Abstract

We present here a stimulated emission based fluorescence lifetime imaging (FLIM) scheme using a pair of synchronized diode lasers operating at gain switched pulse mode. The two semiconductor lasers, with wavelengths at 635 nm and 700 nm, serve as the excitation and the stimulation light sources for the ATTO647N labeled sample, respectively. FLIM is readily achieved with their relative time delay controlled electronically. The coherent nature of the stimulated emission signal also allows FLIM at long working distance. In this way, a high performance all-semiconductor FLIM module is realized in a flexible, compact, and cost effective configuration.

© 2012 OSA

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    [CrossRef]
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  4. W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, “Fluorescence lifetime imaging by time-correlated single-photon counting,” Microsc. Res. Tech.63(1), 58–66 (2004).
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    [CrossRef] [PubMed]
  28. K. Kolmakov, V. N. Belov, J. Bierwagen, C. Ringemann, V. Müller, C. Eggeling, and S. W. Hell, “Red-emitting rhodamine dyes for fluorescence microscopy and nanoscopy,” Chemistry16(1), 158–166 (2010).
    [CrossRef] [PubMed]
  29. W. Min, C. W. Freudiger, S. Lu, and X. S. Xie, “Coherent nonlinear optical imaging: beyond fluorescence microscopy,” Annu. Rev. Phys. Chem.62(1), 507–530 (2011).
    [CrossRef] [PubMed]
  30. E. Rittweger, B. R. Rankin, V. Westphal, and S. W. Hell, “Fluorescence depletion mechanisms in super-resolving STED microscopy,” Chem. Phys. Lett.442(4-6), 483–487 (2007).
    [CrossRef]

2012

2011

W. Min, C. W. Freudiger, S. Lu, and X. S. Xie, “Coherent nonlinear optical imaging: beyond fluorescence microscopy,” Annu. Rev. Phys. Chem.62(1), 507–530 (2011).
[CrossRef] [PubMed]

J. Bückers, D. Wildanger, G. Vicidomini, L. Kastrup, and S. W. Hell, “Simultaneous multi-lifetime multi-color STED imaging for colocalization analyses,” Opt. Express19(4), 3130–3143 (2011).
[CrossRef] [PubMed]

2010

M. R. Foreman, T. Dellwig, and F.-J. Kao, “Coherent long-distance signal detection using stimulated emission: a feasibility study,” Chin. Phys. J.48, 873–884 (2010).

K. Kolmakov, V. N. Belov, J. Bierwagen, C. Ringemann, V. Müller, C. Eggeling, and S. W. Hell, “Red-emitting rhodamine dyes for fluorescence microscopy and nanoscopy,” Chemistry16(1), 158–166 (2010).
[CrossRef] [PubMed]

S. Lu, W. Min, S. Chong, G. R. Holtom, and X. S. Xie, “Label-free imaging of heme proteins with two-photon excited photothermal lens microscopy,” Appl. Phys. Lett.96(11), 113701 (2010).
[CrossRef]

2009

W. Min, S. Lu, S. Chong, R. Roy, G. R. Holtom, and X. S. Xie, “Imaging chromophores with undetectable fluorescence by stimulated emission microscopy,” Nature461(7267), 1105–1109 (2009).
[CrossRef] [PubMed]

V. V. Ghukasyan and F.-J. Kao, “Monitoring cellular metabolism with fluorescence lifetime of reduced nicotinamide adenine dinucleotide,” J. Phys. Chem. C113(27), 11532–11540 (2009).
[CrossRef]

S. Tyagi, “Imaging intracellular RNA distribution and dynamics in living cells,” Nat. Methods6(5), 331–338 (2009).
[CrossRef] [PubMed]

2008

H.-J. van Manen, P. Verkuijlen, P. Wittendorp, V. Subramaniam, T. K. van den Berg, D. Roos, and C. Otto, “Refractive index sensing of green fluorescent proteins in living cells using fluorescence lifetime imaging microscopy,” Biophys. J.94(8), L67–L69 (2008).
[CrossRef] [PubMed]

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. He, J. C. Tsai, J. X. Kang, and X. S. Xie, “Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy,” Science322(5909), 1857–1861 (2008).
[CrossRef] [PubMed]

D. Li, W. Zheng, and J. Y. Qu, “Time-resolved spectroscopic imaging reveals the fundamentals of cellular NADH fluorescence,” Opt. Lett.33(20), 2365–2367 (2008).
[CrossRef] [PubMed]

2007

E. Rittweger, B. R. Rankin, V. Westphal, and S. W. Hell, “Fluorescence depletion mechanisms in super-resolving STED microscopy,” Chem. Phys. Lett.442(4-6), 483–487 (2007).
[CrossRef]

2005

J. W. Borst, M. A. Hink, A. Hoek, and A. J. W. G. Visser, “Effects of refractive index and viscosity on fluorescence and anisotropy decays of enhanced cyan and yellow fluorescent proteins,” J. Fluoresc.15(2), 153–160 (2005).
[CrossRef] [PubMed]

R. J. Errington, S. M. Ameer-Beg, B. Vojnovic, L. H. Patterson, M. Zloh, and P. J. Smith, “Advanced microscopy solutions for monitoring the kinetics and dynamics of drug-DNA targeting in living cells,” Adv. Drug Deliv. Rev.57(1), 153–167 (2005).
[CrossRef] [PubMed]

2004

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, “Fluorescence lifetime imaging by time-correlated single-photon counting,” Microsc. Res. Tech.63(1), 58–66 (2004).
[CrossRef] [PubMed]

2003

H.-J. Lin, P. Herman, and J. R. Lakowicz, “Fluorescence lifetime-resolved pH imaging of living cells,” Cytometry AA52(2), 77–89 (2003).
[CrossRef] [PubMed]

1998

1997

J. B. Guild, C. Xu, and W. W. Webb, “Measurement of group delay dispersion of high numerical aperture objective lenses using two-photon excited fluorescence,” Appl. Opt.36(1), 397–401 (1997).
[CrossRef] [PubMed]

H. Gerritsen, R. Sanders, A. Draaijer, C. Ince, and Y. Levine, “Fluorescence lifetime imaging of oxygen in living cells,” J. Fluoresc.7(1), 11–15 (1997).
[CrossRef]

B. Gompf, R. Günther, G. Nick, R. Pecha, and W. Eisenmenger, “Resolving sonoluminescence pulse width with time-correlated single photon counting,” Phys. Rev. Lett.79(7), 1405–1408 (1997).
[CrossRef]

1995

R. Sanders, A. Draaijer, H. C. Gerritsen, P. M. Houpt, and Y. K. Levine, “Quantitative pH imaging in cells using confocal fluorescence lifetime imaging microscopy,” Anal. Biochem.227(2), 302–308 (1995).
[CrossRef] [PubMed]

C. Y. Dong, P. T. So, T. French, and E. Gratton, “Fluorescence lifetime imaging by asynchronous pump-probe microscopy,” Biophys. J.69(6), 2234–2242 (1995).
[CrossRef] [PubMed]

1994

R. Sanders, H. C. Gerritsen, A. Draaijer, P. M. Houpt, and Y. K. Levine, “Fluorescence lifetime imaging of free calcium in single cells,” Bioimaging2(3), 131–138 (1994).
[CrossRef]

1993

H. Szmacinski and J. R. Lakowicz, “Optical measurements of pH using fluorescence lifetimes and phase-modulation fluorometry,” Anal. Chem.65(13), 1668–1674 (1993).
[CrossRef] [PubMed]

T. Oida, Y. Sako, and A. Kusumi, “Fluorescence lifetime imaging microscopy (flimscopy). Methodology development and application to studies of endosome fusion in single cells,” Biophys. J.64(3), 676–685 (1993).
[CrossRef] [PubMed]

1992

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, and M. L. Johnson, “Fluorescence lifetime imaging of free and protein-bound NADH,” Proc. Natl. Acad. Sci. U.S.A.89(4), 1271–1275 (1992).
[CrossRef] [PubMed]

1986

C. E. Hamilton, J. L. Kinsey, and R. W. Field, “Stimulated emission pumping: new methods in spectroscopy and molecular dynamics,” Annu. Rev. Phys. Chem.37(1), 493–524 (1986).
[CrossRef]

1979

G. J. Brakenhoff, P. Blom, and P. Barends, “Confocal scanning light microscopy with high aperture immersion lenses,” J. Microsc.117(2), 219–232 (1979).
[CrossRef]

Ameer-Beg, S. M.

R. J. Errington, S. M. Ameer-Beg, B. Vojnovic, L. H. Patterson, M. Zloh, and P. J. Smith, “Advanced microscopy solutions for monitoring the kinetics and dynamics of drug-DNA targeting in living cells,” Adv. Drug Deliv. Rev.57(1), 153–167 (2005).
[CrossRef] [PubMed]

Barends, P.

G. J. Brakenhoff, P. Blom, and P. Barends, “Confocal scanning light microscopy with high aperture immersion lenses,” J. Microsc.117(2), 219–232 (1979).
[CrossRef]

Becker, W.

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, “Fluorescence lifetime imaging by time-correlated single-photon counting,” Microsc. Res. Tech.63(1), 58–66 (2004).
[CrossRef] [PubMed]

Belov, V. N.

K. Kolmakov, V. N. Belov, J. Bierwagen, C. Ringemann, V. Müller, C. Eggeling, and S. W. Hell, “Red-emitting rhodamine dyes for fluorescence microscopy and nanoscopy,” Chemistry16(1), 158–166 (2010).
[CrossRef] [PubMed]

Benndorf, K.

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, “Fluorescence lifetime imaging by time-correlated single-photon counting,” Microsc. Res. Tech.63(1), 58–66 (2004).
[CrossRef] [PubMed]

Bergmann, A.

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, “Fluorescence lifetime imaging by time-correlated single-photon counting,” Microsc. Res. Tech.63(1), 58–66 (2004).
[CrossRef] [PubMed]

Bierwagen, J.

K. Kolmakov, V. N. Belov, J. Bierwagen, C. Ringemann, V. Müller, C. Eggeling, and S. W. Hell, “Red-emitting rhodamine dyes for fluorescence microscopy and nanoscopy,” Chemistry16(1), 158–166 (2010).
[CrossRef] [PubMed]

Biskup, C.

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, “Fluorescence lifetime imaging by time-correlated single-photon counting,” Microsc. Res. Tech.63(1), 58–66 (2004).
[CrossRef] [PubMed]

Blom, P.

G. J. Brakenhoff, P. Blom, and P. Barends, “Confocal scanning light microscopy with high aperture immersion lenses,” J. Microsc.117(2), 219–232 (1979).
[CrossRef]

Borst, J. W.

J. W. Borst, M. A. Hink, A. Hoek, and A. J. W. G. Visser, “Effects of refractive index and viscosity on fluorescence and anisotropy decays of enhanced cyan and yellow fluorescent proteins,” J. Fluoresc.15(2), 153–160 (2005).
[CrossRef] [PubMed]

Brakenhoff, G. J.

G. J. Brakenhoff, P. Blom, and P. Barends, “Confocal scanning light microscopy with high aperture immersion lenses,” J. Microsc.117(2), 219–232 (1979).
[CrossRef]

Bückers, J.

Chang, C.-S.

Chong, S.

S. Lu, W. Min, S. Chong, G. R. Holtom, and X. S. Xie, “Label-free imaging of heme proteins with two-photon excited photothermal lens microscopy,” Appl. Phys. Lett.96(11), 113701 (2010).
[CrossRef]

W. Min, S. Lu, S. Chong, R. Roy, G. R. Holtom, and X. S. Xie, “Imaging chromophores with undetectable fluorescence by stimulated emission microscopy,” Nature461(7267), 1105–1109 (2009).
[CrossRef] [PubMed]

Dellwig, T.

T. Dellwig, P.-Y. Lin, and F.-J. Kao, “Long-distance fluorescence lifetime imaging using stimulated emission,” J. Biomed. Opt.17(1), 011009 (2012).
[CrossRef] [PubMed]

M. R. Foreman, T. Dellwig, and F.-J. Kao, “Coherent long-distance signal detection using stimulated emission: a feasibility study,” Chin. Phys. J.48, 873–884 (2010).

Dong, C. Y.

C. Y. Dong, P. T. So, T. French, and E. Gratton, “Fluorescence lifetime imaging by asynchronous pump-probe microscopy,” Biophys. J.69(6), 2234–2242 (1995).
[CrossRef] [PubMed]

Draaijer, A.

H. Gerritsen, R. Sanders, A. Draaijer, C. Ince, and Y. Levine, “Fluorescence lifetime imaging of oxygen in living cells,” J. Fluoresc.7(1), 11–15 (1997).
[CrossRef]

R. Sanders, A. Draaijer, H. C. Gerritsen, P. M. Houpt, and Y. K. Levine, “Quantitative pH imaging in cells using confocal fluorescence lifetime imaging microscopy,” Anal. Biochem.227(2), 302–308 (1995).
[CrossRef] [PubMed]

R. Sanders, H. C. Gerritsen, A. Draaijer, P. M. Houpt, and Y. K. Levine, “Fluorescence lifetime imaging of free calcium in single cells,” Bioimaging2(3), 131–138 (1994).
[CrossRef]

Eggeling, C.

K. Kolmakov, V. N. Belov, J. Bierwagen, C. Ringemann, V. Müller, C. Eggeling, and S. W. Hell, “Red-emitting rhodamine dyes for fluorescence microscopy and nanoscopy,” Chemistry16(1), 158–166 (2010).
[CrossRef] [PubMed]

Eisenmenger, W.

B. Gompf, R. Günther, G. Nick, R. Pecha, and W. Eisenmenger, “Resolving sonoluminescence pulse width with time-correlated single photon counting,” Phys. Rev. Lett.79(7), 1405–1408 (1997).
[CrossRef]

Errington, R. J.

R. J. Errington, S. M. Ameer-Beg, B. Vojnovic, L. H. Patterson, M. Zloh, and P. J. Smith, “Advanced microscopy solutions for monitoring the kinetics and dynamics of drug-DNA targeting in living cells,” Adv. Drug Deliv. Rev.57(1), 153–167 (2005).
[CrossRef] [PubMed]

Field, R. W.

C. E. Hamilton, J. L. Kinsey, and R. W. Field, “Stimulated emission pumping: new methods in spectroscopy and molecular dynamics,” Annu. Rev. Phys. Chem.37(1), 493–524 (1986).
[CrossRef]

Foreman, M. R.

M. R. Foreman, T. Dellwig, and F.-J. Kao, “Coherent long-distance signal detection using stimulated emission: a feasibility study,” Chin. Phys. J.48, 873–884 (2010).

French, T.

C. Y. Dong, P. T. So, T. French, and E. Gratton, “Fluorescence lifetime imaging by asynchronous pump-probe microscopy,” Biophys. J.69(6), 2234–2242 (1995).
[CrossRef] [PubMed]

Freudiger, C. W.

W. Min, C. W. Freudiger, S. Lu, and X. S. Xie, “Coherent nonlinear optical imaging: beyond fluorescence microscopy,” Annu. Rev. Phys. Chem.62(1), 507–530 (2011).
[CrossRef] [PubMed]

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. He, J. C. Tsai, J. X. Kang, and X. S. Xie, “Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy,” Science322(5909), 1857–1861 (2008).
[CrossRef] [PubMed]

Gerritsen, H.

H. Gerritsen, R. Sanders, A. Draaijer, C. Ince, and Y. Levine, “Fluorescence lifetime imaging of oxygen in living cells,” J. Fluoresc.7(1), 11–15 (1997).
[CrossRef]

Gerritsen, H. C.

R. Sanders, A. Draaijer, H. C. Gerritsen, P. M. Houpt, and Y. K. Levine, “Quantitative pH imaging in cells using confocal fluorescence lifetime imaging microscopy,” Anal. Biochem.227(2), 302–308 (1995).
[CrossRef] [PubMed]

R. Sanders, H. C. Gerritsen, A. Draaijer, P. M. Houpt, and Y. K. Levine, “Fluorescence lifetime imaging of free calcium in single cells,” Bioimaging2(3), 131–138 (1994).
[CrossRef]

Ghukasyan, V. V.

V. V. Ghukasyan and F.-J. Kao, “Monitoring cellular metabolism with fluorescence lifetime of reduced nicotinamide adenine dinucleotide,” J. Phys. Chem. C113(27), 11532–11540 (2009).
[CrossRef]

Gompf, B.

B. Gompf, R. Günther, G. Nick, R. Pecha, and W. Eisenmenger, “Resolving sonoluminescence pulse width with time-correlated single photon counting,” Phys. Rev. Lett.79(7), 1405–1408 (1997).
[CrossRef]

Gratton, E.

C. Y. Dong, P. T. So, T. French, and E. Gratton, “Fluorescence lifetime imaging by asynchronous pump-probe microscopy,” Biophys. J.69(6), 2234–2242 (1995).
[CrossRef] [PubMed]

Guild, J. B.

Günther, R.

B. Gompf, R. Günther, G. Nick, R. Pecha, and W. Eisenmenger, “Resolving sonoluminescence pulse width with time-correlated single photon counting,” Phys. Rev. Lett.79(7), 1405–1408 (1997).
[CrossRef]

Hall, J. L.

Hamilton, C. E.

C. E. Hamilton, J. L. Kinsey, and R. W. Field, “Stimulated emission pumping: new methods in spectroscopy and molecular dynamics,” Annu. Rev. Phys. Chem.37(1), 493–524 (1986).
[CrossRef]

He, C.

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. He, J. C. Tsai, J. X. Kang, and X. S. Xie, “Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy,” Science322(5909), 1857–1861 (2008).
[CrossRef] [PubMed]

Hell, S. W.

J. Bückers, D. Wildanger, G. Vicidomini, L. Kastrup, and S. W. Hell, “Simultaneous multi-lifetime multi-color STED imaging for colocalization analyses,” Opt. Express19(4), 3130–3143 (2011).
[CrossRef] [PubMed]

K. Kolmakov, V. N. Belov, J. Bierwagen, C. Ringemann, V. Müller, C. Eggeling, and S. W. Hell, “Red-emitting rhodamine dyes for fluorescence microscopy and nanoscopy,” Chemistry16(1), 158–166 (2010).
[CrossRef] [PubMed]

E. Rittweger, B. R. Rankin, V. Westphal, and S. W. Hell, “Fluorescence depletion mechanisms in super-resolving STED microscopy,” Chem. Phys. Lett.442(4-6), 483–487 (2007).
[CrossRef]

Herman, P.

H.-J. Lin, P. Herman, and J. R. Lakowicz, “Fluorescence lifetime-resolved pH imaging of living cells,” Cytometry AA52(2), 77–89 (2003).
[CrossRef] [PubMed]

Hink, M. A.

J. W. Borst, M. A. Hink, A. Hoek, and A. J. W. G. Visser, “Effects of refractive index and viscosity on fluorescence and anisotropy decays of enhanced cyan and yellow fluorescent proteins,” J. Fluoresc.15(2), 153–160 (2005).
[CrossRef] [PubMed]

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, “Fluorescence lifetime imaging by time-correlated single-photon counting,” Microsc. Res. Tech.63(1), 58–66 (2004).
[CrossRef] [PubMed]

Hoek, A.

J. W. Borst, M. A. Hink, A. Hoek, and A. J. W. G. Visser, “Effects of refractive index and viscosity on fluorescence and anisotropy decays of enhanced cyan and yellow fluorescent proteins,” J. Fluoresc.15(2), 153–160 (2005).
[CrossRef] [PubMed]

Holtom, G. R.

S. Lu, W. Min, S. Chong, G. R. Holtom, and X. S. Xie, “Label-free imaging of heme proteins with two-photon excited photothermal lens microscopy,” Appl. Phys. Lett.96(11), 113701 (2010).
[CrossRef]

W. Min, S. Lu, S. Chong, R. Roy, G. R. Holtom, and X. S. Xie, “Imaging chromophores with undetectable fluorescence by stimulated emission microscopy,” Nature461(7267), 1105–1109 (2009).
[CrossRef] [PubMed]

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. He, J. C. Tsai, J. X. Kang, and X. S. Xie, “Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy,” Science322(5909), 1857–1861 (2008).
[CrossRef] [PubMed]

Houpt, P. M.

R. Sanders, A. Draaijer, H. C. Gerritsen, P. M. Houpt, and Y. K. Levine, “Quantitative pH imaging in cells using confocal fluorescence lifetime imaging microscopy,” Anal. Biochem.227(2), 302–308 (1995).
[CrossRef] [PubMed]

R. Sanders, H. C. Gerritsen, A. Draaijer, P. M. Houpt, and Y. K. Levine, “Fluorescence lifetime imaging of free calcium in single cells,” Bioimaging2(3), 131–138 (1994).
[CrossRef]

Ince, C.

H. Gerritsen, R. Sanders, A. Draaijer, C. Ince, and Y. Levine, “Fluorescence lifetime imaging of oxygen in living cells,” J. Fluoresc.7(1), 11–15 (1997).
[CrossRef]

Johnson, M. L.

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, and M. L. Johnson, “Fluorescence lifetime imaging of free and protein-bound NADH,” Proc. Natl. Acad. Sci. U.S.A.89(4), 1271–1275 (1992).
[CrossRef] [PubMed]

Kang, J. X.

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. He, J. C. Tsai, J. X. Kang, and X. S. Xie, “Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy,” Science322(5909), 1857–1861 (2008).
[CrossRef] [PubMed]

Kao, F.-J.

T. Dellwig, P.-Y. Lin, and F.-J. Kao, “Long-distance fluorescence lifetime imaging using stimulated emission,” J. Biomed. Opt.17(1), 011009 (2012).
[CrossRef] [PubMed]

P.-Y. Lin, S.-S. Lee, C.-S. Chang, and F.-J. Kao, “Long working distance fluorescence lifetime imaging with stimulated emission and electronic time delay,” Opt. Express20(10), 11445–11450 (2012).
[CrossRef] [PubMed]

M. R. Foreman, T. Dellwig, and F.-J. Kao, “Coherent long-distance signal detection using stimulated emission: a feasibility study,” Chin. Phys. J.48, 873–884 (2010).

V. V. Ghukasyan and F.-J. Kao, “Monitoring cellular metabolism with fluorescence lifetime of reduced nicotinamide adenine dinucleotide,” J. Phys. Chem. C113(27), 11532–11540 (2009).
[CrossRef]

Kastrup, L.

Kinsey, J. L.

C. E. Hamilton, J. L. Kinsey, and R. W. Field, “Stimulated emission pumping: new methods in spectroscopy and molecular dynamics,” Annu. Rev. Phys. Chem.37(1), 493–524 (1986).
[CrossRef]

Kolmakov, K.

K. Kolmakov, V. N. Belov, J. Bierwagen, C. Ringemann, V. Müller, C. Eggeling, and S. W. Hell, “Red-emitting rhodamine dyes for fluorescence microscopy and nanoscopy,” Chemistry16(1), 158–166 (2010).
[CrossRef] [PubMed]

König, K.

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, “Fluorescence lifetime imaging by time-correlated single-photon counting,” Microsc. Res. Tech.63(1), 58–66 (2004).
[CrossRef] [PubMed]

Kusumi, A.

T. Oida, Y. Sako, and A. Kusumi, “Fluorescence lifetime imaging microscopy (flimscopy). Methodology development and application to studies of endosome fusion in single cells,” Biophys. J.64(3), 676–685 (1993).
[CrossRef] [PubMed]

Lakowicz, J. R.

H.-J. Lin, P. Herman, and J. R. Lakowicz, “Fluorescence lifetime-resolved pH imaging of living cells,” Cytometry AA52(2), 77–89 (2003).
[CrossRef] [PubMed]

H. Szmacinski and J. R. Lakowicz, “Optical measurements of pH using fluorescence lifetimes and phase-modulation fluorometry,” Anal. Chem.65(13), 1668–1674 (1993).
[CrossRef] [PubMed]

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, and M. L. Johnson, “Fluorescence lifetime imaging of free and protein-bound NADH,” Proc. Natl. Acad. Sci. U.S.A.89(4), 1271–1275 (1992).
[CrossRef] [PubMed]

Lee, S.-S.

Levine, Y.

H. Gerritsen, R. Sanders, A. Draaijer, C. Ince, and Y. Levine, “Fluorescence lifetime imaging of oxygen in living cells,” J. Fluoresc.7(1), 11–15 (1997).
[CrossRef]

Levine, Y. K.

R. Sanders, A. Draaijer, H. C. Gerritsen, P. M. Houpt, and Y. K. Levine, “Quantitative pH imaging in cells using confocal fluorescence lifetime imaging microscopy,” Anal. Biochem.227(2), 302–308 (1995).
[CrossRef] [PubMed]

R. Sanders, H. C. Gerritsen, A. Draaijer, P. M. Houpt, and Y. K. Levine, “Fluorescence lifetime imaging of free calcium in single cells,” Bioimaging2(3), 131–138 (1994).
[CrossRef]

Li, D.

Lin, H.-J.

H.-J. Lin, P. Herman, and J. R. Lakowicz, “Fluorescence lifetime-resolved pH imaging of living cells,” Cytometry AA52(2), 77–89 (2003).
[CrossRef] [PubMed]

Lin, P.-Y.

Lu, S.

W. Min, C. W. Freudiger, S. Lu, and X. S. Xie, “Coherent nonlinear optical imaging: beyond fluorescence microscopy,” Annu. Rev. Phys. Chem.62(1), 507–530 (2011).
[CrossRef] [PubMed]

S. Lu, W. Min, S. Chong, G. R. Holtom, and X. S. Xie, “Label-free imaging of heme proteins with two-photon excited photothermal lens microscopy,” Appl. Phys. Lett.96(11), 113701 (2010).
[CrossRef]

W. Min, S. Lu, S. Chong, R. Roy, G. R. Holtom, and X. S. Xie, “Imaging chromophores with undetectable fluorescence by stimulated emission microscopy,” Nature461(7267), 1105–1109 (2009).
[CrossRef] [PubMed]

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. He, J. C. Tsai, J. X. Kang, and X. S. Xie, “Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy,” Science322(5909), 1857–1861 (2008).
[CrossRef] [PubMed]

Ma, L.-S.

Müller, V.

K. Kolmakov, V. N. Belov, J. Bierwagen, C. Ringemann, V. Müller, C. Eggeling, and S. W. Hell, “Red-emitting rhodamine dyes for fluorescence microscopy and nanoscopy,” Chemistry16(1), 158–166 (2010).
[CrossRef] [PubMed]

Min, W.

W. Min, C. W. Freudiger, S. Lu, and X. S. Xie, “Coherent nonlinear optical imaging: beyond fluorescence microscopy,” Annu. Rev. Phys. Chem.62(1), 507–530 (2011).
[CrossRef] [PubMed]

S. Lu, W. Min, S. Chong, G. R. Holtom, and X. S. Xie, “Label-free imaging of heme proteins with two-photon excited photothermal lens microscopy,” Appl. Phys. Lett.96(11), 113701 (2010).
[CrossRef]

W. Min, S. Lu, S. Chong, R. Roy, G. R. Holtom, and X. S. Xie, “Imaging chromophores with undetectable fluorescence by stimulated emission microscopy,” Nature461(7267), 1105–1109 (2009).
[CrossRef] [PubMed]

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. He, J. C. Tsai, J. X. Kang, and X. S. Xie, “Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy,” Science322(5909), 1857–1861 (2008).
[CrossRef] [PubMed]

Nick, G.

B. Gompf, R. Günther, G. Nick, R. Pecha, and W. Eisenmenger, “Resolving sonoluminescence pulse width with time-correlated single photon counting,” Phys. Rev. Lett.79(7), 1405–1408 (1997).
[CrossRef]

Nowaczyk, K.

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, and M. L. Johnson, “Fluorescence lifetime imaging of free and protein-bound NADH,” Proc. Natl. Acad. Sci. U.S.A.89(4), 1271–1275 (1992).
[CrossRef] [PubMed]

Oida, T.

T. Oida, Y. Sako, and A. Kusumi, “Fluorescence lifetime imaging microscopy (flimscopy). Methodology development and application to studies of endosome fusion in single cells,” Biophys. J.64(3), 676–685 (1993).
[CrossRef] [PubMed]

Otto, C.

H.-J. van Manen, P. Verkuijlen, P. Wittendorp, V. Subramaniam, T. K. van den Berg, D. Roos, and C. Otto, “Refractive index sensing of green fluorescent proteins in living cells using fluorescence lifetime imaging microscopy,” Biophys. J.94(8), L67–L69 (2008).
[CrossRef] [PubMed]

Patterson, L. H.

R. J. Errington, S. M. Ameer-Beg, B. Vojnovic, L. H. Patterson, M. Zloh, and P. J. Smith, “Advanced microscopy solutions for monitoring the kinetics and dynamics of drug-DNA targeting in living cells,” Adv. Drug Deliv. Rev.57(1), 153–167 (2005).
[CrossRef] [PubMed]

Pecha, R.

B. Gompf, R. Günther, G. Nick, R. Pecha, and W. Eisenmenger, “Resolving sonoluminescence pulse width with time-correlated single photon counting,” Phys. Rev. Lett.79(7), 1405–1408 (1997).
[CrossRef]

Qu, J. Y.

Rankin, B. R.

E. Rittweger, B. R. Rankin, V. Westphal, and S. W. Hell, “Fluorescence depletion mechanisms in super-resolving STED microscopy,” Chem. Phys. Lett.442(4-6), 483–487 (2007).
[CrossRef]

Ringemann, C.

K. Kolmakov, V. N. Belov, J. Bierwagen, C. Ringemann, V. Müller, C. Eggeling, and S. W. Hell, “Red-emitting rhodamine dyes for fluorescence microscopy and nanoscopy,” Chemistry16(1), 158–166 (2010).
[CrossRef] [PubMed]

Rittweger, E.

E. Rittweger, B. R. Rankin, V. Westphal, and S. W. Hell, “Fluorescence depletion mechanisms in super-resolving STED microscopy,” Chem. Phys. Lett.442(4-6), 483–487 (2007).
[CrossRef]

Roos, D.

H.-J. van Manen, P. Verkuijlen, P. Wittendorp, V. Subramaniam, T. K. van den Berg, D. Roos, and C. Otto, “Refractive index sensing of green fluorescent proteins in living cells using fluorescence lifetime imaging microscopy,” Biophys. J.94(8), L67–L69 (2008).
[CrossRef] [PubMed]

Roy, R.

W. Min, S. Lu, S. Chong, R. Roy, G. R. Holtom, and X. S. Xie, “Imaging chromophores with undetectable fluorescence by stimulated emission microscopy,” Nature461(7267), 1105–1109 (2009).
[CrossRef] [PubMed]

Saar, B. G.

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. He, J. C. Tsai, J. X. Kang, and X. S. Xie, “Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy,” Science322(5909), 1857–1861 (2008).
[CrossRef] [PubMed]

Sako, Y.

T. Oida, Y. Sako, and A. Kusumi, “Fluorescence lifetime imaging microscopy (flimscopy). Methodology development and application to studies of endosome fusion in single cells,” Biophys. J.64(3), 676–685 (1993).
[CrossRef] [PubMed]

Sanders, R.

H. Gerritsen, R. Sanders, A. Draaijer, C. Ince, and Y. Levine, “Fluorescence lifetime imaging of oxygen in living cells,” J. Fluoresc.7(1), 11–15 (1997).
[CrossRef]

R. Sanders, A. Draaijer, H. C. Gerritsen, P. M. Houpt, and Y. K. Levine, “Quantitative pH imaging in cells using confocal fluorescence lifetime imaging microscopy,” Anal. Biochem.227(2), 302–308 (1995).
[CrossRef] [PubMed]

R. Sanders, H. C. Gerritsen, A. Draaijer, P. M. Houpt, and Y. K. Levine, “Fluorescence lifetime imaging of free calcium in single cells,” Bioimaging2(3), 131–138 (1994).
[CrossRef]

Smith, P. J.

R. J. Errington, S. M. Ameer-Beg, B. Vojnovic, L. H. Patterson, M. Zloh, and P. J. Smith, “Advanced microscopy solutions for monitoring the kinetics and dynamics of drug-DNA targeting in living cells,” Adv. Drug Deliv. Rev.57(1), 153–167 (2005).
[CrossRef] [PubMed]

So, P. T.

C. Y. Dong, P. T. So, T. French, and E. Gratton, “Fluorescence lifetime imaging by asynchronous pump-probe microscopy,” Biophys. J.69(6), 2234–2242 (1995).
[CrossRef] [PubMed]

Subramaniam, V.

H.-J. van Manen, P. Verkuijlen, P. Wittendorp, V. Subramaniam, T. K. van den Berg, D. Roos, and C. Otto, “Refractive index sensing of green fluorescent proteins in living cells using fluorescence lifetime imaging microscopy,” Biophys. J.94(8), L67–L69 (2008).
[CrossRef] [PubMed]

Szmacinski, H.

H. Szmacinski and J. R. Lakowicz, “Optical measurements of pH using fluorescence lifetimes and phase-modulation fluorometry,” Anal. Chem.65(13), 1668–1674 (1993).
[CrossRef] [PubMed]

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, and M. L. Johnson, “Fluorescence lifetime imaging of free and protein-bound NADH,” Proc. Natl. Acad. Sci. U.S.A.89(4), 1271–1275 (1992).
[CrossRef] [PubMed]

Tsai, J. C.

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. He, J. C. Tsai, J. X. Kang, and X. S. Xie, “Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy,” Science322(5909), 1857–1861 (2008).
[CrossRef] [PubMed]

Tyagi, S.

S. Tyagi, “Imaging intracellular RNA distribution and dynamics in living cells,” Nat. Methods6(5), 331–338 (2009).
[CrossRef] [PubMed]

van den Berg, T. K.

H.-J. van Manen, P. Verkuijlen, P. Wittendorp, V. Subramaniam, T. K. van den Berg, D. Roos, and C. Otto, “Refractive index sensing of green fluorescent proteins in living cells using fluorescence lifetime imaging microscopy,” Biophys. J.94(8), L67–L69 (2008).
[CrossRef] [PubMed]

van Manen, H.-J.

H.-J. van Manen, P. Verkuijlen, P. Wittendorp, V. Subramaniam, T. K. van den Berg, D. Roos, and C. Otto, “Refractive index sensing of green fluorescent proteins in living cells using fluorescence lifetime imaging microscopy,” Biophys. J.94(8), L67–L69 (2008).
[CrossRef] [PubMed]

Verkuijlen, P.

H.-J. van Manen, P. Verkuijlen, P. Wittendorp, V. Subramaniam, T. K. van den Berg, D. Roos, and C. Otto, “Refractive index sensing of green fluorescent proteins in living cells using fluorescence lifetime imaging microscopy,” Biophys. J.94(8), L67–L69 (2008).
[CrossRef] [PubMed]

Vicidomini, G.

Visser, A. J. W. G.

J. W. Borst, M. A. Hink, A. Hoek, and A. J. W. G. Visser, “Effects of refractive index and viscosity on fluorescence and anisotropy decays of enhanced cyan and yellow fluorescent proteins,” J. Fluoresc.15(2), 153–160 (2005).
[CrossRef] [PubMed]

Vojnovic, B.

R. J. Errington, S. M. Ameer-Beg, B. Vojnovic, L. H. Patterson, M. Zloh, and P. J. Smith, “Advanced microscopy solutions for monitoring the kinetics and dynamics of drug-DNA targeting in living cells,” Adv. Drug Deliv. Rev.57(1), 153–167 (2005).
[CrossRef] [PubMed]

Webb, W. W.

Westphal, V.

E. Rittweger, B. R. Rankin, V. Westphal, and S. W. Hell, “Fluorescence depletion mechanisms in super-resolving STED microscopy,” Chem. Phys. Lett.442(4-6), 483–487 (2007).
[CrossRef]

Wildanger, D.

Wittendorp, P.

H.-J. van Manen, P. Verkuijlen, P. Wittendorp, V. Subramaniam, T. K. van den Berg, D. Roos, and C. Otto, “Refractive index sensing of green fluorescent proteins in living cells using fluorescence lifetime imaging microscopy,” Biophys. J.94(8), L67–L69 (2008).
[CrossRef] [PubMed]

Xie, X. S.

W. Min, C. W. Freudiger, S. Lu, and X. S. Xie, “Coherent nonlinear optical imaging: beyond fluorescence microscopy,” Annu. Rev. Phys. Chem.62(1), 507–530 (2011).
[CrossRef] [PubMed]

S. Lu, W. Min, S. Chong, G. R. Holtom, and X. S. Xie, “Label-free imaging of heme proteins with two-photon excited photothermal lens microscopy,” Appl. Phys. Lett.96(11), 113701 (2010).
[CrossRef]

W. Min, S. Lu, S. Chong, R. Roy, G. R. Holtom, and X. S. Xie, “Imaging chromophores with undetectable fluorescence by stimulated emission microscopy,” Nature461(7267), 1105–1109 (2009).
[CrossRef] [PubMed]

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. He, J. C. Tsai, J. X. Kang, and X. S. Xie, “Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy,” Science322(5909), 1857–1861 (2008).
[CrossRef] [PubMed]

Xu, C.

Ye, J.

Zheng, W.

Zloh, M.

R. J. Errington, S. M. Ameer-Beg, B. Vojnovic, L. H. Patterson, M. Zloh, and P. J. Smith, “Advanced microscopy solutions for monitoring the kinetics and dynamics of drug-DNA targeting in living cells,” Adv. Drug Deliv. Rev.57(1), 153–167 (2005).
[CrossRef] [PubMed]

Adv. Drug Deliv. Rev.

R. J. Errington, S. M. Ameer-Beg, B. Vojnovic, L. H. Patterson, M. Zloh, and P. J. Smith, “Advanced microscopy solutions for monitoring the kinetics and dynamics of drug-DNA targeting in living cells,” Adv. Drug Deliv. Rev.57(1), 153–167 (2005).
[CrossRef] [PubMed]

Anal. Biochem.

R. Sanders, A. Draaijer, H. C. Gerritsen, P. M. Houpt, and Y. K. Levine, “Quantitative pH imaging in cells using confocal fluorescence lifetime imaging microscopy,” Anal. Biochem.227(2), 302–308 (1995).
[CrossRef] [PubMed]

Anal. Chem.

H. Szmacinski and J. R. Lakowicz, “Optical measurements of pH using fluorescence lifetimes and phase-modulation fluorometry,” Anal. Chem.65(13), 1668–1674 (1993).
[CrossRef] [PubMed]

Annu. Rev. Phys. Chem.

C. E. Hamilton, J. L. Kinsey, and R. W. Field, “Stimulated emission pumping: new methods in spectroscopy and molecular dynamics,” Annu. Rev. Phys. Chem.37(1), 493–524 (1986).
[CrossRef]

W. Min, C. W. Freudiger, S. Lu, and X. S. Xie, “Coherent nonlinear optical imaging: beyond fluorescence microscopy,” Annu. Rev. Phys. Chem.62(1), 507–530 (2011).
[CrossRef] [PubMed]

Appl. Opt.

Appl. Phys. Lett.

S. Lu, W. Min, S. Chong, G. R. Holtom, and X. S. Xie, “Label-free imaging of heme proteins with two-photon excited photothermal lens microscopy,” Appl. Phys. Lett.96(11), 113701 (2010).
[CrossRef]

Bioimaging

R. Sanders, H. C. Gerritsen, A. Draaijer, P. M. Houpt, and Y. K. Levine, “Fluorescence lifetime imaging of free calcium in single cells,” Bioimaging2(3), 131–138 (1994).
[CrossRef]

Biophys. J.

H.-J. van Manen, P. Verkuijlen, P. Wittendorp, V. Subramaniam, T. K. van den Berg, D. Roos, and C. Otto, “Refractive index sensing of green fluorescent proteins in living cells using fluorescence lifetime imaging microscopy,” Biophys. J.94(8), L67–L69 (2008).
[CrossRef] [PubMed]

T. Oida, Y. Sako, and A. Kusumi, “Fluorescence lifetime imaging microscopy (flimscopy). Methodology development and application to studies of endosome fusion in single cells,” Biophys. J.64(3), 676–685 (1993).
[CrossRef] [PubMed]

C. Y. Dong, P. T. So, T. French, and E. Gratton, “Fluorescence lifetime imaging by asynchronous pump-probe microscopy,” Biophys. J.69(6), 2234–2242 (1995).
[CrossRef] [PubMed]

Chem. Phys. Lett.

E. Rittweger, B. R. Rankin, V. Westphal, and S. W. Hell, “Fluorescence depletion mechanisms in super-resolving STED microscopy,” Chem. Phys. Lett.442(4-6), 483–487 (2007).
[CrossRef]

Chemistry

K. Kolmakov, V. N. Belov, J. Bierwagen, C. Ringemann, V. Müller, C. Eggeling, and S. W. Hell, “Red-emitting rhodamine dyes for fluorescence microscopy and nanoscopy,” Chemistry16(1), 158–166 (2010).
[CrossRef] [PubMed]

Chin. Phys. J.

M. R. Foreman, T. Dellwig, and F.-J. Kao, “Coherent long-distance signal detection using stimulated emission: a feasibility study,” Chin. Phys. J.48, 873–884 (2010).

Cytometry A

H.-J. Lin, P. Herman, and J. R. Lakowicz, “Fluorescence lifetime-resolved pH imaging of living cells,” Cytometry AA52(2), 77–89 (2003).
[CrossRef] [PubMed]

J. Biomed. Opt.

T. Dellwig, P.-Y. Lin, and F.-J. Kao, “Long-distance fluorescence lifetime imaging using stimulated emission,” J. Biomed. Opt.17(1), 011009 (2012).
[CrossRef] [PubMed]

J. Fluoresc.

J. W. Borst, M. A. Hink, A. Hoek, and A. J. W. G. Visser, “Effects of refractive index and viscosity on fluorescence and anisotropy decays of enhanced cyan and yellow fluorescent proteins,” J. Fluoresc.15(2), 153–160 (2005).
[CrossRef] [PubMed]

H. Gerritsen, R. Sanders, A. Draaijer, C. Ince, and Y. Levine, “Fluorescence lifetime imaging of oxygen in living cells,” J. Fluoresc.7(1), 11–15 (1997).
[CrossRef]

J. Microsc.

G. J. Brakenhoff, P. Blom, and P. Barends, “Confocal scanning light microscopy with high aperture immersion lenses,” J. Microsc.117(2), 219–232 (1979).
[CrossRef]

J. Opt. Soc. Am. B

J. Phys. Chem. C

V. V. Ghukasyan and F.-J. Kao, “Monitoring cellular metabolism with fluorescence lifetime of reduced nicotinamide adenine dinucleotide,” J. Phys. Chem. C113(27), 11532–11540 (2009).
[CrossRef]

Microsc. Res. Tech.

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, “Fluorescence lifetime imaging by time-correlated single-photon counting,” Microsc. Res. Tech.63(1), 58–66 (2004).
[CrossRef] [PubMed]

Nat. Methods

S. Tyagi, “Imaging intracellular RNA distribution and dynamics in living cells,” Nat. Methods6(5), 331–338 (2009).
[CrossRef] [PubMed]

Nature

W. Min, S. Lu, S. Chong, R. Roy, G. R. Holtom, and X. S. Xie, “Imaging chromophores with undetectable fluorescence by stimulated emission microscopy,” Nature461(7267), 1105–1109 (2009).
[CrossRef] [PubMed]

Opt. Express

Opt. Lett.

Phys. Rev. Lett.

B. Gompf, R. Günther, G. Nick, R. Pecha, and W. Eisenmenger, “Resolving sonoluminescence pulse width with time-correlated single photon counting,” Phys. Rev. Lett.79(7), 1405–1408 (1997).
[CrossRef]

Proc. Natl. Acad. Sci. U.S.A.

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, and M. L. Johnson, “Fluorescence lifetime imaging of free and protein-bound NADH,” Proc. Natl. Acad. Sci. U.S.A.89(4), 1271–1275 (1992).
[CrossRef] [PubMed]

Science

C. W. Freudiger, W. Min, B. G. Saar, S. Lu, G. R. Holtom, C. He, J. C. Tsai, J. X. Kang, and X. S. Xie, “Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy,” Science322(5909), 1857–1861 (2008).
[CrossRef] [PubMed]

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Figures (3)

Fig. 1
Fig. 1

Schematic of stimulated emission based FLIM setup. LD1, LD2: laserdiode. LC1, LC2: laser driver. W1, W2: half-wave plate. P1, P2, P3: polarizer. EOM: Electro-optical modulator. R: retro-reflector. PH: pinhole. DM: dichroic mirror. OL: objective lens. S: sample. F: filter. D: detector. LA: lock-in amplifier.

Fig. 2
Fig. 2

Images reconstructed from stimulated emission at (a) 0 ns time delay; (b) 1.5 ns time delay; (c) 3 ns time delay; (d) 4.5 ns time delay. Note that the intensity of these images is color coded. The regions of very low intensity are non-fluorescent defects on the surface of the sample container. The scale bar is 100 μm.

Fig. 3
Fig. 3

(a) Stimulated emission signal as a function of time delay between the excitation and the stimulation laser pulses. The decay curve is obtained from the region of interest (marked in inset). Inset: the corresponding FLIM image. The areas of very short lifetime are non-fluorescent defects on the surface of the sample container (r.f. Fig. 2). The scale bar is 100 μm. (b) The standard deviation of the signal as a function of the modulation frequency on the excitation beam.

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