Abstract

We report fast, non-scanning, wide-field two-photon fluorescence excitation with spectral and lifetime detection for in vivo biomedical applications. We determined the optical characteristics of the technique, developed a Gaussian flat-field correction method to reduce artifacts resulting from non-uniform excitation such that contrast is enhanced, and showed that it can be used for ex vivo and in vivo cellular-level imaging. Two applications were demonstrated: (i) ex vivo measurements of beta-amyloid plaques in retinas of transgenic mice, and (ii) in vivo imaging of sulfonated gallium(III) corroles injected into tumors. We demonstrate that wide-field two photon fluorescence excitation with flat-field correction provides more penetration depth as well as better contrast and axial resolution than the corresponding one-photon wide field excitation for the same dye. Importantly, when this technique is used together with spectral and fluorescence lifetime detection modules, it offers improved discrimination between fluorescence from molecules of interest and autofluorescence, with higher sensitivity and specificity for in vivo applications.

© 2011 OSA

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    [CrossRef] [PubMed]
  26. B. Rajwa, T. Bernas, H. Acker, J. Dobrucki, and J. P. Robinson, “Single- and two-photon spectral imaging of intrinsic fluorescence of transformed human hepatocytes,” Microsc. Res. Tech. 70(10), 869–879 (2007).
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2011

M. Koronyo-Hamaoui, Y. Koronyo, A. V. Ljubimov, C. A. Miller, M. K. Ko, K. L. Black, M. Schwartz, and D. L. Farkas, “Identification of amyloid plaques in retinas from Alzheimer’s patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model,” Neuroimage 54, S204–S217 (2011).
[CrossRef] [PubMed]

2010

J. Palero, S. I. C. O. Santos, D. Artigas, and P. Loza-Alvarez, “A simple scanless two-photon fluorescence microscope using selective plane illumination,” Opt. Express 18(8), 8491–8498 (2010).
[CrossRef] [PubMed]

L. Kupershmidt, Z. Okun, T. Amit, S. Mandel, I. Saltsman, A. Mahammed, O. Bar-Am, Z. Gross, and M. B. Youdim, “Metallocorroles as cytoprotective agents against oxidative and nitrative stress in cellular models of neurodegeneration,” J. Neurochem. 113(2), 363–373 (2010).
[CrossRef] [PubMed]

A. Kanamori, M. M. Catrinescu, A. Mahammed, Z. Gross, and L. A. Levin, “Neuroprotection against superoxide anion radical by metallocorroles in cellular and murine models of optic neuropathy,” J. Neurochem. 114(2), 488–498 (2010).
[PubMed]

2009

H. Agadjanian, J. Ma, A. Rentsendorj, V. Valluripalli, J. Y. Hwang, A. Mahammed, D. L. Farkas, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Tumor detection and elimination by a targeted gallium corrole,” Proc. Natl. Acad. Sci. U.S.A. 106(15), 6105–6110 (2009).
[CrossRef] [PubMed]

Z. Okun, L. Kupershmidt, T. Amit, S. Mandel, O. Bar-Am, M. B. Youdim, and Z. Gross, “Manganese corroles prevent intracellular nitration and subsequent death of insulin-producing cells,” ACS Chem. Biol. 4(11), 910–914 (2009).
[CrossRef] [PubMed]

E. Papagiakoumou, V. de Sars, V. Emiliani, and D. Oron, “Temporal focusing with spatially modulated excitation,” Opt. Express 17(7), 5391–5401 (2009).
[CrossRef] [PubMed]

2008

V. Nikolenko, B. O. Watson, R. Araya, A. Woodruff, D. S. Peterka, and R. Yuste, “SLM microscopy: scanless two-photon imaging and photostimulation using spatial light modulators,” Front. Neural Circuits 2, 5 (2008).
[CrossRef] [PubMed]

2007

S. Wachsmann-Hogiu, J. Y. Hwang, E. Lindsley, and D. L. Farkas, “Wide-field two-photon microscopy: features and advantages for biomedical applications,” Prog. Biomed. Opt. Imaging 8, 1–8 (2007).

A. Deniset-Besseau, S. Lévêque-Fort, M. P. Fontaine-Aupart, G. Roger, and P. Georges, “Three-dimensional time-resolved fluorescence imaging by multifocal multiphoton microscopy for a photosensitizer study in living cells,” Appl. Opt. 46(33), 8045–8051 (2007).
[CrossRef] [PubMed]

B. Rajwa, T. Bernas, H. Acker, J. Dobrucki, and J. P. Robinson, “Single- and two-photon spectral imaging of intrinsic fluorescence of transformed human hepatocytes,” Microsc. Res. Tech. 70(10), 869–879 (2007).
[CrossRef] [PubMed]

2006

H. Agadjanian, J. J. Weaver, A. Mahammed, A. Rentsendorj, S. Bass, J. Kim, I. J. Dmochowski, R. Margalit, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Specific delivery of corroles to cells via noncovalent conjugates with viral proteins,” Pharm. Res. 23(2), 367–377 (2006).
[CrossRef] [PubMed]

A. Chung, S. Karlan, E. Lindsley, S. Wachsmann-Hogiu, and D. L. Farkas, “In vivo cytometry: a spectrum of possibilities,” Cytometry A 69A(3), 142–146 (2006).
[CrossRef] [PubMed]

2005

2004

J. C. Jung, A. D. Mehta, E. Aksay, R. Stepnoski, and M. J. Schnitzer, “In vivo mammalian brain imaging using one- and two-photon fluorescence microendoscopy,” J. Neurophysiol. 92(5), 3121–3133 (2004).
[CrossRef] [PubMed]

M. Rubart, “Two-photon microscopy of cells and tissue,” Circ. Res. 95(12), 1154–1166 (2004).
[CrossRef] [PubMed]

2003

M. E. Dickinson, E. Simbuerger, B. Zimmermann, C. W. Waters, and S. E. Fraser, “Multiphoton excitation spectra in biological samples,” J. Biomed. Opt. 8(3), 329–338 (2003).
[CrossRef] [PubMed]

2002

K. M. Hanson, M. J. Behne, N. P. Barry, T. M. Mauro, E. Gratton, and R. M. Clegg, “Two-photon fluorescence lifetime imaging of the skin stratum corneum pH gradient,” Biophys. J. 83(3), 1682–1690 (2002).
[CrossRef] [PubMed]

2001

Q. T. Nguyen, N. Callamaras, C. Hsieh, and I. Parker, “Construction of a two-photon microscope for video-rate Ca(2+) imaging,” Cell Calcium 30(6), 383–393 (2001).
[CrossRef] [PubMed]

M. V. Macville, J. A. Van der Laak, E. J. Speel, N. Katzir, Y. Garini, D. Soenksen, G. McNamara, P. C. de Wilde, A. G. Hanselaar, A. H. Hopman, and T. Ried, “Spectral imaging of multi-color chromogenic dyes in pathological specimens,” Anal. Cell. Pathol. 22(3), 133–142 (2001).
[PubMed]

2000

1998

V. E. Centonze and J. G. White, “Multiphoton excitation provides optical sections from deeper within scattering specimens than confocal imaging,” Biophys. J. 75(4), 2015–2024 (1998).
[CrossRef] [PubMed]

1996

G. J. Brakenhoff, J. Squier, T. Norris, A. C. Bliton, M. H. Wade, and B. Athey, “Real-time two-photon confocal microscopy using a femtosecond, amplified Ti:sapphire system,” J. Microsc. 181(3), 253–259 (1996).
[CrossRef] [PubMed]

J. R. Lakowicz, “Emerging applications of fluorescence spectroscopy to cellular imaging: lifetime imaging, metal-ligand probes, multi-photon excitation and light quenching,” Scanning Microsc. Suppl. 10, 213–224 (1996).
[PubMed]

1992

S. T. Flock, S. L. Jacques, B. C. Wilson, W. M. Star, and M. J. van Gemert, “Optical properties of Intralipid: a phantom medium for light propagation studies,” Lasers Surg. Med. 12(5), 510–519 (1992).
[CrossRef] [PubMed]

1990

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248(4951), 73–76 (1990).
[CrossRef] [PubMed]

1970

S. D. Foss, “A method of exponential curve fitting by numerical integration,” Biometrics 26(4), 815–821 (1970).
[CrossRef]

Acker, H.

B. Rajwa, T. Bernas, H. Acker, J. Dobrucki, and J. P. Robinson, “Single- and two-photon spectral imaging of intrinsic fluorescence of transformed human hepatocytes,” Microsc. Res. Tech. 70(10), 869–879 (2007).
[CrossRef] [PubMed]

Agadjanian, H.

H. Agadjanian, J. Ma, A. Rentsendorj, V. Valluripalli, J. Y. Hwang, A. Mahammed, D. L. Farkas, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Tumor detection and elimination by a targeted gallium corrole,” Proc. Natl. Acad. Sci. U.S.A. 106(15), 6105–6110 (2009).
[CrossRef] [PubMed]

H. Agadjanian, J. J. Weaver, A. Mahammed, A. Rentsendorj, S. Bass, J. Kim, I. J. Dmochowski, R. Margalit, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Specific delivery of corroles to cells via noncovalent conjugates with viral proteins,” Pharm. Res. 23(2), 367–377 (2006).
[CrossRef] [PubMed]

Aksay, E.

J. C. Jung, A. D. Mehta, E. Aksay, R. Stepnoski, and M. J. Schnitzer, “In vivo mammalian brain imaging using one- and two-photon fluorescence microendoscopy,” J. Neurophysiol. 92(5), 3121–3133 (2004).
[CrossRef] [PubMed]

Amit, T.

L. Kupershmidt, Z. Okun, T. Amit, S. Mandel, I. Saltsman, A. Mahammed, O. Bar-Am, Z. Gross, and M. B. Youdim, “Metallocorroles as cytoprotective agents against oxidative and nitrative stress in cellular models of neurodegeneration,” J. Neurochem. 113(2), 363–373 (2010).
[CrossRef] [PubMed]

Z. Okun, L. Kupershmidt, T. Amit, S. Mandel, O. Bar-Am, M. B. Youdim, and Z. Gross, “Manganese corroles prevent intracellular nitration and subsequent death of insulin-producing cells,” ACS Chem. Biol. 4(11), 910–914 (2009).
[CrossRef] [PubMed]

Anderson, E. P.

Araya, R.

V. Nikolenko, B. O. Watson, R. Araya, A. Woodruff, D. S. Peterka, and R. Yuste, “SLM microscopy: scanless two-photon imaging and photostimulation using spatial light modulators,” Front. Neural Circuits 2, 5 (2008).
[CrossRef] [PubMed]

Artigas, D.

Athey, B.

G. J. Brakenhoff, J. Squier, T. Norris, A. C. Bliton, M. H. Wade, and B. Athey, “Real-time two-photon confocal microscopy using a femtosecond, amplified Ti:sapphire system,” J. Microsc. 181(3), 253–259 (1996).
[CrossRef] [PubMed]

Bar-Am, O.

L. Kupershmidt, Z. Okun, T. Amit, S. Mandel, I. Saltsman, A. Mahammed, O. Bar-Am, Z. Gross, and M. B. Youdim, “Metallocorroles as cytoprotective agents against oxidative and nitrative stress in cellular models of neurodegeneration,” J. Neurochem. 113(2), 363–373 (2010).
[CrossRef] [PubMed]

Z. Okun, L. Kupershmidt, T. Amit, S. Mandel, O. Bar-Am, M. B. Youdim, and Z. Gross, “Manganese corroles prevent intracellular nitration and subsequent death of insulin-producing cells,” ACS Chem. Biol. 4(11), 910–914 (2009).
[CrossRef] [PubMed]

Barry, N. P.

K. M. Hanson, M. J. Behne, N. P. Barry, T. M. Mauro, E. Gratton, and R. M. Clegg, “Two-photon fluorescence lifetime imaging of the skin stratum corneum pH gradient,” Biophys. J. 83(3), 1682–1690 (2002).
[CrossRef] [PubMed]

Bass, S.

H. Agadjanian, J. J. Weaver, A. Mahammed, A. Rentsendorj, S. Bass, J. Kim, I. J. Dmochowski, R. Margalit, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Specific delivery of corroles to cells via noncovalent conjugates with viral proteins,” Pharm. Res. 23(2), 367–377 (2006).
[CrossRef] [PubMed]

Behne, M. J.

K. M. Hanson, M. J. Behne, N. P. Barry, T. M. Mauro, E. Gratton, and R. M. Clegg, “Two-photon fluorescence lifetime imaging of the skin stratum corneum pH gradient,” Biophys. J. 83(3), 1682–1690 (2002).
[CrossRef] [PubMed]

Bernas, T.

B. Rajwa, T. Bernas, H. Acker, J. Dobrucki, and J. P. Robinson, “Single- and two-photon spectral imaging of intrinsic fluorescence of transformed human hepatocytes,” Microsc. Res. Tech. 70(10), 869–879 (2007).
[CrossRef] [PubMed]

Black, K. L.

M. Koronyo-Hamaoui, Y. Koronyo, A. V. Ljubimov, C. A. Miller, M. K. Ko, K. L. Black, M. Schwartz, and D. L. Farkas, “Identification of amyloid plaques in retinas from Alzheimer’s patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model,” Neuroimage 54, S204–S217 (2011).
[CrossRef] [PubMed]

Bliton, A. C.

G. J. Brakenhoff, J. Squier, T. Norris, A. C. Bliton, M. H. Wade, and B. Athey, “Real-time two-photon confocal microscopy using a femtosecond, amplified Ti:sapphire system,” J. Microsc. 181(3), 253–259 (1996).
[CrossRef] [PubMed]

Brakenhoff, G. J.

G. J. Brakenhoff, J. Squier, T. Norris, A. C. Bliton, M. H. Wade, and B. Athey, “Real-time two-photon confocal microscopy using a femtosecond, amplified Ti:sapphire system,” J. Microsc. 181(3), 253–259 (1996).
[CrossRef] [PubMed]

Callamaras, N.

Q. T. Nguyen, N. Callamaras, C. Hsieh, and I. Parker, “Construction of a two-photon microscope for video-rate Ca(2+) imaging,” Cell Calcium 30(6), 383–393 (2001).
[CrossRef] [PubMed]

Catrinescu, M. M.

A. Kanamori, M. M. Catrinescu, A. Mahammed, Z. Gross, and L. A. Levin, “Neuroprotection against superoxide anion radical by metallocorroles in cellular and murine models of optic neuropathy,” J. Neurochem. 114(2), 488–498 (2010).
[PubMed]

Centonze, V. E.

V. E. Centonze and J. G. White, “Multiphoton excitation provides optical sections from deeper within scattering specimens than confocal imaging,” Biophys. J. 75(4), 2015–2024 (1998).
[CrossRef] [PubMed]

Chung, A.

A. Chung, S. Karlan, E. Lindsley, S. Wachsmann-Hogiu, and D. L. Farkas, “In vivo cytometry: a spectrum of possibilities,” Cytometry A 69A(3), 142–146 (2006).
[CrossRef] [PubMed]

Clegg, R. M.

K. M. Hanson, M. J. Behne, N. P. Barry, T. M. Mauro, E. Gratton, and R. M. Clegg, “Two-photon fluorescence lifetime imaging of the skin stratum corneum pH gradient,” Biophys. J. 83(3), 1682–1690 (2002).
[CrossRef] [PubMed]

Cocker, E. D.

de Sars, V.

de Wilde, P. C.

M. V. Macville, J. A. Van der Laak, E. J. Speel, N. Katzir, Y. Garini, D. Soenksen, G. McNamara, P. C. de Wilde, A. G. Hanselaar, A. H. Hopman, and T. Ried, “Spectral imaging of multi-color chromogenic dyes in pathological specimens,” Anal. Cell. Pathol. 22(3), 133–142 (2001).
[PubMed]

Deniset-Besseau, A.

Denk, W.

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248(4951), 73–76 (1990).
[CrossRef] [PubMed]

Dickinson, M. E.

M. E. Dickinson, E. Simbuerger, B. Zimmermann, C. W. Waters, and S. E. Fraser, “Multiphoton excitation spectra in biological samples,” J. Biomed. Opt. 8(3), 329–338 (2003).
[CrossRef] [PubMed]

Dmochowski, I. J.

H. Agadjanian, J. J. Weaver, A. Mahammed, A. Rentsendorj, S. Bass, J. Kim, I. J. Dmochowski, R. Margalit, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Specific delivery of corroles to cells via noncovalent conjugates with viral proteins,” Pharm. Res. 23(2), 367–377 (2006).
[CrossRef] [PubMed]

Dobrucki, J.

B. Rajwa, T. Bernas, H. Acker, J. Dobrucki, and J. P. Robinson, “Single- and two-photon spectral imaging of intrinsic fluorescence of transformed human hepatocytes,” Microsc. Res. Tech. 70(10), 869–879 (2007).
[CrossRef] [PubMed]

Egner, A.

Emiliani, V.

Farkas, D. L.

M. Koronyo-Hamaoui, Y. Koronyo, A. V. Ljubimov, C. A. Miller, M. K. Ko, K. L. Black, M. Schwartz, and D. L. Farkas, “Identification of amyloid plaques in retinas from Alzheimer’s patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model,” Neuroimage 54, S204–S217 (2011).
[CrossRef] [PubMed]

H. Agadjanian, J. Ma, A. Rentsendorj, V. Valluripalli, J. Y. Hwang, A. Mahammed, D. L. Farkas, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Tumor detection and elimination by a targeted gallium corrole,” Proc. Natl. Acad. Sci. U.S.A. 106(15), 6105–6110 (2009).
[CrossRef] [PubMed]

S. Wachsmann-Hogiu, J. Y. Hwang, E. Lindsley, and D. L. Farkas, “Wide-field two-photon microscopy: features and advantages for biomedical applications,” Prog. Biomed. Opt. Imaging 8, 1–8 (2007).

A. Chung, S. Karlan, E. Lindsley, S. Wachsmann-Hogiu, and D. L. Farkas, “In vivo cytometry: a spectrum of possibilities,” Cytometry A 69A(3), 142–146 (2006).
[CrossRef] [PubMed]

Fittinghoff, D. N.

Flock, S. T.

S. T. Flock, S. L. Jacques, B. C. Wilson, W. M. Star, and M. J. van Gemert, “Optical properties of Intralipid: a phantom medium for light propagation studies,” Lasers Surg. Med. 12(5), 510–519 (1992).
[CrossRef] [PubMed]

Flusberg, B. A.

Fontaine-Aupart, M. P.

Foss, S. D.

S. D. Foss, “A method of exponential curve fitting by numerical integration,” Biometrics 26(4), 815–821 (1970).
[CrossRef]

Fraser, S. E.

M. E. Dickinson, E. Simbuerger, B. Zimmermann, C. W. Waters, and S. E. Fraser, “Multiphoton excitation spectra in biological samples,” J. Biomed. Opt. 8(3), 329–338 (2003).
[CrossRef] [PubMed]

Garini, Y.

M. V. Macville, J. A. Van der Laak, E. J. Speel, N. Katzir, Y. Garini, D. Soenksen, G. McNamara, P. C. de Wilde, A. G. Hanselaar, A. H. Hopman, and T. Ried, “Spectral imaging of multi-color chromogenic dyes in pathological specimens,” Anal. Cell. Pathol. 22(3), 133–142 (2001).
[PubMed]

Georges, P.

Gratton, E.

K. M. Hanson, M. J. Behne, N. P. Barry, T. M. Mauro, E. Gratton, and R. M. Clegg, “Two-photon fluorescence lifetime imaging of the skin stratum corneum pH gradient,” Biophys. J. 83(3), 1682–1690 (2002).
[CrossRef] [PubMed]

Gray, H. B.

H. Agadjanian, J. Ma, A. Rentsendorj, V. Valluripalli, J. Y. Hwang, A. Mahammed, D. L. Farkas, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Tumor detection and elimination by a targeted gallium corrole,” Proc. Natl. Acad. Sci. U.S.A. 106(15), 6105–6110 (2009).
[CrossRef] [PubMed]

H. Agadjanian, J. J. Weaver, A. Mahammed, A. Rentsendorj, S. Bass, J. Kim, I. J. Dmochowski, R. Margalit, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Specific delivery of corroles to cells via noncovalent conjugates with viral proteins,” Pharm. Res. 23(2), 367–377 (2006).
[CrossRef] [PubMed]

Gross, Z.

L. Kupershmidt, Z. Okun, T. Amit, S. Mandel, I. Saltsman, A. Mahammed, O. Bar-Am, Z. Gross, and M. B. Youdim, “Metallocorroles as cytoprotective agents against oxidative and nitrative stress in cellular models of neurodegeneration,” J. Neurochem. 113(2), 363–373 (2010).
[CrossRef] [PubMed]

A. Kanamori, M. M. Catrinescu, A. Mahammed, Z. Gross, and L. A. Levin, “Neuroprotection against superoxide anion radical by metallocorroles in cellular and murine models of optic neuropathy,” J. Neurochem. 114(2), 488–498 (2010).
[PubMed]

H. Agadjanian, J. Ma, A. Rentsendorj, V. Valluripalli, J. Y. Hwang, A. Mahammed, D. L. Farkas, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Tumor detection and elimination by a targeted gallium corrole,” Proc. Natl. Acad. Sci. U.S.A. 106(15), 6105–6110 (2009).
[CrossRef] [PubMed]

Z. Okun, L. Kupershmidt, T. Amit, S. Mandel, O. Bar-Am, M. B. Youdim, and Z. Gross, “Manganese corroles prevent intracellular nitration and subsequent death of insulin-producing cells,” ACS Chem. Biol. 4(11), 910–914 (2009).
[CrossRef] [PubMed]

H. Agadjanian, J. J. Weaver, A. Mahammed, A. Rentsendorj, S. Bass, J. Kim, I. J. Dmochowski, R. Margalit, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Specific delivery of corroles to cells via noncovalent conjugates with viral proteins,” Pharm. Res. 23(2), 367–377 (2006).
[CrossRef] [PubMed]

Hanselaar, A. G.

M. V. Macville, J. A. Van der Laak, E. J. Speel, N. Katzir, Y. Garini, D. Soenksen, G. McNamara, P. C. de Wilde, A. G. Hanselaar, A. H. Hopman, and T. Ried, “Spectral imaging of multi-color chromogenic dyes in pathological specimens,” Anal. Cell. Pathol. 22(3), 133–142 (2001).
[PubMed]

Hanson, K. M.

K. M. Hanson, M. J. Behne, N. P. Barry, T. M. Mauro, E. Gratton, and R. M. Clegg, “Two-photon fluorescence lifetime imaging of the skin stratum corneum pH gradient,” Biophys. J. 83(3), 1682–1690 (2002).
[CrossRef] [PubMed]

Hell, S. W.

Hopman, A. H.

M. V. Macville, J. A. Van der Laak, E. J. Speel, N. Katzir, Y. Garini, D. Soenksen, G. McNamara, P. C. de Wilde, A. G. Hanselaar, A. H. Hopman, and T. Ried, “Spectral imaging of multi-color chromogenic dyes in pathological specimens,” Anal. Cell. Pathol. 22(3), 133–142 (2001).
[PubMed]

Hsieh, C.

Q. T. Nguyen, N. Callamaras, C. Hsieh, and I. Parker, “Construction of a two-photon microscope for video-rate Ca(2+) imaging,” Cell Calcium 30(6), 383–393 (2001).
[CrossRef] [PubMed]

Hwang, J. Y.

H. Agadjanian, J. Ma, A. Rentsendorj, V. Valluripalli, J. Y. Hwang, A. Mahammed, D. L. Farkas, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Tumor detection and elimination by a targeted gallium corrole,” Proc. Natl. Acad. Sci. U.S.A. 106(15), 6105–6110 (2009).
[CrossRef] [PubMed]

S. Wachsmann-Hogiu, J. Y. Hwang, E. Lindsley, and D. L. Farkas, “Wide-field two-photon microscopy: features and advantages for biomedical applications,” Prog. Biomed. Opt. Imaging 8, 1–8 (2007).

Jacques, S. L.

S. T. Flock, S. L. Jacques, B. C. Wilson, W. M. Star, and M. J. van Gemert, “Optical properties of Intralipid: a phantom medium for light propagation studies,” Lasers Surg. Med. 12(5), 510–519 (1992).
[CrossRef] [PubMed]

Jung, J. C.

B. A. Flusberg, J. C. Jung, E. D. Cocker, E. P. Anderson, and M. J. Schnitzer, “In vivo brain imaging using a portable 3.9 gram two-photon fluorescence microendoscope,” Opt. Lett. 30(17), 2272–2274 (2005).
[CrossRef] [PubMed]

J. C. Jung, A. D. Mehta, E. Aksay, R. Stepnoski, and M. J. Schnitzer, “In vivo mammalian brain imaging using one- and two-photon fluorescence microendoscopy,” J. Neurophysiol. 92(5), 3121–3133 (2004).
[CrossRef] [PubMed]

Kanamori, A.

A. Kanamori, M. M. Catrinescu, A. Mahammed, Z. Gross, and L. A. Levin, “Neuroprotection against superoxide anion radical by metallocorroles in cellular and murine models of optic neuropathy,” J. Neurochem. 114(2), 488–498 (2010).
[PubMed]

Karlan, S.

A. Chung, S. Karlan, E. Lindsley, S. Wachsmann-Hogiu, and D. L. Farkas, “In vivo cytometry: a spectrum of possibilities,” Cytometry A 69A(3), 142–146 (2006).
[CrossRef] [PubMed]

Katzir, N.

M. V. Macville, J. A. Van der Laak, E. J. Speel, N. Katzir, Y. Garini, D. Soenksen, G. McNamara, P. C. de Wilde, A. G. Hanselaar, A. H. Hopman, and T. Ried, “Spectral imaging of multi-color chromogenic dyes in pathological specimens,” Anal. Cell. Pathol. 22(3), 133–142 (2001).
[PubMed]

Kim, J.

H. Agadjanian, J. J. Weaver, A. Mahammed, A. Rentsendorj, S. Bass, J. Kim, I. J. Dmochowski, R. Margalit, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Specific delivery of corroles to cells via noncovalent conjugates with viral proteins,” Pharm. Res. 23(2), 367–377 (2006).
[CrossRef] [PubMed]

Ko, M. K.

M. Koronyo-Hamaoui, Y. Koronyo, A. V. Ljubimov, C. A. Miller, M. K. Ko, K. L. Black, M. Schwartz, and D. L. Farkas, “Identification of amyloid plaques in retinas from Alzheimer’s patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model,” Neuroimage 54, S204–S217 (2011).
[CrossRef] [PubMed]

Koronyo, Y.

M. Koronyo-Hamaoui, Y. Koronyo, A. V. Ljubimov, C. A. Miller, M. K. Ko, K. L. Black, M. Schwartz, and D. L. Farkas, “Identification of amyloid plaques in retinas from Alzheimer’s patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model,” Neuroimage 54, S204–S217 (2011).
[CrossRef] [PubMed]

Koronyo-Hamaoui, M.

M. Koronyo-Hamaoui, Y. Koronyo, A. V. Ljubimov, C. A. Miller, M. K. Ko, K. L. Black, M. Schwartz, and D. L. Farkas, “Identification of amyloid plaques in retinas from Alzheimer’s patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model,” Neuroimage 54, S204–S217 (2011).
[CrossRef] [PubMed]

Kupershmidt, L.

L. Kupershmidt, Z. Okun, T. Amit, S. Mandel, I. Saltsman, A. Mahammed, O. Bar-Am, Z. Gross, and M. B. Youdim, “Metallocorroles as cytoprotective agents against oxidative and nitrative stress in cellular models of neurodegeneration,” J. Neurochem. 113(2), 363–373 (2010).
[CrossRef] [PubMed]

Z. Okun, L. Kupershmidt, T. Amit, S. Mandel, O. Bar-Am, M. B. Youdim, and Z. Gross, “Manganese corroles prevent intracellular nitration and subsequent death of insulin-producing cells,” ACS Chem. Biol. 4(11), 910–914 (2009).
[CrossRef] [PubMed]

Lakowicz, J. R.

J. R. Lakowicz, “Emerging applications of fluorescence spectroscopy to cellular imaging: lifetime imaging, metal-ligand probes, multi-photon excitation and light quenching,” Scanning Microsc. Suppl. 10, 213–224 (1996).
[PubMed]

Lévêque-Fort, S.

Levin, L. A.

A. Kanamori, M. M. Catrinescu, A. Mahammed, Z. Gross, and L. A. Levin, “Neuroprotection against superoxide anion radical by metallocorroles in cellular and murine models of optic neuropathy,” J. Neurochem. 114(2), 488–498 (2010).
[PubMed]

Lindsley, E.

S. Wachsmann-Hogiu, J. Y. Hwang, E. Lindsley, and D. L. Farkas, “Wide-field two-photon microscopy: features and advantages for biomedical applications,” Prog. Biomed. Opt. Imaging 8, 1–8 (2007).

A. Chung, S. Karlan, E. Lindsley, S. Wachsmann-Hogiu, and D. L. Farkas, “In vivo cytometry: a spectrum of possibilities,” Cytometry A 69A(3), 142–146 (2006).
[CrossRef] [PubMed]

Ljubimov, A. V.

M. Koronyo-Hamaoui, Y. Koronyo, A. V. Ljubimov, C. A. Miller, M. K. Ko, K. L. Black, M. Schwartz, and D. L. Farkas, “Identification of amyloid plaques in retinas from Alzheimer’s patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model,” Neuroimage 54, S204–S217 (2011).
[CrossRef] [PubMed]

Loza-Alvarez, P.

Ma, J.

H. Agadjanian, J. Ma, A. Rentsendorj, V. Valluripalli, J. Y. Hwang, A. Mahammed, D. L. Farkas, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Tumor detection and elimination by a targeted gallium corrole,” Proc. Natl. Acad. Sci. U.S.A. 106(15), 6105–6110 (2009).
[CrossRef] [PubMed]

Macville, M. V.

M. V. Macville, J. A. Van der Laak, E. J. Speel, N. Katzir, Y. Garini, D. Soenksen, G. McNamara, P. C. de Wilde, A. G. Hanselaar, A. H. Hopman, and T. Ried, “Spectral imaging of multi-color chromogenic dyes in pathological specimens,” Anal. Cell. Pathol. 22(3), 133–142 (2001).
[PubMed]

Mahammed, A.

L. Kupershmidt, Z. Okun, T. Amit, S. Mandel, I. Saltsman, A. Mahammed, O. Bar-Am, Z. Gross, and M. B. Youdim, “Metallocorroles as cytoprotective agents against oxidative and nitrative stress in cellular models of neurodegeneration,” J. Neurochem. 113(2), 363–373 (2010).
[CrossRef] [PubMed]

A. Kanamori, M. M. Catrinescu, A. Mahammed, Z. Gross, and L. A. Levin, “Neuroprotection against superoxide anion radical by metallocorroles in cellular and murine models of optic neuropathy,” J. Neurochem. 114(2), 488–498 (2010).
[PubMed]

H. Agadjanian, J. Ma, A. Rentsendorj, V. Valluripalli, J. Y. Hwang, A. Mahammed, D. L. Farkas, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Tumor detection and elimination by a targeted gallium corrole,” Proc. Natl. Acad. Sci. U.S.A. 106(15), 6105–6110 (2009).
[CrossRef] [PubMed]

H. Agadjanian, J. J. Weaver, A. Mahammed, A. Rentsendorj, S. Bass, J. Kim, I. J. Dmochowski, R. Margalit, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Specific delivery of corroles to cells via noncovalent conjugates with viral proteins,” Pharm. Res. 23(2), 367–377 (2006).
[CrossRef] [PubMed]

Mandel, S.

L. Kupershmidt, Z. Okun, T. Amit, S. Mandel, I. Saltsman, A. Mahammed, O. Bar-Am, Z. Gross, and M. B. Youdim, “Metallocorroles as cytoprotective agents against oxidative and nitrative stress in cellular models of neurodegeneration,” J. Neurochem. 113(2), 363–373 (2010).
[CrossRef] [PubMed]

Z. Okun, L. Kupershmidt, T. Amit, S. Mandel, O. Bar-Am, M. B. Youdim, and Z. Gross, “Manganese corroles prevent intracellular nitration and subsequent death of insulin-producing cells,” ACS Chem. Biol. 4(11), 910–914 (2009).
[CrossRef] [PubMed]

Margalit, R.

H. Agadjanian, J. J. Weaver, A. Mahammed, A. Rentsendorj, S. Bass, J. Kim, I. J. Dmochowski, R. Margalit, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Specific delivery of corroles to cells via noncovalent conjugates with viral proteins,” Pharm. Res. 23(2), 367–377 (2006).
[CrossRef] [PubMed]

Mauro, T. M.

K. M. Hanson, M. J. Behne, N. P. Barry, T. M. Mauro, E. Gratton, and R. M. Clegg, “Two-photon fluorescence lifetime imaging of the skin stratum corneum pH gradient,” Biophys. J. 83(3), 1682–1690 (2002).
[CrossRef] [PubMed]

McNamara, G.

M. V. Macville, J. A. Van der Laak, E. J. Speel, N. Katzir, Y. Garini, D. Soenksen, G. McNamara, P. C. de Wilde, A. G. Hanselaar, A. H. Hopman, and T. Ried, “Spectral imaging of multi-color chromogenic dyes in pathological specimens,” Anal. Cell. Pathol. 22(3), 133–142 (2001).
[PubMed]

Medina-Kauwe, L. K.

H. Agadjanian, J. Ma, A. Rentsendorj, V. Valluripalli, J. Y. Hwang, A. Mahammed, D. L. Farkas, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Tumor detection and elimination by a targeted gallium corrole,” Proc. Natl. Acad. Sci. U.S.A. 106(15), 6105–6110 (2009).
[CrossRef] [PubMed]

H. Agadjanian, J. J. Weaver, A. Mahammed, A. Rentsendorj, S. Bass, J. Kim, I. J. Dmochowski, R. Margalit, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Specific delivery of corroles to cells via noncovalent conjugates with viral proteins,” Pharm. Res. 23(2), 367–377 (2006).
[CrossRef] [PubMed]

Mehta, A. D.

J. C. Jung, A. D. Mehta, E. Aksay, R. Stepnoski, and M. J. Schnitzer, “In vivo mammalian brain imaging using one- and two-photon fluorescence microendoscopy,” J. Neurophysiol. 92(5), 3121–3133 (2004).
[CrossRef] [PubMed]

Miller, C. A.

M. Koronyo-Hamaoui, Y. Koronyo, A. V. Ljubimov, C. A. Miller, M. K. Ko, K. L. Black, M. Schwartz, and D. L. Farkas, “Identification of amyloid plaques in retinas from Alzheimer’s patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model,” Neuroimage 54, S204–S217 (2011).
[CrossRef] [PubMed]

Nguyen, Q. T.

Q. T. Nguyen, N. Callamaras, C. Hsieh, and I. Parker, “Construction of a two-photon microscope for video-rate Ca(2+) imaging,” Cell Calcium 30(6), 383–393 (2001).
[CrossRef] [PubMed]

Nikolenko, V.

V. Nikolenko, B. O. Watson, R. Araya, A. Woodruff, D. S. Peterka, and R. Yuste, “SLM microscopy: scanless two-photon imaging and photostimulation using spatial light modulators,” Front. Neural Circuits 2, 5 (2008).
[CrossRef] [PubMed]

Norris, T.

G. J. Brakenhoff, J. Squier, T. Norris, A. C. Bliton, M. H. Wade, and B. Athey, “Real-time two-photon confocal microscopy using a femtosecond, amplified Ti:sapphire system,” J. Microsc. 181(3), 253–259 (1996).
[CrossRef] [PubMed]

Okun, Z.

L. Kupershmidt, Z. Okun, T. Amit, S. Mandel, I. Saltsman, A. Mahammed, O. Bar-Am, Z. Gross, and M. B. Youdim, “Metallocorroles as cytoprotective agents against oxidative and nitrative stress in cellular models of neurodegeneration,” J. Neurochem. 113(2), 363–373 (2010).
[CrossRef] [PubMed]

Z. Okun, L. Kupershmidt, T. Amit, S. Mandel, O. Bar-Am, M. B. Youdim, and Z. Gross, “Manganese corroles prevent intracellular nitration and subsequent death of insulin-producing cells,” ACS Chem. Biol. 4(11), 910–914 (2009).
[CrossRef] [PubMed]

Oron, D.

Palero, J.

Papagiakoumou, E.

Parker, I.

Q. T. Nguyen, N. Callamaras, C. Hsieh, and I. Parker, “Construction of a two-photon microscope for video-rate Ca(2+) imaging,” Cell Calcium 30(6), 383–393 (2001).
[CrossRef] [PubMed]

Patterson, G. H.

G. H. Patterson and D. W. Piston, “Photobleaching in two-photon excitation microscopy,” Biophys. J. 78(4), 2159–2162 (2000).
[CrossRef] [PubMed]

Peterka, D. S.

V. Nikolenko, B. O. Watson, R. Araya, A. Woodruff, D. S. Peterka, and R. Yuste, “SLM microscopy: scanless two-photon imaging and photostimulation using spatial light modulators,” Front. Neural Circuits 2, 5 (2008).
[CrossRef] [PubMed]

Piston, D. W.

G. H. Patterson and D. W. Piston, “Photobleaching in two-photon excitation microscopy,” Biophys. J. 78(4), 2159–2162 (2000).
[CrossRef] [PubMed]

Rajwa, B.

B. Rajwa, T. Bernas, H. Acker, J. Dobrucki, and J. P. Robinson, “Single- and two-photon spectral imaging of intrinsic fluorescence of transformed human hepatocytes,” Microsc. Res. Tech. 70(10), 869–879 (2007).
[CrossRef] [PubMed]

Rentsendorj, A.

H. Agadjanian, J. Ma, A. Rentsendorj, V. Valluripalli, J. Y. Hwang, A. Mahammed, D. L. Farkas, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Tumor detection and elimination by a targeted gallium corrole,” Proc. Natl. Acad. Sci. U.S.A. 106(15), 6105–6110 (2009).
[CrossRef] [PubMed]

H. Agadjanian, J. J. Weaver, A. Mahammed, A. Rentsendorj, S. Bass, J. Kim, I. J. Dmochowski, R. Margalit, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Specific delivery of corroles to cells via noncovalent conjugates with viral proteins,” Pharm. Res. 23(2), 367–377 (2006).
[CrossRef] [PubMed]

Ried, T.

M. V. Macville, J. A. Van der Laak, E. J. Speel, N. Katzir, Y. Garini, D. Soenksen, G. McNamara, P. C. de Wilde, A. G. Hanselaar, A. H. Hopman, and T. Ried, “Spectral imaging of multi-color chromogenic dyes in pathological specimens,” Anal. Cell. Pathol. 22(3), 133–142 (2001).
[PubMed]

Robinson, J. P.

B. Rajwa, T. Bernas, H. Acker, J. Dobrucki, and J. P. Robinson, “Single- and two-photon spectral imaging of intrinsic fluorescence of transformed human hepatocytes,” Microsc. Res. Tech. 70(10), 869–879 (2007).
[CrossRef] [PubMed]

Roger, G.

Rubart, M.

M. Rubart, “Two-photon microscopy of cells and tissue,” Circ. Res. 95(12), 1154–1166 (2004).
[CrossRef] [PubMed]

Saltsman, I.

L. Kupershmidt, Z. Okun, T. Amit, S. Mandel, I. Saltsman, A. Mahammed, O. Bar-Am, Z. Gross, and M. B. Youdim, “Metallocorroles as cytoprotective agents against oxidative and nitrative stress in cellular models of neurodegeneration,” J. Neurochem. 113(2), 363–373 (2010).
[CrossRef] [PubMed]

Santos, S. I. C. O.

Schnitzer, M. J.

B. A. Flusberg, J. C. Jung, E. D. Cocker, E. P. Anderson, and M. J. Schnitzer, “In vivo brain imaging using a portable 3.9 gram two-photon fluorescence microendoscope,” Opt. Lett. 30(17), 2272–2274 (2005).
[CrossRef] [PubMed]

J. C. Jung, A. D. Mehta, E. Aksay, R. Stepnoski, and M. J. Schnitzer, “In vivo mammalian brain imaging using one- and two-photon fluorescence microendoscopy,” J. Neurophysiol. 92(5), 3121–3133 (2004).
[CrossRef] [PubMed]

Schwartz, M.

M. Koronyo-Hamaoui, Y. Koronyo, A. V. Ljubimov, C. A. Miller, M. K. Ko, K. L. Black, M. Schwartz, and D. L. Farkas, “Identification of amyloid plaques in retinas from Alzheimer’s patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model,” Neuroimage 54, S204–S217 (2011).
[CrossRef] [PubMed]

Simbuerger, E.

M. E. Dickinson, E. Simbuerger, B. Zimmermann, C. W. Waters, and S. E. Fraser, “Multiphoton excitation spectra in biological samples,” J. Biomed. Opt. 8(3), 329–338 (2003).
[CrossRef] [PubMed]

Soenksen, D.

M. V. Macville, J. A. Van der Laak, E. J. Speel, N. Katzir, Y. Garini, D. Soenksen, G. McNamara, P. C. de Wilde, A. G. Hanselaar, A. H. Hopman, and T. Ried, “Spectral imaging of multi-color chromogenic dyes in pathological specimens,” Anal. Cell. Pathol. 22(3), 133–142 (2001).
[PubMed]

Speel, E. J.

M. V. Macville, J. A. Van der Laak, E. J. Speel, N. Katzir, Y. Garini, D. Soenksen, G. McNamara, P. C. de Wilde, A. G. Hanselaar, A. H. Hopman, and T. Ried, “Spectral imaging of multi-color chromogenic dyes in pathological specimens,” Anal. Cell. Pathol. 22(3), 133–142 (2001).
[PubMed]

Squier, J.

G. J. Brakenhoff, J. Squier, T. Norris, A. C. Bliton, M. H. Wade, and B. Athey, “Real-time two-photon confocal microscopy using a femtosecond, amplified Ti:sapphire system,” J. Microsc. 181(3), 253–259 (1996).
[CrossRef] [PubMed]

Squier, J. A.

Star, W. M.

S. T. Flock, S. L. Jacques, B. C. Wilson, W. M. Star, and M. J. van Gemert, “Optical properties of Intralipid: a phantom medium for light propagation studies,” Lasers Surg. Med. 12(5), 510–519 (1992).
[CrossRef] [PubMed]

Stepnoski, R.

J. C. Jung, A. D. Mehta, E. Aksay, R. Stepnoski, and M. J. Schnitzer, “In vivo mammalian brain imaging using one- and two-photon fluorescence microendoscopy,” J. Neurophysiol. 92(5), 3121–3133 (2004).
[CrossRef] [PubMed]

Strickler, J. H.

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248(4951), 73–76 (1990).
[CrossRef] [PubMed]

Valluripalli, V.

H. Agadjanian, J. Ma, A. Rentsendorj, V. Valluripalli, J. Y. Hwang, A. Mahammed, D. L. Farkas, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Tumor detection and elimination by a targeted gallium corrole,” Proc. Natl. Acad. Sci. U.S.A. 106(15), 6105–6110 (2009).
[CrossRef] [PubMed]

Van der Laak, J. A.

M. V. Macville, J. A. Van der Laak, E. J. Speel, N. Katzir, Y. Garini, D. Soenksen, G. McNamara, P. C. de Wilde, A. G. Hanselaar, A. H. Hopman, and T. Ried, “Spectral imaging of multi-color chromogenic dyes in pathological specimens,” Anal. Cell. Pathol. 22(3), 133–142 (2001).
[PubMed]

van Gemert, M. J.

S. T. Flock, S. L. Jacques, B. C. Wilson, W. M. Star, and M. J. van Gemert, “Optical properties of Intralipid: a phantom medium for light propagation studies,” Lasers Surg. Med. 12(5), 510–519 (1992).
[CrossRef] [PubMed]

Wachsmann-Hogiu, S.

S. Wachsmann-Hogiu, J. Y. Hwang, E. Lindsley, and D. L. Farkas, “Wide-field two-photon microscopy: features and advantages for biomedical applications,” Prog. Biomed. Opt. Imaging 8, 1–8 (2007).

A. Chung, S. Karlan, E. Lindsley, S. Wachsmann-Hogiu, and D. L. Farkas, “In vivo cytometry: a spectrum of possibilities,” Cytometry A 69A(3), 142–146 (2006).
[CrossRef] [PubMed]

Wade, M. H.

G. J. Brakenhoff, J. Squier, T. Norris, A. C. Bliton, M. H. Wade, and B. Athey, “Real-time two-photon confocal microscopy using a femtosecond, amplified Ti:sapphire system,” J. Microsc. 181(3), 253–259 (1996).
[CrossRef] [PubMed]

Waters, C. W.

M. E. Dickinson, E. Simbuerger, B. Zimmermann, C. W. Waters, and S. E. Fraser, “Multiphoton excitation spectra in biological samples,” J. Biomed. Opt. 8(3), 329–338 (2003).
[CrossRef] [PubMed]

Watson, B. O.

V. Nikolenko, B. O. Watson, R. Araya, A. Woodruff, D. S. Peterka, and R. Yuste, “SLM microscopy: scanless two-photon imaging and photostimulation using spatial light modulators,” Front. Neural Circuits 2, 5 (2008).
[CrossRef] [PubMed]

Weaver, J. J.

H. Agadjanian, J. J. Weaver, A. Mahammed, A. Rentsendorj, S. Bass, J. Kim, I. J. Dmochowski, R. Margalit, H. B. Gray, Z. Gross, and L. K. Medina-Kauwe, “Specific delivery of corroles to cells via noncovalent conjugates with viral proteins,” Pharm. Res. 23(2), 367–377 (2006).
[CrossRef] [PubMed]

Webb, W. W.

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248(4951), 73–76 (1990).
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Figures (5)

Fig. 1
Fig. 1

Schematics of the experimental set-up for wide-field two-photon excitation: (A) multimode optical imaging with wide-field two-photon excitation (B) wide-field two-photon excitation set-up combined with scanning confocal microscopy on an Olympus Fluoview 300 platform. FR: faraday rotator, TGI: time gated intensifier, L1: a doublet lens (focal length: 200mm)

Fig. 2
Fig. 2

Optical characteristics of wide-field two-photon excited fluorescence: (A) power dependence of the fluorescence of gallium corroles (50μM) (B) fluorescence intensity versus wavelength of the mouse intestine stained with Alexa 568 phalloidin [power density: 64μW/μm2, ex: 780-910 nm (step: 10 nm), em: 620 ± 60 nm, and a 40x air objective]. (C) fluorescence intensity versus numerical aperture of the objective lens [ex: 780 nm, power density: 64μW/μm2, 10x (NA: 0.45, FOV: 256 μm x 244 μm), 40x (NA: 0.75, FOV: 64 μm x 61 μm), 40x (NA: 1.30, FOV: 64 μm x 61 μm), and 60x (NA: 1.45, FOV: 43 μm x 41 μm)]. The rectangles represent the size of FOV.

Fig. 3
Fig. 3

Comparisons of the depth dependence in scanning two-photon, wide-field two-photon, and wide-field one-photon excitation for a tissue phantom: (A) schematic of the tissue phantom (B) Intensity profiles over the selected regions (microspheres) along the axial (depth) coordinate (C) Scanning two-photon excited fluorescence image obtained with a fs pulsed laser light source at 780nm. (D) Wide-field two-photon excited fluorescence image without Gaussian correction (excitation with a fs laser at 780 nm,) (E) Wide-field one-photon excited fluorescence image (excitation at 488 ± 30 nm). The scale bar is 50μm.

Fig. 4
Fig. 4

Wide-field one photon and wide-field two-photon imaging of an eye specimen from an AD transgenic mouse model: (A) One photon excited fluorescence image (excitation at 560 nm, emission at 630 nm) (B) Wide-field two-photon excited fluorescence image without Gaussian correction (excitation at 830nm, emission at 630nm) (C) Gaussian corrected wide-field two-photon excited fluorescence image (scale bar: 25μm): The plaques can be visualized and appear as brighter white signal compared to the background; the arrows indicate plaques (D) Profile of cross-sections of the original and the corrected image along a horizontal line (a’).

Fig. 5
Fig. 5

Multimodal optical imaging with wide-field two-photon excitation of a nude mouse: (A) A nude mouse: solid circle indicates the corroles-injected tumor region; the dotted circle indicates the microsphere solution injected region. (B) One-photon and (C) wide-field two-photon excited fluorescence images (before Gaussian-correction) of microspheres at the indicated different depths (center: 10 μm, insets: 10.5 μm, 13.5 μm, and 17 μm) beneath the skin around the regions selected by the dotted circle. The insets are the depth-resolved images. The arrows indicate microspheres. (D) Spectral and (E) fluorescence lifetime images of a microsphere obtained with wide-field two-photon excitation. The spectral and fluorescence lifetime images were obtained at the same depth (10 μm) and field of view with Fig. 5(C) (center). (F) One-photon (excitation 425nm and emission 620nm, field of view: 75 μm x 75 µm) and (G) wide-field two-photon (excitation 800nm and emission 620nm) image around the tumor regions (indicated by the solid circle), indication the presence and spatial distribution of corroles. (H) Spectral classification and (I) fluorescence lifetime images of corroles.

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