Abstract

Ultrafast lasers have potential use in ophthalmology for diagnoses through non-invasive imaging as well as for surgical therapies or for evaluating pharmacological therapies. New ultrafast laser sources, operating at 1.07 μm and sub-40 fs pulse durations, offer exciting possibilities in multiphoton imagining of the retina as the bulk of the eye is relatively transparent to this wavelength, three-photon excitation is not absorbed by DNA, and this wavelength has a greater penetration depth compared to the commonly used 800 nm Ti:Sapphire laser. In this work, we present the first epi-direction detected cross-section and depth-resolved images of unstained isolated retinas obtained using multiphoton microscopy with an ultrafast fiber laser centered at 1.07 μm and a ~38 fs pulse duration. Spectral and temporal characterization of the autofluorescence signals show two distinct regions; the first one from the nerve fiber layer to the inner receptor layer, and the second being the retinal pigmented epithelium and choroid.

© 2017 Optical Society of America

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2017 (1)

A. D. Marmorstein, L. Y. Marmorstein, H. Sakaguchi, and J. G. Hollyfield, “Spectral Profiling of Autofluorescence Associated with Lipofuscin, Bruch ’ s Membrane, and Sub-RPE Deposits in Normal and AMD Eyes,” Invest. Ophthalmol. Vis. Sci. 43, 2435–2441 (2017).

2016 (1)

G. Palczewska, A. Maeda, M. Golczak, E. Arai, Z. Dong, L. Perusek, B. Kevany, and K. Palczewski, “Receptor MER tyrosine kinase proto-oncogene (MERTK) is not required for transfer of bis-retinoids to the retinal pigmented epithelium,” J. Biol. Chem. 291(52), 26937–26949 (2016).
[PubMed]

2015 (4)

O. Masihzadeh, T. C. Lei, S. R. Domingue, M. Y. Kahook, R. A. Bartels, and D. A. Ammar, “Third harmonic generation microscopy of a mouse retina,” Mol. Vis. 21, 538–547 (2015).
[PubMed]

S. He, C. Ye, Q. Sun, C. K. S. Leung, and J. Y. Qu, “Label-free nonlinear optical imaging of mouse retina,” Biomed. Opt. Express 6(3), 1055–1066 (2015).
[PubMed]

O. Masihzadeh, T. C. Lei, S. R. Domingue, M. Y. Kahook, R. A. Bartels, and D. A. Ammar, “Third harmonic generation microscopy of a mouse retina,” Mol. Vis. 21, 538–547 (2015).
[PubMed]

M. Balu, I. Saytashev, J. Hou, M. Dantus, and B. J. Tromberg, “Sub-40 fs, 1060-nm Yb-fiber laser enhances penetration depth in nonlinear optical microscopy of human skin,” J. Biomed. Opt. 20(12), 120501 (2015).
[PubMed]

2014 (3)

M. Hoon, H. Okawa, L. Della Santina, and R. O. L. Wong, “Functional architecture of the retina: development and disease,” Prog. Retin. Eye Res. 42, 44–84 (2014).
[PubMed]

M. E. Boulton, “Studying melanin and lipofuscin in RPE cell culture models,” Exp. Eye Res. 126, 61–67 (2014).
[PubMed]

J. R. Sparrow and T. Duncker, “Fundus Autofluorescence and RPE Lipofuscin in Age-Related Macular Degeneration,” J. Clin. Med. 3(4), 1302–1321 (2014).
[PubMed]

2013 (1)

S. L. Jacques, “Physics in Medicine & Biology Optical properties of biological tissues: a review Optical properties of human tissues A N Bashkatov, E A Genina, V I Kochubey et al. - Optical absorption and scattering properties of bulk porcine muscle phantoms from int,” Phys. Med. Biol. 58, 2431 (2013).

2012 (1)

J. R. Sparrow, E. Gregory-Roberts, K. Yamamoto, A. Blonska, S. K. Ghosh, K. Ueda, and J. Zhou, “The bisretinoids of retinal pigment epithelium,” Prog. Retin. Eye Res. 31(2), 121–135 (2012).
[PubMed]

2011 (3)

E. A. Gibson, O. Masihzadeh, T. C. Lei, D. A. Ammar, and M. Y. Kahook, “Multiphoton Microscopy for Ophthalmic Imaging,” J. Ophthalmol. 2011, 870879 (2011).
[PubMed]

B. Nie, D. Pestov, F. W. Wise, and M. Dantus, “Generation of 42-fs and 10-nJ pulses from a fiber laser with self-similar evolution in the gain segment,” Opt. Express 19(13), 12074–12080 (2011).
[PubMed]

E. A. Gibson, O. Masihzadeh, T. C. Lei, D. A. Ammar, and M. Y. Kahook, “Multiphoton microscopy for ophthalmic imaging,” J. Ophthalmol. 2011, 870879 (2011).
[PubMed]

2010 (4)

J. M. Bueno, E. J. Gualda, and P. Artal, “Adaptive optics multiphoton microscopy to study ex vivo ocular tissues,” J. Biomed. Opt. 15(6), 066004 (2010).
[PubMed]

F. Aptel, N. Olivier, A. Deniset-Besseau, J.-M. Legeais, K. Plamann, M.-C. Schanne-Klein, and E. Beaurepaire, “Multimodal Nonlinear Imaging of the Human Cornea,” Invest. Ophthalmol. Vis. Sci. 51(5), 2459–2465 (2010).
[PubMed]

F. Aptel, N. Olivier, A. Deniset-Besseau, J. M. Legeais, K. Plamann, M. C. Schanne-Klein, and E. Beaurepaire, “Multimodal nonlinear imaging of the human cornea,” Invest. Ophthalmol. Vis. Sci. 51(5), 2459–2465 (2010).
[PubMed]

J. R. Sparrow, Y. Wu, T. Nagasaki, K. D. Yoon, K. Yamamoto, and J. Zhou, “Fundus autofluorescence and the bisretinoids of retina,” Photochem. Photobiol. Sci. 9(11), 1480–1489 (2010).
[PubMed]

2009 (2)

M. W. Conklin, P. P. Provenzano, K. W. Eliceiri, R. Sullivan, and P. J. Keely, “Fluorescence lifetime imaging of endogenous fluorophores in histopathology sections reveals differences between normal and tumor epithelium in carcinoma in situ of the breast,” Cell Biochem. Biophys. 53(3), 145–157 (2009).
[PubMed]

P. Xi, Y. Andegeko, D. Pestov, V. V. Lovozoy, and M. Dantus, “Two-photon imaging using adaptive phase compensated ultrashort laser pulses,” J. Biomed. Opt. 14(1), 014002 (2009).
[PubMed]

2008 (2)

Y. Coello, V. V. Lozovoy, T. C. Gunaratne, B. Xu, I. Borukhovich, C. Tseng, T. Weinacht, and M. Dantus, “Interference without an interferometer: a different approach to measuring, compressing, and shaping ultrashort laser pulses,” J. Opt. Soc. Am. B 25, A140 (2008).

P. Xi, Y. Andegeko, L. R. Weisel, V. V. Lozovoy, and M. Dantus, “Greater signal, increased depth, and less photobleaching in two-photon microscopy with 10 fs pulses,” Opt. Commun. 281, 1841–1849 (2008).

2007 (5)

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[PubMed]

T. E. Oliphant, “Python for scientific computing,” Comput. Sci. Eng. 9, 10–20 (2007).

D. Schweitzer, S. Schenke, M. Hammer, F. Schweitzer, S. Jentsch, E. Birckner, W. Becker, and A. Bergmann, “Towards metabolic mapping of the human retina,” Microsc. Res. Tech. 70(5), 410–419 (2007).
[PubMed]

S. Warburton, W. E. Davis, K. Southwick, H. Xin, A. T. Woolley, G. F. Burton, and C. D. Thulin, “Proteomic and phototoxic characterization of melanolipofuscin: correlation to disease and model for its origin,” Mol. Vis. 13, 318–329 (2007).
[PubMed]

I. Rocha-Mendoza, D. R. Yankelevich, M. Wang, K. M. Reiser, C. W. Frank, and A. Knoesen, “Sum Frequency Vibrational Spectroscopy: The Molecular Origins of the Optical Second-Order Nonlinearity of Collagen,” Biophys. J. 93(12), 4433–4444 (2007).
[PubMed]

2006 (1)

D. Débarre, W. Supatto, A.-M. Pena, A. Fabre, T. Tordjmann, L. Combettes, M.-C. Schanne-Klein, and E. Beaurepaire, “Imaging lipid bodies in cells and tissues using third-harmonic generation microscopy,” Nat. Methods 3(1), 47–53 (2006).
[PubMed]

2005 (1)

R. M. Williams, W. R. Zipfel, and W. W. Webb, “Interpreting second-harmonic generation images of collagen I fibrils,” Biophys. J. 88(2), 1377–1386 (2005).
[PubMed]

2004 (1)

2002 (2)

S. Huang, A. A. Heikal, and W. W. Webb, “Two-photon fluorescence spectroscopy and microscopy of NAD(P)H and flavoprotein,” Biophys. J. 82(5), 2811–2825 (2002).
[PubMed]

B. Chang, N. L. Hawes, R. E. Hurd, M. T. Davisson, S. Nusinowitz, and J. R. Heckenlively, “Retinal degeneration mutants in the mouse,” Vision Res. 42(4), 517–525 (2002).
[PubMed]

2000 (1)

N. L. Mata, J. Weng, and G. H. Travis, “Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration,” Proc. Natl. Acad. Sci. U.S.A. 97(13), 7154–7159 (2000).
[PubMed]

1999 (2)

F. Bevilacqua, D. Piguet, P. Marquet, J. D. Gross, B. J. Tromberg, and C. Depeursinge, “In vivo local determination of tissue optical properties: applications to human brain,” Appl. Opt. 38(22), 4939–4950 (1999).
[PubMed]

J. R. Sparrow, C. A. Parish, M. Hashimoto, and K. Nakanishi, “Pigmented Epithelial Cells in Culture,” Invest. Ophthalmol. Vis. Sci. 40, 2988–2995 (1999).
[PubMed]

1998 (1)

M. Müller, J. Squier, K. R. Wilson, and G. J. Brakenhoff, “3D microscopy of transparent objects using third-harmonic generation,” J. Microsc. 191(3), 266–274 (1998).
[PubMed]

1996 (1)

M. L. Katz, C.-L. Gao, and L. M. Rice, “Formation of lipofuscin-like fluorophores by reaction of retinal with photoreceptor outer segments and liposomes,” Mech. Ageing Dev. 92(2-3), 159–174 (1996).
[PubMed]

1995 (3)

M. R. Hee, J. A. Izatt, E. A. Swanson, D. Huang, J. S. Schuman, C. P. Lin, C. A. Puliafito, and J. G. Fujimoto, “Optical coherence tomography of the human retina,” Arch. Ophthalmol. 113(3), 325–332 (1995).
[PubMed]

F. C. Delori, C. K. Dorey, G. Staurenghi, O. Arend, D. G. Goger, and J. J. Writer, “In Vivo Fluorescence of the Ocular Fundus Exhibits Retinal Pigment Epithelium Lipofuscin Characteristics,” Investigative Ophthalmol. Vis. Sci. 36, 718–729 (1995).

C. J. Kennedy, P. E. Rakoczy, and I. J. Constable, “Lipofuscin of the retinal pigment epithelium: a review,” Eye (Lond.) 9(Pt 6), 763–771 (1995).
[PubMed]

1991 (1)

D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and J. G. Fujimoto, “Optical coherence tomography,” Science 254(5035), 1178–1181 (1991).
[PubMed]

1990 (3)

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

L. K. Barthel and P. A. Raymond, “Improved method for obtaining 3-microns cryosections for immunocytochemistry,” J. Histochem. Cytochem. 38(9), 1383–1388 (1990).
[PubMed]

M. Boulton, F. Docchio, P. Dayhaw-Barker, R. Ramponi, and R. Cubeddu, “Age-related changes in the morphology, absorption and fluorescence of melanosomes and lipofuscin granules of the retinal pigment epithelium,” Vision Res. 30(9), 1291–1303 (1990).
[PubMed]

1988 (1)

S. Watanabe, G. Matthews, M. L. Woodruff, I. V. Peshenko, A. B. Savchenko, C. L. Makino, Y.-S. Ho, G. L. Fain, and A. M. Dizhoor, “Regional distribution of cGMP-activated ion channels in the plasma membrane of the rod photoreceptor,” J. Neurosci. 8(7), 2334–2337 (1988).
[PubMed]

1986 (1)

J. J. Weiter, F. C. Delori, G. L. Wing, and K. A. Fitch, “Retinal pigment epithelial lipofuscin and melanin and choroidal melanin in human eyes,” Invest. Ophthalmol. Vis. Sci. 27(2), 145–152 (1986).
[PubMed]

1981 (1)

J. C. Sutherland and K. P. Griffin, “Absorption Spectrum of DNA for Wavelengths Greater than 300 nm,” Radiat. Res. 86(3), 399–409 (1981).
[PubMed]

1979 (1)

P. V. Sarthy and D. M. Lam, “Isolated cells from a mammalian retina,” Brain Res. 176(1), 208–212 (1979).
[PubMed]

1978 (1)

M. L. Katz, W. L. Stone, and E. A. Dratz, “Fluorescent pigment accumulation in retinal pigment epithelium of antioxidant-deficient rats,” Invest. Ophthalmol. Vis. Sci. 17(11), 1049–1058 (1978).
[PubMed]

1969 (1)

R. W. Young and D. Bok, “Participation of the retinal pigment epithelium in the rod outer segment renewal process,” J. Cell Biol. 42(2), 392–403 (1969).
[PubMed]

Ammar, D. A.

O. Masihzadeh, T. C. Lei, S. R. Domingue, M. Y. Kahook, R. A. Bartels, and D. A. Ammar, “Third harmonic generation microscopy of a mouse retina,” Mol. Vis. 21, 538–547 (2015).
[PubMed]

O. Masihzadeh, T. C. Lei, S. R. Domingue, M. Y. Kahook, R. A. Bartels, and D. A. Ammar, “Third harmonic generation microscopy of a mouse retina,” Mol. Vis. 21, 538–547 (2015).
[PubMed]

E. A. Gibson, O. Masihzadeh, T. C. Lei, D. A. Ammar, and M. Y. Kahook, “Multiphoton Microscopy for Ophthalmic Imaging,” J. Ophthalmol. 2011, 870879 (2011).
[PubMed]

E. A. Gibson, O. Masihzadeh, T. C. Lei, D. A. Ammar, and M. Y. Kahook, “Multiphoton microscopy for ophthalmic imaging,” J. Ophthalmol. 2011, 870879 (2011).
[PubMed]

Andegeko, Y.

P. Xi, Y. Andegeko, D. Pestov, V. V. Lovozoy, and M. Dantus, “Two-photon imaging using adaptive phase compensated ultrashort laser pulses,” J. Biomed. Opt. 14(1), 014002 (2009).
[PubMed]

P. Xi, Y. Andegeko, L. R. Weisel, V. V. Lozovoy, and M. Dantus, “Greater signal, increased depth, and less photobleaching in two-photon microscopy with 10 fs pulses,” Opt. Commun. 281, 1841–1849 (2008).

Aptel, F.

F. Aptel, N. Olivier, A. Deniset-Besseau, J. M. Legeais, K. Plamann, M. C. Schanne-Klein, and E. Beaurepaire, “Multimodal nonlinear imaging of the human cornea,” Invest. Ophthalmol. Vis. Sci. 51(5), 2459–2465 (2010).
[PubMed]

F. Aptel, N. Olivier, A. Deniset-Besseau, J.-M. Legeais, K. Plamann, M.-C. Schanne-Klein, and E. Beaurepaire, “Multimodal Nonlinear Imaging of the Human Cornea,” Invest. Ophthalmol. Vis. Sci. 51(5), 2459–2465 (2010).
[PubMed]

Arai, E.

G. Palczewska, A. Maeda, M. Golczak, E. Arai, Z. Dong, L. Perusek, B. Kevany, and K. Palczewski, “Receptor MER tyrosine kinase proto-oncogene (MERTK) is not required for transfer of bis-retinoids to the retinal pigmented epithelium,” J. Biol. Chem. 291(52), 26937–26949 (2016).
[PubMed]

Arend, O.

F. C. Delori, C. K. Dorey, G. Staurenghi, O. Arend, D. G. Goger, and J. J. Writer, “In Vivo Fluorescence of the Ocular Fundus Exhibits Retinal Pigment Epithelium Lipofuscin Characteristics,” Investigative Ophthalmol. Vis. Sci. 36, 718–729 (1995).

Artal, P.

J. M. Bueno, E. J. Gualda, and P. Artal, “Adaptive optics multiphoton microscopy to study ex vivo ocular tissues,” J. Biomed. Opt. 15(6), 066004 (2010).
[PubMed]

Balu, M.

M. Balu, I. Saytashev, J. Hou, M. Dantus, and B. J. Tromberg, “Sub-40 fs, 1060-nm Yb-fiber laser enhances penetration depth in nonlinear optical microscopy of human skin,” J. Biomed. Opt. 20(12), 120501 (2015).
[PubMed]

Bartels, R. A.

O. Masihzadeh, T. C. Lei, S. R. Domingue, M. Y. Kahook, R. A. Bartels, and D. A. Ammar, “Third harmonic generation microscopy of a mouse retina,” Mol. Vis. 21, 538–547 (2015).
[PubMed]

O. Masihzadeh, T. C. Lei, S. R. Domingue, M. Y. Kahook, R. A. Bartels, and D. A. Ammar, “Third harmonic generation microscopy of a mouse retina,” Mol. Vis. 21, 538–547 (2015).
[PubMed]

Barthel, L. K.

L. K. Barthel and P. A. Raymond, “Improved method for obtaining 3-microns cryosections for immunocytochemistry,” J. Histochem. Cytochem. 38(9), 1383–1388 (1990).
[PubMed]

Beaurepaire, E.

F. Aptel, N. Olivier, A. Deniset-Besseau, J.-M. Legeais, K. Plamann, M.-C. Schanne-Klein, and E. Beaurepaire, “Multimodal Nonlinear Imaging of the Human Cornea,” Invest. Ophthalmol. Vis. Sci. 51(5), 2459–2465 (2010).
[PubMed]

F. Aptel, N. Olivier, A. Deniset-Besseau, J. M. Legeais, K. Plamann, M. C. Schanne-Klein, and E. Beaurepaire, “Multimodal nonlinear imaging of the human cornea,” Invest. Ophthalmol. Vis. Sci. 51(5), 2459–2465 (2010).
[PubMed]

D. Débarre, W. Supatto, A.-M. Pena, A. Fabre, T. Tordjmann, L. Combettes, M.-C. Schanne-Klein, and E. Beaurepaire, “Imaging lipid bodies in cells and tissues using third-harmonic generation microscopy,” Nat. Methods 3(1), 47–53 (2006).
[PubMed]

Becker, W.

D. Schweitzer, S. Schenke, M. Hammer, F. Schweitzer, S. Jentsch, E. Birckner, W. Becker, and A. Bergmann, “Towards metabolic mapping of the human retina,” Microsc. Res. Tech. 70(5), 410–419 (2007).
[PubMed]

Bergmann, A.

D. Schweitzer, S. Schenke, M. Hammer, F. Schweitzer, S. Jentsch, E. Birckner, W. Becker, and A. Bergmann, “Towards metabolic mapping of the human retina,” Microsc. Res. Tech. 70(5), 410–419 (2007).
[PubMed]

Bevilacqua, F.

Birckner, E.

D. Schweitzer, S. Schenke, M. Hammer, F. Schweitzer, S. Jentsch, E. Birckner, W. Becker, and A. Bergmann, “Towards metabolic mapping of the human retina,” Microsc. Res. Tech. 70(5), 410–419 (2007).
[PubMed]

Blonska, A.

J. R. Sparrow, E. Gregory-Roberts, K. Yamamoto, A. Blonska, S. K. Ghosh, K. Ueda, and J. Zhou, “The bisretinoids of retinal pigment epithelium,” Prog. Retin. Eye Res. 31(2), 121–135 (2012).
[PubMed]

Bok, D.

R. W. Young and D. Bok, “Participation of the retinal pigment epithelium in the rod outer segment renewal process,” J. Cell Biol. 42(2), 392–403 (1969).
[PubMed]

Borukhovich, I.

Boulton, M.

M. Boulton, F. Docchio, P. Dayhaw-Barker, R. Ramponi, and R. Cubeddu, “Age-related changes in the morphology, absorption and fluorescence of melanosomes and lipofuscin granules of the retinal pigment epithelium,” Vision Res. 30(9), 1291–1303 (1990).
[PubMed]

Boulton, M. E.

M. E. Boulton, “Studying melanin and lipofuscin in RPE cell culture models,” Exp. Eye Res. 126, 61–67 (2014).
[PubMed]

Brakenhoff, G. J.

M. Müller, J. Squier, K. R. Wilson, and G. J. Brakenhoff, “3D microscopy of transparent objects using third-harmonic generation,” J. Microsc. 191(3), 266–274 (1998).
[PubMed]

Bueno, J. M.

J. M. Bueno, E. J. Gualda, and P. Artal, “Adaptive optics multiphoton microscopy to study ex vivo ocular tissues,” J. Biomed. Opt. 15(6), 066004 (2010).
[PubMed]

Burton, G. F.

S. Warburton, W. E. Davis, K. Southwick, H. Xin, A. T. Woolley, G. F. Burton, and C. D. Thulin, “Proteomic and phototoxic characterization of melanolipofuscin: correlation to disease and model for its origin,” Mol. Vis. 13, 318–329 (2007).
[PubMed]

Chang, B.

B. Chang, N. L. Hawes, R. E. Hurd, M. T. Davisson, S. Nusinowitz, and J. R. Heckenlively, “Retinal degeneration mutants in the mouse,” Vision Res. 42(4), 517–525 (2002).
[PubMed]

Chang, W.

D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and J. G. Fujimoto, “Optical coherence tomography,” Science 254(5035), 1178–1181 (1991).
[PubMed]

Coello, Y.

Y. Coello, V. V. Lozovoy, T. C. Gunaratne, B. Xu, I. Borukhovich, C. Tseng, T. Weinacht, and M. Dantus, “Interference without an interferometer: a different approach to measuring, compressing, and shaping ultrashort laser pulses,” J. Opt. Soc. Am. B 25, A140 (2008).

Y. Coello, B. Xu, T. L. Miller, V. V Lozovoy, and M. Dantus, “Group-velocity dispersion measurements of water, seawater, and ocular components using multiphoton intrapulse interference phase scan,” (n.d.).

Combettes, L.

D. Débarre, W. Supatto, A.-M. Pena, A. Fabre, T. Tordjmann, L. Combettes, M.-C. Schanne-Klein, and E. Beaurepaire, “Imaging lipid bodies in cells and tissues using third-harmonic generation microscopy,” Nat. Methods 3(1), 47–53 (2006).
[PubMed]

Conklin, M. W.

M. W. Conklin, P. P. Provenzano, K. W. Eliceiri, R. Sullivan, and P. J. Keely, “Fluorescence lifetime imaging of endogenous fluorophores in histopathology sections reveals differences between normal and tumor epithelium in carcinoma in situ of the breast,” Cell Biochem. Biophys. 53(3), 145–157 (2009).
[PubMed]

Constable, I. J.

C. J. Kennedy, P. E. Rakoczy, and I. J. Constable, “Lipofuscin of the retinal pigment epithelium: a review,” Eye (Lond.) 9(Pt 6), 763–771 (1995).
[PubMed]

Cubeddu, R.

M. Boulton, F. Docchio, P. Dayhaw-Barker, R. Ramponi, and R. Cubeddu, “Age-related changes in the morphology, absorption and fluorescence of melanosomes and lipofuscin granules of the retinal pigment epithelium,” Vision Res. 30(9), 1291–1303 (1990).
[PubMed]

Dantus, M.

M. Balu, I. Saytashev, J. Hou, M. Dantus, and B. J. Tromberg, “Sub-40 fs, 1060-nm Yb-fiber laser enhances penetration depth in nonlinear optical microscopy of human skin,” J. Biomed. Opt. 20(12), 120501 (2015).
[PubMed]

B. Nie, D. Pestov, F. W. Wise, and M. Dantus, “Generation of 42-fs and 10-nJ pulses from a fiber laser with self-similar evolution in the gain segment,” Opt. Express 19(13), 12074–12080 (2011).
[PubMed]

P. Xi, Y. Andegeko, D. Pestov, V. V. Lovozoy, and M. Dantus, “Two-photon imaging using adaptive phase compensated ultrashort laser pulses,” J. Biomed. Opt. 14(1), 014002 (2009).
[PubMed]

Y. Coello, V. V. Lozovoy, T. C. Gunaratne, B. Xu, I. Borukhovich, C. Tseng, T. Weinacht, and M. Dantus, “Interference without an interferometer: a different approach to measuring, compressing, and shaping ultrashort laser pulses,” J. Opt. Soc. Am. B 25, A140 (2008).

P. Xi, Y. Andegeko, L. R. Weisel, V. V. Lozovoy, and M. Dantus, “Greater signal, increased depth, and less photobleaching in two-photon microscopy with 10 fs pulses,” Opt. Commun. 281, 1841–1849 (2008).

V. V. Lozovoy, I. Pastirk, and M. Dantus, “Multiphoton intrapulse interference. IV. Ultrashort laser pulse spectral phase characterization and compensation,” Opt. Lett. 29(7), 775–777 (2004).
[PubMed]

Y. Coello, B. Xu, T. L. Miller, V. V Lozovoy, and M. Dantus, “Group-velocity dispersion measurements of water, seawater, and ocular components using multiphoton intrapulse interference phase scan,” (n.d.).

Davis, W. E.

S. Warburton, W. E. Davis, K. Southwick, H. Xin, A. T. Woolley, G. F. Burton, and C. D. Thulin, “Proteomic and phototoxic characterization of melanolipofuscin: correlation to disease and model for its origin,” Mol. Vis. 13, 318–329 (2007).
[PubMed]

Davisson, M. T.

B. Chang, N. L. Hawes, R. E. Hurd, M. T. Davisson, S. Nusinowitz, and J. R. Heckenlively, “Retinal degeneration mutants in the mouse,” Vision Res. 42(4), 517–525 (2002).
[PubMed]

Dayhaw-Barker, P.

M. Boulton, F. Docchio, P. Dayhaw-Barker, R. Ramponi, and R. Cubeddu, “Age-related changes in the morphology, absorption and fluorescence of melanosomes and lipofuscin granules of the retinal pigment epithelium,” Vision Res. 30(9), 1291–1303 (1990).
[PubMed]

Débarre, D.

D. Débarre, W. Supatto, A.-M. Pena, A. Fabre, T. Tordjmann, L. Combettes, M.-C. Schanne-Klein, and E. Beaurepaire, “Imaging lipid bodies in cells and tissues using third-harmonic generation microscopy,” Nat. Methods 3(1), 47–53 (2006).
[PubMed]

Della Santina, L.

M. Hoon, H. Okawa, L. Della Santina, and R. O. L. Wong, “Functional architecture of the retina: development and disease,” Prog. Retin. Eye Res. 42, 44–84 (2014).
[PubMed]

Delori, F. C.

F. C. Delori, C. K. Dorey, G. Staurenghi, O. Arend, D. G. Goger, and J. J. Writer, “In Vivo Fluorescence of the Ocular Fundus Exhibits Retinal Pigment Epithelium Lipofuscin Characteristics,” Investigative Ophthalmol. Vis. Sci. 36, 718–729 (1995).

J. J. Weiter, F. C. Delori, G. L. Wing, and K. A. Fitch, “Retinal pigment epithelial lipofuscin and melanin and choroidal melanin in human eyes,” Invest. Ophthalmol. Vis. Sci. 27(2), 145–152 (1986).
[PubMed]

Deniset-Besseau, A.

F. Aptel, N. Olivier, A. Deniset-Besseau, J.-M. Legeais, K. Plamann, M.-C. Schanne-Klein, and E. Beaurepaire, “Multimodal Nonlinear Imaging of the Human Cornea,” Invest. Ophthalmol. Vis. Sci. 51(5), 2459–2465 (2010).
[PubMed]

F. Aptel, N. Olivier, A. Deniset-Besseau, J. M. Legeais, K. Plamann, M. C. Schanne-Klein, and E. Beaurepaire, “Multimodal nonlinear imaging of the human cornea,” Invest. Ophthalmol. Vis. Sci. 51(5), 2459–2465 (2010).
[PubMed]

Denk, W.

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

Depeursinge, C.

Dizhoor, A. M.

S. Watanabe, G. Matthews, M. L. Woodruff, I. V. Peshenko, A. B. Savchenko, C. L. Makino, Y.-S. Ho, G. L. Fain, and A. M. Dizhoor, “Regional distribution of cGMP-activated ion channels in the plasma membrane of the rod photoreceptor,” J. Neurosci. 8(7), 2334–2337 (1988).
[PubMed]

Docchio, F.

M. Boulton, F. Docchio, P. Dayhaw-Barker, R. Ramponi, and R. Cubeddu, “Age-related changes in the morphology, absorption and fluorescence of melanosomes and lipofuscin granules of the retinal pigment epithelium,” Vision Res. 30(9), 1291–1303 (1990).
[PubMed]

Domingue, S. R.

O. Masihzadeh, T. C. Lei, S. R. Domingue, M. Y. Kahook, R. A. Bartels, and D. A. Ammar, “Third harmonic generation microscopy of a mouse retina,” Mol. Vis. 21, 538–547 (2015).
[PubMed]

O. Masihzadeh, T. C. Lei, S. R. Domingue, M. Y. Kahook, R. A. Bartels, and D. A. Ammar, “Third harmonic generation microscopy of a mouse retina,” Mol. Vis. 21, 538–547 (2015).
[PubMed]

Dong, Z.

G. Palczewska, A. Maeda, M. Golczak, E. Arai, Z. Dong, L. Perusek, B. Kevany, and K. Palczewski, “Receptor MER tyrosine kinase proto-oncogene (MERTK) is not required for transfer of bis-retinoids to the retinal pigmented epithelium,” J. Biol. Chem. 291(52), 26937–26949 (2016).
[PubMed]

Dorey, C. K.

F. C. Delori, C. K. Dorey, G. Staurenghi, O. Arend, D. G. Goger, and J. J. Writer, “In Vivo Fluorescence of the Ocular Fundus Exhibits Retinal Pigment Epithelium Lipofuscin Characteristics,” Investigative Ophthalmol. Vis. Sci. 36, 718–729 (1995).

Dratz, E. A.

M. L. Katz, W. L. Stone, and E. A. Dratz, “Fluorescent pigment accumulation in retinal pigment epithelium of antioxidant-deficient rats,” Invest. Ophthalmol. Vis. Sci. 17(11), 1049–1058 (1978).
[PubMed]

Duncker, T.

J. R. Sparrow and T. Duncker, “Fundus Autofluorescence and RPE Lipofuscin in Age-Related Macular Degeneration,” J. Clin. Med. 3(4), 1302–1321 (2014).
[PubMed]

Eickhoff, J.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[PubMed]

Eliceiri, K. W.

M. W. Conklin, P. P. Provenzano, K. W. Eliceiri, R. Sullivan, and P. J. Keely, “Fluorescence lifetime imaging of endogenous fluorophores in histopathology sections reveals differences between normal and tumor epithelium in carcinoma in situ of the breast,” Cell Biochem. Biophys. 53(3), 145–157 (2009).
[PubMed]

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[PubMed]

Fabre, A.

D. Débarre, W. Supatto, A.-M. Pena, A. Fabre, T. Tordjmann, L. Combettes, M.-C. Schanne-Klein, and E. Beaurepaire, “Imaging lipid bodies in cells and tissues using third-harmonic generation microscopy,” Nat. Methods 3(1), 47–53 (2006).
[PubMed]

Fain, G. L.

S. Watanabe, G. Matthews, M. L. Woodruff, I. V. Peshenko, A. B. Savchenko, C. L. Makino, Y.-S. Ho, G. L. Fain, and A. M. Dizhoor, “Regional distribution of cGMP-activated ion channels in the plasma membrane of the rod photoreceptor,” J. Neurosci. 8(7), 2334–2337 (1988).
[PubMed]

Fitch, K. A.

J. J. Weiter, F. C. Delori, G. L. Wing, and K. A. Fitch, “Retinal pigment epithelial lipofuscin and melanin and choroidal melanin in human eyes,” Invest. Ophthalmol. Vis. Sci. 27(2), 145–152 (1986).
[PubMed]

Flotte, T.

D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and J. G. Fujimoto, “Optical coherence tomography,” Science 254(5035), 1178–1181 (1991).
[PubMed]

Frank, C. W.

I. Rocha-Mendoza, D. R. Yankelevich, M. Wang, K. M. Reiser, C. W. Frank, and A. Knoesen, “Sum Frequency Vibrational Spectroscopy: The Molecular Origins of the Optical Second-Order Nonlinearity of Collagen,” Biophys. J. 93(12), 4433–4444 (2007).
[PubMed]

Fujimoto, J. G.

M. R. Hee, J. A. Izatt, E. A. Swanson, D. Huang, J. S. Schuman, C. P. Lin, C. A. Puliafito, and J. G. Fujimoto, “Optical coherence tomography of the human retina,” Arch. Ophthalmol. 113(3), 325–332 (1995).
[PubMed]

D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and J. G. Fujimoto, “Optical coherence tomography,” Science 254(5035), 1178–1181 (1991).
[PubMed]

Gao, C.-L.

M. L. Katz, C.-L. Gao, and L. M. Rice, “Formation of lipofuscin-like fluorophores by reaction of retinal with photoreceptor outer segments and liposomes,” Mech. Ageing Dev. 92(2-3), 159–174 (1996).
[PubMed]

Gendron-Fitzpatrick, A.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[PubMed]

Ghosh, S. K.

J. R. Sparrow, E. Gregory-Roberts, K. Yamamoto, A. Blonska, S. K. Ghosh, K. Ueda, and J. Zhou, “The bisretinoids of retinal pigment epithelium,” Prog. Retin. Eye Res. 31(2), 121–135 (2012).
[PubMed]

Gibson, E. A.

E. A. Gibson, O. Masihzadeh, T. C. Lei, D. A. Ammar, and M. Y. Kahook, “Multiphoton microscopy for ophthalmic imaging,” J. Ophthalmol. 2011, 870879 (2011).
[PubMed]

E. A. Gibson, O. Masihzadeh, T. C. Lei, D. A. Ammar, and M. Y. Kahook, “Multiphoton Microscopy for Ophthalmic Imaging,” J. Ophthalmol. 2011, 870879 (2011).
[PubMed]

Goger, D. G.

F. C. Delori, C. K. Dorey, G. Staurenghi, O. Arend, D. G. Goger, and J. J. Writer, “In Vivo Fluorescence of the Ocular Fundus Exhibits Retinal Pigment Epithelium Lipofuscin Characteristics,” Investigative Ophthalmol. Vis. Sci. 36, 718–729 (1995).

Golczak, M.

G. Palczewska, A. Maeda, M. Golczak, E. Arai, Z. Dong, L. Perusek, B. Kevany, and K. Palczewski, “Receptor MER tyrosine kinase proto-oncogene (MERTK) is not required for transfer of bis-retinoids to the retinal pigmented epithelium,” J. Biol. Chem. 291(52), 26937–26949 (2016).
[PubMed]

Gregory, K.

D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and J. G. Fujimoto, “Optical coherence tomography,” Science 254(5035), 1178–1181 (1991).
[PubMed]

Gregory-Roberts, E.

J. R. Sparrow, E. Gregory-Roberts, K. Yamamoto, A. Blonska, S. K. Ghosh, K. Ueda, and J. Zhou, “The bisretinoids of retinal pigment epithelium,” Prog. Retin. Eye Res. 31(2), 121–135 (2012).
[PubMed]

Griffin, K. P.

J. C. Sutherland and K. P. Griffin, “Absorption Spectrum of DNA for Wavelengths Greater than 300 nm,” Radiat. Res. 86(3), 399–409 (1981).
[PubMed]

Gross, J. D.

Gualda, E. J.

J. M. Bueno, E. J. Gualda, and P. Artal, “Adaptive optics multiphoton microscopy to study ex vivo ocular tissues,” J. Biomed. Opt. 15(6), 066004 (2010).
[PubMed]

Gunaratne, T. C.

Hammer, M.

D. Schweitzer, S. Schenke, M. Hammer, F. Schweitzer, S. Jentsch, E. Birckner, W. Becker, and A. Bergmann, “Towards metabolic mapping of the human retina,” Microsc. Res. Tech. 70(5), 410–419 (2007).
[PubMed]

Hashimoto, M.

J. R. Sparrow, C. A. Parish, M. Hashimoto, and K. Nakanishi, “Pigmented Epithelial Cells in Culture,” Invest. Ophthalmol. Vis. Sci. 40, 2988–2995 (1999).
[PubMed]

Hawes, N. L.

B. Chang, N. L. Hawes, R. E. Hurd, M. T. Davisson, S. Nusinowitz, and J. R. Heckenlively, “Retinal degeneration mutants in the mouse,” Vision Res. 42(4), 517–525 (2002).
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Heckenlively, J. R.

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M. Balu, I. Saytashev, J. Hou, M. Dantus, and B. J. Tromberg, “Sub-40 fs, 1060-nm Yb-fiber laser enhances penetration depth in nonlinear optical microscopy of human skin,” J. Biomed. Opt. 20(12), 120501 (2015).
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M. R. Hee, J. A. Izatt, E. A. Swanson, D. Huang, J. S. Schuman, C. P. Lin, C. A. Puliafito, and J. G. Fujimoto, “Optical coherence tomography of the human retina,” Arch. Ophthalmol. 113(3), 325–332 (1995).
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B. Chang, N. L. Hawes, R. E. Hurd, M. T. Davisson, S. Nusinowitz, and J. R. Heckenlively, “Retinal degeneration mutants in the mouse,” Vision Res. 42(4), 517–525 (2002).
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O. Masihzadeh, T. C. Lei, S. R. Domingue, M. Y. Kahook, R. A. Bartels, and D. A. Ammar, “Third harmonic generation microscopy of a mouse retina,” Mol. Vis. 21, 538–547 (2015).
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M. L. Katz, C.-L. Gao, and L. M. Rice, “Formation of lipofuscin-like fluorophores by reaction of retinal with photoreceptor outer segments and liposomes,” Mech. Ageing Dev. 92(2-3), 159–174 (1996).
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G. Palczewska, A. Maeda, M. Golczak, E. Arai, Z. Dong, L. Perusek, B. Kevany, and K. Palczewski, “Receptor MER tyrosine kinase proto-oncogene (MERTK) is not required for transfer of bis-retinoids to the retinal pigmented epithelium,” J. Biol. Chem. 291(52), 26937–26949 (2016).
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I. Rocha-Mendoza, D. R. Yankelevich, M. Wang, K. M. Reiser, C. W. Frank, and A. Knoesen, “Sum Frequency Vibrational Spectroscopy: The Molecular Origins of the Optical Second-Order Nonlinearity of Collagen,” Biophys. J. 93(12), 4433–4444 (2007).
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P. V. Sarthy and D. M. Lam, “Isolated cells from a mammalian retina,” Brain Res. 176(1), 208–212 (1979).
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F. Aptel, N. Olivier, A. Deniset-Besseau, J.-M. Legeais, K. Plamann, M.-C. Schanne-Klein, and E. Beaurepaire, “Multimodal Nonlinear Imaging of the Human Cornea,” Invest. Ophthalmol. Vis. Sci. 51(5), 2459–2465 (2010).
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O. Masihzadeh, T. C. Lei, S. R. Domingue, M. Y. Kahook, R. A. Bartels, and D. A. Ammar, “Third harmonic generation microscopy of a mouse retina,” Mol. Vis. 21, 538–547 (2015).
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P. Xi, Y. Andegeko, D. Pestov, V. V. Lovozoy, and M. Dantus, “Two-photon imaging using adaptive phase compensated ultrashort laser pulses,” J. Biomed. Opt. 14(1), 014002 (2009).
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G. Palczewska, A. Maeda, M. Golczak, E. Arai, Z. Dong, L. Perusek, B. Kevany, and K. Palczewski, “Receptor MER tyrosine kinase proto-oncogene (MERTK) is not required for transfer of bis-retinoids to the retinal pigmented epithelium,” J. Biol. Chem. 291(52), 26937–26949 (2016).
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A. D. Marmorstein, L. Y. Marmorstein, H. Sakaguchi, and J. G. Hollyfield, “Spectral Profiling of Autofluorescence Associated with Lipofuscin, Bruch ’ s Membrane, and Sub-RPE Deposits in Normal and AMD Eyes,” Invest. Ophthalmol. Vis. Sci. 43, 2435–2441 (2017).

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O. Masihzadeh, T. C. Lei, S. R. Domingue, M. Y. Kahook, R. A. Bartels, and D. A. Ammar, “Third harmonic generation microscopy of a mouse retina,” Mol. Vis. 21, 538–547 (2015).
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B. Chang, N. L. Hawes, R. E. Hurd, M. T. Davisson, S. Nusinowitz, and J. R. Heckenlively, “Retinal degeneration mutants in the mouse,” Vision Res. 42(4), 517–525 (2002).
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G. Palczewska, A. Maeda, M. Golczak, E. Arai, Z. Dong, L. Perusek, B. Kevany, and K. Palczewski, “Receptor MER tyrosine kinase proto-oncogene (MERTK) is not required for transfer of bis-retinoids to the retinal pigmented epithelium,” J. Biol. Chem. 291(52), 26937–26949 (2016).
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G. Palczewska, A. Maeda, M. Golczak, E. Arai, Z. Dong, L. Perusek, B. Kevany, and K. Palczewski, “Receptor MER tyrosine kinase proto-oncogene (MERTK) is not required for transfer of bis-retinoids to the retinal pigmented epithelium,” J. Biol. Chem. 291(52), 26937–26949 (2016).
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S. Watanabe, G. Matthews, M. L. Woodruff, I. V. Peshenko, A. B. Savchenko, C. L. Makino, Y.-S. Ho, G. L. Fain, and A. M. Dizhoor, “Regional distribution of cGMP-activated ion channels in the plasma membrane of the rod photoreceptor,” J. Neurosci. 8(7), 2334–2337 (1988).
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F. Aptel, N. Olivier, A. Deniset-Besseau, J. M. Legeais, K. Plamann, M. C. Schanne-Klein, and E. Beaurepaire, “Multimodal nonlinear imaging of the human cornea,” Invest. Ophthalmol. Vis. Sci. 51(5), 2459–2465 (2010).
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M. R. Hee, J. A. Izatt, E. A. Swanson, D. Huang, J. S. Schuman, C. P. Lin, C. A. Puliafito, and J. G. Fujimoto, “Optical coherence tomography of the human retina,” Arch. Ophthalmol. 113(3), 325–332 (1995).
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M. L. Katz, C.-L. Gao, and L. M. Rice, “Formation of lipofuscin-like fluorophores by reaction of retinal with photoreceptor outer segments and liposomes,” Mech. Ageing Dev. 92(2-3), 159–174 (1996).
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M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
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S. Watanabe, G. Matthews, M. L. Woodruff, I. V. Peshenko, A. B. Savchenko, C. L. Makino, Y.-S. Ho, G. L. Fain, and A. M. Dizhoor, “Regional distribution of cGMP-activated ion channels in the plasma membrane of the rod photoreceptor,” J. Neurosci. 8(7), 2334–2337 (1988).
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M. Balu, I. Saytashev, J. Hou, M. Dantus, and B. J. Tromberg, “Sub-40 fs, 1060-nm Yb-fiber laser enhances penetration depth in nonlinear optical microscopy of human skin,” J. Biomed. Opt. 20(12), 120501 (2015).
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F. Aptel, N. Olivier, A. Deniset-Besseau, J. M. Legeais, K. Plamann, M. C. Schanne-Klein, and E. Beaurepaire, “Multimodal nonlinear imaging of the human cornea,” Invest. Ophthalmol. Vis. Sci. 51(5), 2459–2465 (2010).
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F. Aptel, N. Olivier, A. Deniset-Besseau, J.-M. Legeais, K. Plamann, M.-C. Schanne-Klein, and E. Beaurepaire, “Multimodal Nonlinear Imaging of the Human Cornea,” Invest. Ophthalmol. Vis. Sci. 51(5), 2459–2465 (2010).
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D. Schweitzer, S. Schenke, M. Hammer, F. Schweitzer, S. Jentsch, E. Birckner, W. Becker, and A. Bergmann, “Towards metabolic mapping of the human retina,” Microsc. Res. Tech. 70(5), 410–419 (2007).
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M. R. Hee, J. A. Izatt, E. A. Swanson, D. Huang, J. S. Schuman, C. P. Lin, C. A. Puliafito, and J. G. Fujimoto, “Optical coherence tomography of the human retina,” Arch. Ophthalmol. 113(3), 325–332 (1995).
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D. Schweitzer, S. Schenke, M. Hammer, F. Schweitzer, S. Jentsch, E. Birckner, W. Becker, and A. Bergmann, “Towards metabolic mapping of the human retina,” Microsc. Res. Tech. 70(5), 410–419 (2007).
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D. Schweitzer, S. Schenke, M. Hammer, F. Schweitzer, S. Jentsch, E. Birckner, W. Becker, and A. Bergmann, “Towards metabolic mapping of the human retina,” Microsc. Res. Tech. 70(5), 410–419 (2007).
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Skala, M. C.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
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S. Warburton, W. E. Davis, K. Southwick, H. Xin, A. T. Woolley, G. F. Burton, and C. D. Thulin, “Proteomic and phototoxic characterization of melanolipofuscin: correlation to disease and model for its origin,” Mol. Vis. 13, 318–329 (2007).
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Sparrow, J. R.

J. R. Sparrow and T. Duncker, “Fundus Autofluorescence and RPE Lipofuscin in Age-Related Macular Degeneration,” J. Clin. Med. 3(4), 1302–1321 (2014).
[PubMed]

J. R. Sparrow, E. Gregory-Roberts, K. Yamamoto, A. Blonska, S. K. Ghosh, K. Ueda, and J. Zhou, “The bisretinoids of retinal pigment epithelium,” Prog. Retin. Eye Res. 31(2), 121–135 (2012).
[PubMed]

J. R. Sparrow, Y. Wu, T. Nagasaki, K. D. Yoon, K. Yamamoto, and J. Zhou, “Fundus autofluorescence and the bisretinoids of retina,” Photochem. Photobiol. Sci. 9(11), 1480–1489 (2010).
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J. R. Sparrow, C. A. Parish, M. Hashimoto, and K. Nakanishi, “Pigmented Epithelial Cells in Culture,” Invest. Ophthalmol. Vis. Sci. 40, 2988–2995 (1999).
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M. Müller, J. Squier, K. R. Wilson, and G. J. Brakenhoff, “3D microscopy of transparent objects using third-harmonic generation,” J. Microsc. 191(3), 266–274 (1998).
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F. C. Delori, C. K. Dorey, G. Staurenghi, O. Arend, D. G. Goger, and J. J. Writer, “In Vivo Fluorescence of the Ocular Fundus Exhibits Retinal Pigment Epithelium Lipofuscin Characteristics,” Investigative Ophthalmol. Vis. Sci. 36, 718–729 (1995).

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D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and J. G. Fujimoto, “Optical coherence tomography,” Science 254(5035), 1178–1181 (1991).
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M. L. Katz, W. L. Stone, and E. A. Dratz, “Fluorescent pigment accumulation in retinal pigment epithelium of antioxidant-deficient rats,” Invest. Ophthalmol. Vis. Sci. 17(11), 1049–1058 (1978).
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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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M. W. Conklin, P. P. Provenzano, K. W. Eliceiri, R. Sullivan, and P. J. Keely, “Fluorescence lifetime imaging of endogenous fluorophores in histopathology sections reveals differences between normal and tumor epithelium in carcinoma in situ of the breast,” Cell Biochem. Biophys. 53(3), 145–157 (2009).
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Supatto, W.

D. Débarre, W. Supatto, A.-M. Pena, A. Fabre, T. Tordjmann, L. Combettes, M.-C. Schanne-Klein, and E. Beaurepaire, “Imaging lipid bodies in cells and tissues using third-harmonic generation microscopy,” Nat. Methods 3(1), 47–53 (2006).
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Sutherland, J. C.

J. C. Sutherland and K. P. Griffin, “Absorption Spectrum of DNA for Wavelengths Greater than 300 nm,” Radiat. Res. 86(3), 399–409 (1981).
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Swanson, E. A.

M. R. Hee, J. A. Izatt, E. A. Swanson, D. Huang, J. S. Schuman, C. P. Lin, C. A. Puliafito, and J. G. Fujimoto, “Optical coherence tomography of the human retina,” Arch. Ophthalmol. 113(3), 325–332 (1995).
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D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and J. G. Fujimoto, “Optical coherence tomography,” Science 254(5035), 1178–1181 (1991).
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Thulin, C. D.

S. Warburton, W. E. Davis, K. Southwick, H. Xin, A. T. Woolley, G. F. Burton, and C. D. Thulin, “Proteomic and phototoxic characterization of melanolipofuscin: correlation to disease and model for its origin,” Mol. Vis. 13, 318–329 (2007).
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Tordjmann, T.

D. Débarre, W. Supatto, A.-M. Pena, A. Fabre, T. Tordjmann, L. Combettes, M.-C. Schanne-Klein, and E. Beaurepaire, “Imaging lipid bodies in cells and tissues using third-harmonic generation microscopy,” Nat. Methods 3(1), 47–53 (2006).
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N. L. Mata, J. Weng, and G. H. Travis, “Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration,” Proc. Natl. Acad. Sci. U.S.A. 97(13), 7154–7159 (2000).
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M. Balu, I. Saytashev, J. Hou, M. Dantus, and B. J. Tromberg, “Sub-40 fs, 1060-nm Yb-fiber laser enhances penetration depth in nonlinear optical microscopy of human skin,” J. Biomed. Opt. 20(12), 120501 (2015).
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J. R. Sparrow, E. Gregory-Roberts, K. Yamamoto, A. Blonska, S. K. Ghosh, K. Ueda, and J. Zhou, “The bisretinoids of retinal pigment epithelium,” Prog. Retin. Eye Res. 31(2), 121–135 (2012).
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I. Rocha-Mendoza, D. R. Yankelevich, M. Wang, K. M. Reiser, C. W. Frank, and A. Knoesen, “Sum Frequency Vibrational Spectroscopy: The Molecular Origins of the Optical Second-Order Nonlinearity of Collagen,” Biophys. J. 93(12), 4433–4444 (2007).
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S. Warburton, W. E. Davis, K. Southwick, H. Xin, A. T. Woolley, G. F. Burton, and C. D. Thulin, “Proteomic and phototoxic characterization of melanolipofuscin: correlation to disease and model for its origin,” Mol. Vis. 13, 318–329 (2007).
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S. Watanabe, G. Matthews, M. L. Woodruff, I. V. Peshenko, A. B. Savchenko, C. L. Makino, Y.-S. Ho, G. L. Fain, and A. M. Dizhoor, “Regional distribution of cGMP-activated ion channels in the plasma membrane of the rod photoreceptor,” J. Neurosci. 8(7), 2334–2337 (1988).
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R. M. Williams, W. R. Zipfel, and W. W. Webb, “Interpreting second-harmonic generation images of collagen I fibrils,” Biophys. J. 88(2), 1377–1386 (2005).
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S. Huang, A. A. Heikal, and W. W. Webb, “Two-photon fluorescence spectroscopy and microscopy of NAD(P)H and flavoprotein,” Biophys. J. 82(5), 2811–2825 (2002).
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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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Weisel, L. R.

P. Xi, Y. Andegeko, L. R. Weisel, V. V. Lozovoy, and M. Dantus, “Greater signal, increased depth, and less photobleaching in two-photon microscopy with 10 fs pulses,” Opt. Commun. 281, 1841–1849 (2008).

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J. J. Weiter, F. C. Delori, G. L. Wing, and K. A. Fitch, “Retinal pigment epithelial lipofuscin and melanin and choroidal melanin in human eyes,” Invest. Ophthalmol. Vis. Sci. 27(2), 145–152 (1986).
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N. L. Mata, J. Weng, and G. H. Travis, “Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration,” Proc. Natl. Acad. Sci. U.S.A. 97(13), 7154–7159 (2000).
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M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
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R. M. Williams, W. R. Zipfel, and W. W. Webb, “Interpreting second-harmonic generation images of collagen I fibrils,” Biophys. J. 88(2), 1377–1386 (2005).
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M. Müller, J. Squier, K. R. Wilson, and G. J. Brakenhoff, “3D microscopy of transparent objects using third-harmonic generation,” J. Microsc. 191(3), 266–274 (1998).
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J. J. Weiter, F. C. Delori, G. L. Wing, and K. A. Fitch, “Retinal pigment epithelial lipofuscin and melanin and choroidal melanin in human eyes,” Invest. Ophthalmol. Vis. Sci. 27(2), 145–152 (1986).
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Wong, R. O. L.

M. Hoon, H. Okawa, L. Della Santina, and R. O. L. Wong, “Functional architecture of the retina: development and disease,” Prog. Retin. Eye Res. 42, 44–84 (2014).
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S. Watanabe, G. Matthews, M. L. Woodruff, I. V. Peshenko, A. B. Savchenko, C. L. Makino, Y.-S. Ho, G. L. Fain, and A. M. Dizhoor, “Regional distribution of cGMP-activated ion channels in the plasma membrane of the rod photoreceptor,” J. Neurosci. 8(7), 2334–2337 (1988).
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S. Warburton, W. E. Davis, K. Southwick, H. Xin, A. T. Woolley, G. F. Burton, and C. D. Thulin, “Proteomic and phototoxic characterization of melanolipofuscin: correlation to disease and model for its origin,” Mol. Vis. 13, 318–329 (2007).
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F. C. Delori, C. K. Dorey, G. Staurenghi, O. Arend, D. G. Goger, and J. J. Writer, “In Vivo Fluorescence of the Ocular Fundus Exhibits Retinal Pigment Epithelium Lipofuscin Characteristics,” Investigative Ophthalmol. Vis. Sci. 36, 718–729 (1995).

Wu, Y.

J. R. Sparrow, Y. Wu, T. Nagasaki, K. D. Yoon, K. Yamamoto, and J. Zhou, “Fundus autofluorescence and the bisretinoids of retina,” Photochem. Photobiol. Sci. 9(11), 1480–1489 (2010).
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P. Xi, Y. Andegeko, D. Pestov, V. V. Lovozoy, and M. Dantus, “Two-photon imaging using adaptive phase compensated ultrashort laser pulses,” J. Biomed. Opt. 14(1), 014002 (2009).
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P. Xi, Y. Andegeko, L. R. Weisel, V. V. Lozovoy, and M. Dantus, “Greater signal, increased depth, and less photobleaching in two-photon microscopy with 10 fs pulses,” Opt. Commun. 281, 1841–1849 (2008).

Xin, H.

S. Warburton, W. E. Davis, K. Southwick, H. Xin, A. T. Woolley, G. F. Burton, and C. D. Thulin, “Proteomic and phototoxic characterization of melanolipofuscin: correlation to disease and model for its origin,” Mol. Vis. 13, 318–329 (2007).
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Y. Coello, V. V. Lozovoy, T. C. Gunaratne, B. Xu, I. Borukhovich, C. Tseng, T. Weinacht, and M. Dantus, “Interference without an interferometer: a different approach to measuring, compressing, and shaping ultrashort laser pulses,” J. Opt. Soc. Am. B 25, A140 (2008).

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Yamamoto, K.

J. R. Sparrow, E. Gregory-Roberts, K. Yamamoto, A. Blonska, S. K. Ghosh, K. Ueda, and J. Zhou, “The bisretinoids of retinal pigment epithelium,” Prog. Retin. Eye Res. 31(2), 121–135 (2012).
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J. R. Sparrow, Y. Wu, T. Nagasaki, K. D. Yoon, K. Yamamoto, and J. Zhou, “Fundus autofluorescence and the bisretinoids of retina,” Photochem. Photobiol. Sci. 9(11), 1480–1489 (2010).
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I. Rocha-Mendoza, D. R. Yankelevich, M. Wang, K. M. Reiser, C. W. Frank, and A. Knoesen, “Sum Frequency Vibrational Spectroscopy: The Molecular Origins of the Optical Second-Order Nonlinearity of Collagen,” Biophys. J. 93(12), 4433–4444 (2007).
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J. R. Sparrow, Y. Wu, T. Nagasaki, K. D. Yoon, K. Yamamoto, and J. Zhou, “Fundus autofluorescence and the bisretinoids of retina,” Photochem. Photobiol. Sci. 9(11), 1480–1489 (2010).
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R. W. Young and D. Bok, “Participation of the retinal pigment epithelium in the rod outer segment renewal process,” J. Cell Biol. 42(2), 392–403 (1969).
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J. R. Sparrow, E. Gregory-Roberts, K. Yamamoto, A. Blonska, S. K. Ghosh, K. Ueda, and J. Zhou, “The bisretinoids of retinal pigment epithelium,” Prog. Retin. Eye Res. 31(2), 121–135 (2012).
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J. R. Sparrow, Y. Wu, T. Nagasaki, K. D. Yoon, K. Yamamoto, and J. Zhou, “Fundus autofluorescence and the bisretinoids of retina,” Photochem. Photobiol. Sci. 9(11), 1480–1489 (2010).
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R. M. Williams, W. R. Zipfel, and W. W. Webb, “Interpreting second-harmonic generation images of collagen I fibrils,” Biophys. J. 88(2), 1377–1386 (2005).
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R. M. Williams, W. R. Zipfel, and W. W. Webb, “Interpreting second-harmonic generation images of collagen I fibrils,” Biophys. J. 88(2), 1377–1386 (2005).
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I. Rocha-Mendoza, D. R. Yankelevich, M. Wang, K. M. Reiser, C. W. Frank, and A. Knoesen, “Sum Frequency Vibrational Spectroscopy: The Molecular Origins of the Optical Second-Order Nonlinearity of Collagen,” Biophys. J. 93(12), 4433–4444 (2007).
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J. J. Weiter, F. C. Delori, G. L. Wing, and K. A. Fitch, “Retinal pigment epithelial lipofuscin and melanin and choroidal melanin in human eyes,” Invest. Ophthalmol. Vis. Sci. 27(2), 145–152 (1986).
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F. Aptel, N. Olivier, A. Deniset-Besseau, J. M. Legeais, K. Plamann, M. C. Schanne-Klein, and E. Beaurepaire, “Multimodal nonlinear imaging of the human cornea,” Invest. Ophthalmol. Vis. Sci. 51(5), 2459–2465 (2010).
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Investigative Ophthalmol. Vis. Sci. (1)

F. C. Delori, C. K. Dorey, G. Staurenghi, O. Arend, D. G. Goger, and J. J. Writer, “In Vivo Fluorescence of the Ocular Fundus Exhibits Retinal Pigment Epithelium Lipofuscin Characteristics,” Investigative Ophthalmol. Vis. Sci. 36, 718–729 (1995).

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G. Palczewska, A. Maeda, M. Golczak, E. Arai, Z. Dong, L. Perusek, B. Kevany, and K. Palczewski, “Receptor MER tyrosine kinase proto-oncogene (MERTK) is not required for transfer of bis-retinoids to the retinal pigmented epithelium,” J. Biol. Chem. 291(52), 26937–26949 (2016).
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P. Xi, Y. Andegeko, D. Pestov, V. V. Lovozoy, and M. Dantus, “Two-photon imaging using adaptive phase compensated ultrashort laser pulses,” J. Biomed. Opt. 14(1), 014002 (2009).
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M. Balu, I. Saytashev, J. Hou, M. Dantus, and B. J. Tromberg, “Sub-40 fs, 1060-nm Yb-fiber laser enhances penetration depth in nonlinear optical microscopy of human skin,” J. Biomed. Opt. 20(12), 120501 (2015).
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J. R. Sparrow and T. Duncker, “Fundus Autofluorescence and RPE Lipofuscin in Age-Related Macular Degeneration,” J. Clin. Med. 3(4), 1302–1321 (2014).
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S. Watanabe, G. Matthews, M. L. Woodruff, I. V. Peshenko, A. B. Savchenko, C. L. Makino, Y.-S. Ho, G. L. Fain, and A. M. Dizhoor, “Regional distribution of cGMP-activated ion channels in the plasma membrane of the rod photoreceptor,” J. Neurosci. 8(7), 2334–2337 (1988).
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Mol. Vis. (3)

S. Warburton, W. E. Davis, K. Southwick, H. Xin, A. T. Woolley, G. F. Burton, and C. D. Thulin, “Proteomic and phototoxic characterization of melanolipofuscin: correlation to disease and model for its origin,” Mol. Vis. 13, 318–329 (2007).
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Nat. Methods (1)

D. Débarre, W. Supatto, A.-M. Pena, A. Fabre, T. Tordjmann, L. Combettes, M.-C. Schanne-Klein, and E. Beaurepaire, “Imaging lipid bodies in cells and tissues using third-harmonic generation microscopy,” Nat. Methods 3(1), 47–53 (2006).
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P. Xi, Y. Andegeko, L. R. Weisel, V. V. Lozovoy, and M. Dantus, “Greater signal, increased depth, and less photobleaching in two-photon microscopy with 10 fs pulses,” Opt. Commun. 281, 1841–1849 (2008).

Opt. Express (1)

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Photochem. Photobiol. Sci. (1)

J. R. Sparrow, Y. Wu, T. Nagasaki, K. D. Yoon, K. Yamamoto, and J. Zhou, “Fundus autofluorescence and the bisretinoids of retina,” Photochem. Photobiol. Sci. 9(11), 1480–1489 (2010).
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Proc. Natl. Acad. Sci. U.S.A. (2)

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
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J. R. Sparrow, E. Gregory-Roberts, K. Yamamoto, A. Blonska, S. K. Ghosh, K. Ueda, and J. Zhou, “The bisretinoids of retinal pigment epithelium,” Prog. Retin. Eye Res. 31(2), 121–135 (2012).
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Supplementary Material (1)

NameDescription
» Visualization 1       Depth resolved nonlinear optical imaging of an unstained monkey retina flat mount. The image size is 145x145 microns.

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Figures (7)

Fig. 1
Fig. 1 The experimental apparatus consisted of an ultrafast fiber laser operating at 1.07 μm, a MIIPS pulse shaper, a laser scanning inverted microscope, and a photon detector, mounted in the epi-direction. The TCSPC was used to collect fluorescence spectra and lifetime, whereas the single PMT was used to acquire the depth resolved images.
Fig. 2
Fig. 2 Three colored (red, green, blue) composite multimodal images of the retinal layers from a 7 µm slice of a mouse retina taken with the TCSPC at 6.9 mW of power depths using a 1.07 µm Yb-fiber laser with 35.0 fs pulse durations. Image acquisition was done at 30-second intervals for a total of 4.5 minutes. (a) Here the blue, green, and red channels represent emission centered at 535 nm, 575 nm, and 629 nm, respectively. (b) The blue, green, and red channels represent emission centered at 355 nm, 535 nm, and 629 nm, respectively. The bandwidth of each channel is ~37.5 nm.
Fig. 3
Fig. 3 Spectral emission from 480 to 680 nm detected from a mouse retina. a) The non-normalized emission spectra reveal that the receptor layers (ORL and IRL) have the strongest fluorescence emission. b) The normalized spectra more readily compare the different spectral shapes across retinal layers. Layers from the NFL thru the OPL all have nearly identical spectral shapes. The sclera has a unique spectral shape, where the peak at 535 nm is attributed to SHG (see Discussion).
Fig. 4
Fig. 4 Fluorescence lifetimes across the retinal layers from a mouse over a spectral range of a) 556-594 nm, b) 610-648 nm, and c) short: 556-594 nm and long: 610-648 nm. The plots reveal that for a given spectral band, all the layers from the NFL through the ORL have nearly identical lifetimes, whereas the choroid and RPE have nearly identical lifetimes. Additionally, the lifetimes in the choroid and RPE become shorter for longer detection wavelengths (i.e. from panel a to panel b). This trend is shown directly in panel c, where the lifetimes for the choroid, RPE, IRL, and IPL are fitted for both the short wavelength range and the long wavelength range. Also in panel c is the lifetime measured at 535 nm from the sclera. SHG from collagen in the sclera is the source of this emission and coincides with the IRF of our system.
Fig. 5
Fig. 5 Depth-resolved imaging of an unstained, fixed, Cynomolgus monkey retina flat mount. The total extent of the Cynomolgus monkey retina was 220 μm. The depth of each image is indicated in yellow. The scale bar is 15 μm and can be seen in the NFL panel. Each 2D image was an average of 5 scans, averaged for 5 seconds. Each layer, beginning with the NFL and ending with the ORL and RPE retinosomes, from left to right, was an average of 182 images (9.1 µm), 190 images (9.5 µm), 182 images (9.1 µm), 139 images (7.0 µm), 51 images (2.63 µm), 233 images (11.7 µm), 211 images (10.6 µm), and 33 images (1.7 µm), respectively. The depth resolved stack was obtained with 7 mW of average power at all depths using a 1.07 µm Yb-fiber laser with 34.8 fs pulse durations. In the IRL, inner segments of cone photoreceptors (large white features) and rod photoreceptor inner segments (smaller round features between the cone inner segments) are easily distinguishable. We believe that the bright particles in the bottom right panel are perhaps melanin or RPE retinosomes attached to the tips of photoreceptors. At each depth, the characteristic morphology of the retina layers is clear, indicating that the Yb-fiber laser is effective at achieving the cellular resolution needed for depth resolved imaging. Video of depth resolved imaging of retina used to obtain the images presented in this figure (Visualization 1).
Fig. 6
Fig. 6 (Left). Lifetime decay fits and the corresponding residual plots for the RPE and choroid for the wavelength range of 556-594 nm. This figure shows the RPE and choroid fit poorly to a mono-exponential function. (Right). Lifetime decay fits and the corresponding residual plots for the ORL through NFL for the wavelength range of 610-648 nm. This figure demonstrates that the ORL-NFL layers fit poorly to a tri-exponential function
Fig. 7
Fig. 7 The spectra (Left) and lifetime (Right) from a 1 mM solution of A2E. The spectra peaks near 625 nm, which is the same peak seen in the choroid, RPE, and receptor layers. The lifetime of ~173 ps agrees with the literature values [29].

Tables (2)

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Table 1 Lifetime fitting of data shown in Fig. 4. The parenthetical values correspond to one standard deviation. R2 is the coefficient of determination, a dimensionless quantity.

Tables Icon

Table 2 Fitting with fixed parameters for lifetime decays shown in Fig. 4(a) and 4(b). The parenthetical values are the one standard deviation errors and have units of ns. R2 is the coefficient of determination (R2 error) and is a dimensionless quantity.

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