, A. Rowald, and J. Ries, “Efficient homogeneous illumination and optical sectioning for quantitative single-molecule localization microscopy,” Opt. Express 24(24), 28080–28090 (2016).
[Crossref] [PubMed]

K. M. Douglass, C. Sieben, A. Archetti, A. Lambert, and S. Manley, “Super-resolution imaging of multiple cells by optimised flat-field epi-illumination,” Nat. Photonics 10(11), 705–708 (2016).
[Crossref] [PubMed]

J. R. Moffitt, J. Hao, G. Wang, K. H. Chen, H. P. Babcock, and X. Zhuang, “High-throughput single-cell gene-expression profiling with multiplexed error-robust fluorescence in situ hybridization,” Proc. Natl. Acad. Sci. U.S.A. 113(39), 11046–11051 (2016).
[Crossref] [PubMed]

2015 (2)

K. Smith, Y. Li, F. Piccinini, G. Csucs, C. Balazs, A. Bevilacqua, and P. Horvath, “CIDRE: an illumination-correction method for optical microscopy,” Nat. Methods 12(5), 404–406 (2015).
[Crossref] [PubMed]

F. Bergermann, L. Alber, S. J. Sahl, J. Engelhardt, and S. W. Hell, “2000-fold parallelized dual-color STED fluorescence nanoscopy,” Opt. Express 23(1), 211–223 (2015).
[Crossref] [PubMed]

2013 (1)

J. Burré, S. Vivona, J. Diao, M. Sharma, A. T. Brunger, and T. C. Südhof, “Properties of native brain α-synuclein,” Nature 498(7453), E4–E6 (2013).
[Crossref] [PubMed]

2012 (3)

J. Schindelin, I. Arganda-Carreras, E. Frise, V. Kaynig, M. Longair, T. Pietzsch, S. Preibisch, C. Rueden, S. Saalfeld, B. Schmid, J. Y. Tinevez, D. J. White, V. Hartenstein, K. Eliceiri, P. Tomancak, and A. Cardona, “Fiji: an open-source platform for biological-image analysis,” Nat. Methods 9(7), 676–682 (2012).
[Crossref] [PubMed]

C. A. Schneider, W. S. Rasband, and K. W. Eliceiri, “NIH Image to ImageJ: 25 years of image analysis,” Nat. Methods 9(7), 671–675 (2012).
[Crossref] [PubMed]

F. A. W. Coumans, E. van der Pol, and L. W. M. M. Terstappen, “Flat-top illumination profile in an epifluorescence microscope by dual microlens arrays,” Cytometry A 81(4), 324–331 (2012).
[Crossref] [PubMed]

2011 (2)

A. Jain, R. Liu, B. Ramani, E. Arauz, Y. Ishitsuka, K. Ragunathan, J. Park, J. Chen, Y. K. Xiang, and T. Ha, “Probing cellular protein complexes using single-molecule pull-down,” Nature 473(7348), 484–488 (2011).
[Crossref] [PubMed]

T. M. Scholtens, F. Schreuder, S. T. Ligthart, J. F. Swennenhuis, A. G. J. Tibbe, J. Greve, and L. W. M. M. Terstappen, “CellTracks TDI: An image cytometer for cell characterization,” Cytometry A 79(3), 203–213 (2011).
[Crossref] [PubMed]

2010 (1)

R. Jungmann, C. Steinhauer, M. Scheible, A. Kuzyk, P. Tinnefeld, and F. C. Simmel, “Single-molecule kinetics and super-resolution microscopy by fluorescence imaging of transient binding on DNA origami,” Nano Lett. 10(11), 4756–4761 (2010).
[Crossref] [PubMed]

2008 (2)

B. Harke, J. Keller, C. K. Ullal, V. Westphal, A. Schönle, and S. W. Hell, “Resolution scaling in STED microscopy,” Opt. Express 16(6), 4154–4162 (2008).
[Crossref] [PubMed]

J. Fölling, M. Bossi, H. Bock, R. Medda, C. A. Wurm, B. Hein, S. Jakobs, C. Eggeling, and S. W. Hell, “Fluorescence nanoscopy by ground-state depletion and single-molecule return,” Nat. Methods 5(11), 943–945 (2008).
[Crossref] [PubMed]

2007 (1)

M. H. Ulbrich and E. Y. Isacoff, “Subunit counting in membrane-bound proteins,” Nat. Methods 4(4), 319–321 (2007).
[Crossref] [PubMed]

2006 (2)

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(5793), 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(10), 793–796 (2006).
[Crossref] [PubMed]

2005 (1)

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(5), 791–804 (2005).
[Crossref] [PubMed]

2001 (2)

D. Axelrod, “Total internal reflection fluorescence microscopy in cell biology,” Traffic 2(11), 764–774 (2001).
[Crossref] [PubMed]

A. Edelstein, N. Amodaj, K. Hoover, R. Vale, and N. Stuurman, “Computer control of microscopes using µManager,” Curr. Protoc. Mol. Biol. 92, 142011 (2001).

2000 (2)

J. A. Hoffnagle and C. M. Jefferson, “Design and performance of a refractive optical system that converts a Gaussian to a flattop beam,” Appl. Opt. 39(30), 5488–5499 (2000).
[Crossref] [PubMed]

Y. Sako, S. Minoghchi, and T. Yanagida, “Single-molecule imaging of EGFR signalling on the surface of living cells,” Nat. Cell Biol. 2(3), 168–172 (2000).
[Crossref] [PubMed]

1999 (2)

P. Kask, K. Palo, D. Ullmann, and K. Gall, “Fluorescence-intensity distribution analysis and its application in biomolecular detection technology,” Proc. Natl. Acad. Sci. U.S.A. 96(24), 13756–13761 (1999).
[Crossref] [PubMed]

Y. Chen, J. D. Müller, P. T. C. So, and E. Gratton, “The photon counting histogram in fluorescence fluctuation spectroscopy,” Biophys. J. 77(1), 553–567 (1999).
[Crossref] [PubMed]

1994 (1)

1965 (1)

Alber, L.

Altman, R. B.

M. F. Juette, D. S. Terry, M. R. Wasserman, R. B. Altman, Z. Zhou, H. Zhao, and S. C. Blanchard, “Single-molecule imaging of non-equilibrium molecular ensembles on the millisecond timescale,” Nat. Methods 13(4), 341–344 (2016).
[Crossref] [PubMed]

Amodaj, N.

A. Edelstein, N. Amodaj, K. Hoover, R. Vale, and N. Stuurman, “Computer control of microscopes using µManager,” Curr. Protoc. Mol. Biol. 92, 142011 (2001).

Arauz, E.

A. Jain, R. Liu, B. Ramani, E. Arauz, Y. Ishitsuka, K. Ragunathan, J. Park, J. Chen, Y. K. Xiang, and T. Ha, “Probing cellular protein complexes using single-molecule pull-down,” Nature 473(7348), 484–488 (2011).
[Crossref] [PubMed]

Archetti, A.

K. M. Douglass, C. Sieben, A. Archetti, A. Lambert, and S. Manley, “Super-resolution imaging of multiple cells by optimised flat-field epi-illumination,” Nat. Photonics 10(11), 705–708 (2016).
[Crossref] [PubMed]

Arganda-Carreras, I.

J. Schindelin, I. Arganda-Carreras, E. Frise, V. Kaynig, M. Longair, T. Pietzsch, S. Preibisch, C. Rueden, S. Saalfeld, B. Schmid, J. Y. Tinevez, D. J. White, V. Hartenstein, K. Eliceiri, P. Tomancak, and A. Cardona, “Fiji: an open-source platform for biological-image analysis,” Nat. Methods 9(7), 676–682 (2012).
[Crossref] [PubMed]

Axelrod, D.

D. Axelrod, “Total internal reflection fluorescence microscopy in cell biology,” Traffic 2(11), 764–774 (2001).
[Crossref] [PubMed]

Babcock, H. P.

J. R. Moffitt, J. Hao, G. Wang, K. H. Chen, H. P. Babcock, and X. Zhuang, “High-throughput single-cell gene-expression profiling with multiplexed error-robust fluorescence in situ hybridization,” Proc. Natl. Acad. Sci. U.S.A. 113(39), 11046–11051 (2016).
[Crossref] [PubMed]

Balazs, C.

K. Smith, Y. Li, F. Piccinini, G. Csucs, C. Balazs, A. Bevilacqua, and P. Horvath, “CIDRE: an illumination-correction method for optical microscopy,” Nat. Methods 12(5), 404–406 (2015).
[Crossref] [PubMed]

Bansal, H. S.

J. C. Caicedo, S. Cooper, F. Heigwer, S. Warchal, P. Qiu, C. Molnar, A. S. Vasilevich, J. D. Barry, H. S. Bansal, O. Kraus, M. Wawer, L. Paavolainen, M. D. Herrmann, M. Rohban, J. Hung, H. Hennig, J. Concannon, I. Smith, P. A. Clemons, S. Singh, P. Rees, P. Horvath, R. G. Linington, and A. E. Carpenter, “Data-analysis strategies for image-based cell profiling,” Nat. Methods 14(9), 849–863 (2017).
[Crossref] [PubMed]

Barry, J. D.

J. C. Caicedo, S. Cooper, F. Heigwer, S. Warchal, P. Qiu, C. Molnar, A. S. Vasilevich, J. D. Barry, H. S. Bansal, O. Kraus, M. Wawer, L. Paavolainen, M. D. Herrmann, M. Rohban, J. Hung, H. Hennig, J. Concannon, I. Smith, P. A. Clemons, S. Singh, P. Rees, P. Horvath, R. G. Linington, and A. E. Carpenter, “Data-analysis strategies for image-based cell profiling,” Nat. Methods 14(9), 849–863 (2017).
[Crossref] [PubMed]

Basu, S.

G. Je, B. Croop, S. Basu, J. Tang, K. Y. Han, and Y.-S. Kim, “Endogenous alpha-synuclein protein analysis from human brain tissues using single-molecule pull-down assay,” Anal. Chem. 89(24), 13044–13048 (2017).
[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(10), 793–796 (2006).
[Crossref] [PubMed]

Bergermann, F.

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(5793), 1642–1645 (2006).
[Crossref] [PubMed]

Bevilacqua, A.

K. Smith, Y. Li, F. Piccinini, G. Csucs, C. Balazs, A. Bevilacqua, and P. Horvath, “CIDRE: an illumination-correction method for optical microscopy,” Nat. Methods 12(5), 404–406 (2015).
[Crossref] [PubMed]

Blanchard, S. C.

M. F. Juette, D. S. Terry, M. R. Wasserman, R. B. Altman, Z. Zhou, H. Zhao, and S. C. Blanchard, “Single-molecule imaging of non-equilibrium molecular ensembles on the millisecond timescale,” Nat. Methods 13(4), 341–344 (2016).
[Crossref] [PubMed]

Bock, H.

J. Fölling, M. Bossi, H. Bock, R. Medda, C. A. Wurm, B. Hein, S. Jakobs, C. Eggeling, and S. W. Hell, “Fluorescence nanoscopy by ground-state depletion and single-molecule return,” Nat. Methods 5(11), 943–945 (2008).
[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(5793), 1642–1645 (2006).
[Crossref] [PubMed]

Bossi, M.

J. Fölling, M. Bossi, H. Bock, R. Medda, C. A. Wurm, B. Hein, S. Jakobs, C. Eggeling, and S. W. Hell, “Fluorescence nanoscopy by ground-state depletion and single-molecule return,” Nat. Methods 5(11), 943–945 (2008).
[Crossref] [PubMed]

Brunger, A. T.

J. Burré, S. Vivona, J. Diao, M. Sharma, A. T. Brunger, and T. C. Südhof, “Properties of native brain α-synuclein,” Nature 498(7453), E4–E6 (2013).
[Crossref] [PubMed]

Burré, J.

J. Burré, S. Vivona, J. Diao, M. Sharma, A. T. Brunger, and T. C. Südhof, “Properties of native brain α-synuclein,” Nature 498(7453), E4–E6 (2013).
[Crossref] [PubMed]

Caicedo, J. C.

J. C. Caicedo, S. Cooper, F. Heigwer, S. Warchal, P. Qiu, C. Molnar, A. S. Vasilevich, J. D. Barry, H. S. Bansal, O. Kraus, M. Wawer, L. Paavolainen, M. D. Herrmann, M. Rohban, J. Hung, H. Hennig, J. Concannon, I. Smith, P. A. Clemons, S. Singh, P. Rees, P. Horvath, R. G. Linington, and A. E. Carpenter, “Data-analysis strategies for image-based cell profiling,” Nat. Methods 14(9), 849–863 (2017).
[Crossref] [PubMed]

Cardona, A.

J. Schindelin, I. Arganda-Carreras, E. Frise, V. Kaynig, M. Longair, T. Pietzsch, S. Preibisch, C. Rueden, S. Saalfeld, B. Schmid, J. Y. Tinevez, D. J. White, V. Hartenstein, K. Eliceiri, P. Tomancak, and A. Cardona, “Fiji: an open-source platform for biological-image analysis,” Nat. Methods 9(7), 676–682 (2012).
[Crossref] [PubMed]

Carpenter, A. E.

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Adv. Opt. Technol. (1)

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Appl. Opt. (2)

Biophys. J. (1)

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Figures (8)

Fig. 1
Fig. 1 Experimental characterization of FFI. (a) Beam reshaping schematic. (b) Experimental setup. BE, 1.5x beam expander; DM, dichroic mirror; F1-2, excitation/emission filters; FM, flip mirror; L1-3, lenses; M1-6, mirrors; Obj, objective; SMF1-2, single mode fibers; TL, tube lens. (c) Beam profiles of Gaussian beams collimated by a lens with 80 mm or 150 mm focal length and FFI beams without and with an iris. (d) Lineouts taken from the beam profiles in (c) along dashed lines. Vertical dashed lines in (d) indicate a detection region of a camera. (e) Excitation wavelength dependence of FFI. Lineouts taken from multicolor images (inserts) with an iris. Working distance dependence of FFI with 638 nm (f) and 561 nm laser (g). Scale bars, 10 μm.
Fig. 2
Fig. 2 Simulated flat-top intensity distributions. Working distance dependence at a system wavelength of 640 nm without (a) and with (b) an additional beam expander (BE). (c) Excitation wavelength dependence at a working distance of 300 mm.
Fig. 3
Fig. 3 Flat-field single-molecule imaging. (a) Representative single-molecule images (AF647) taken under Gaussian illumination and FFI. Scale bar, 10 μm. (b) 1D intensity data taken from the boxed region of (a).
Fig. 4
Fig. 4 Quantitative single-molecule imaging analysis with FFI. (a) Threshold curve showing the dependence of the average number of detected molecules on the background thresholding parameter. Error bars represent the standard deviation from the mean. (b) Intensity distributions of single and dual probe samples imaged under Gaussian illumination and FFI. Images taken from 20 different regions were used for each analysis.
Fig. 5
Fig. 5 Dual color single-molecule imaging using FFI. Representative images (a) and intensity distributions of dual color samples. AF647 was imaged under 4 mW of 638 nm laser excitation, while Cy3B was imaged using 3 mW of 561 nm excitation. Scale bar, 10 μm.
Fig. 6
Fig. 6 Uniform photobleaching via FFI. Representative single-molecule images taken at times of 0, 30, and 60 seconds under Gaussian illumination and FFI. Colormap showing the average photobleaching time analyzed with images taken from 10 different regions. Scale bars, 10 μm.
Fig. 7
Fig. 7 Background reduction by TIRF illumination. Representative images taken under illumination by a multimode fiber (MMF) combined with a speckle scrambler and under FFI in the presence of 5 nM background. Lineouts taken as indicated by the dashed yellow lines show the MMF only achieved partial TIRF as evident by the elevated background level, while FFI achieves full TIRF as seen by the minimal background. Scale bar, 10 μm.
Fig. 8
Fig. 8 Borderless image stitching under FFI. (a) High-throughput 3x3 multicolor imaging of mitochondria (green) and actin (red) in A549 cells under Gaussian illumination with 150 mm focal length lens and FFI with a 1.5x beam expander. 100x objective was used. (b) 3x3 stitched image of mitochondria under FFI with a 1.5x beam expander and a 20x objective. (c) Stitched epi and TIRF images of actin labeled with phalloidin AF647 in U2OS cells using Gaussian illumination with 80 mm focal length lens and FFI without a 1.5x beam expander. Image overlap, 5% (a), 10% (b,c). Scale bars, 50 μm (a,c), 200 μm (b).

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