Abstract

A multimodal multiphoton microscopy (MPM) is developed to acquire both two-photon microscopy (2PM) and three-photon microscopy (3PM) signals. A dual-wavelength Er-doped fiber laser is used as the light source, which provides the fundamental pulse at 1580 nm to excite third harmonic generation (THG) and the frequency-doubled pulse at 790 nm to excite intrinsic two-photon excitation fluorescence (TPEF) and second harmonic generation (SHG). Due to their different contrast mechanisms, the TPEF, SHG, and THG images can acquire complementary information about tissues, including cells, collagen fibers, lipids, and interfaces, all label-free. The compact MPM imaging probe is developed using miniature objective lens and a micro-electro-mechanical scanner. Furthermore, the femtosecond laser pulses are delivered by a single mode fiber and the signals are collected by a multimode fiber, which makes the miniaturized MPM directly fiber-coupled, compact, and portable. Design considerations on using the dual excitation wavelengths are discussed. Multimodal and label-free imaging by TPEF, SHG, and THG are demonstrated on biological samples. The miniaturized multimodal MPM is shown to have great potential for label-free imaging of thick and live tissues.

© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

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References

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2018 (4)

A. Filippi, E. Dal Sasso, L. Iop, A. Armani, M. Gintoli, M. Sandri, G. Gerosa, F. Romanato, and G. Borile, “Multimodal label-free ex vivo imaging using a dual-wavelength microscope with axial chromatic aberration compensation,” J. Biomed. Opt. 23(9), 1–9 (2018).
[Crossref]

D. M. Small, J. S. Jones, I. I. Tendler, P. E. Miller, A. Ghetti, and N. Nishimura, “Label-free imaging of atherosclerotic plaques using third-harmonic generation microscopy,” Biomed. Opt. Express 9(1), 214–229 (2018).
[Crossref]

F. Akhoundi, Y. Qin, N. Peyghambarian, J. K. Barton, and K. Kieu, “Compact fiber-based multi-photon endoscope working at 1700nm,” Biomed. Opt. Express 9(5), 2326–2335 (2018).
[Crossref]

L. Huang, X. Zhou, and S. Tang, “Optimization of frequency-doubled Er-doped fiber laser for miniature multiphoton endoscopy,” J. Biomed. Opt. 23(12), 1–12 (2018).
[Crossref]

2017 (2)

D. G. Ouzounov, T. Wang, M. Wang, D. D. Feng, N. G. Horton, J. C. Cruz-Hernández, Y. T. Cheng, J. Reimer, A. S. Tolias, and N. Nishimura, “In vivo three-photon imaging of activity of GCaMP6-labeled neurons deep in intact mouse brain,” Nat. Methods 14(4), 388–390 (2017).
[Crossref]

R. Genthial, E. Beaurepaire, M. C. Schanne-Klein, F. Peyrin, D. Farlay, C. Olivier, Y. Bala, G. Boivin, J. C. Vial, and D. Débarre, “Label-free imaging of bone multiscale porosity and interfaces using third-harmonic generation microscopy,” Sci. Rep. 7(1), 3419 (2017).
[Crossref]

2016 (1)

2015 (2)

M. D. Young, J. J. Field, K. E. Sheetz, R. A. Bartels, and J. Squier, “A pragmatic guide to multiphoton microscope design,” Adv. Opt. Photonics 7(2), 276–378 (2015).
[Crossref]

R. Kumar, K. M. Grønhaug, C. L. Davies, J. O. Drogset, and M. B. Lilledahl, “Nonlinear optical microscopy of early stage (ICRS Grade-I) osteoarthritic human cartilage,” Biomed. Opt. Express 6(5), 1895–1903 (2015).
[Crossref]

2014 (1)

S. Dietzel, J. Pircher, A. K. Nekolla, M. Gull, A. W. Brändli, U. Pohl, and M. Rehberg, “Label-free determination of hemodynamic parameters in the microcirculaton with third harmonic generation microscopy,” PLoS One 9(6), e99615 (2014).
[Crossref]

2013 (2)

J. H. Yu, S. H. Kwon, Z. Petrášek, O. K. Park, S. W. Jun, K. Shin, M. Choi, Y. I. Park, K. Park, and H. B. Na, “High-resolution three-photon biomedical imaging using doped ZnS nanocrystals,” Nat. Mater. 12(4), 359–366 (2013).
[Crossref]

K. Kieu, S. Mehravar, R. Gowda, R. A. Norwood, and N. Peyghambarian, “Label-free multi-photon imaging using a compact femtosecond fiber laser mode-locked by carbon nanotube saturable absorber,” Biomed. Opt. Express 4(10), 2187–2195 (2013).
[Crossref]

2012 (3)

B. Weigelin, G. J. Bakker, and P. Friedl, “Intravital third harmonic generation microscopy of collective melanoma cell invasion: principles of interface guidance and microvesicle dynamics,” IntraVital 1(1), 32–43 (2012).
[Crossref]

K. Wang, T. M. Liu, J. Wu, N. G. Horton, C. P. Lin, and C. Xu, “Three-color femtosecond source for simultaneous excitation of three fluorescent proteins in two-photon fluorescence microscopy,” Biomed. Opt. Express 3(9), 1972–1977 (2012).
[Crossref]

J. C. Mansfield and C. Peter Winlove, “A multi-modal multiphoton investigation of microstructure in the deep zone and calcified cartilage,” J. Anat. 220(4), 405–416 (2012).
[Crossref]

2010 (1)

N. Olivier, M. A. Luengo-Oroz, L. Duloquin, E. Faure, T. Savy, I. Veilleux, X. Solinas, D. Débarre, P. Bourgine, and A. Santos, “Cell lineage reconstruction of early zebrafish embryos using label-free nonlinear microscopy,” Science 329(5994), 967–971 (2010).
[Crossref]

2009 (1)

S. Tang, W. Jung, D. McCormick, T. Xie, J. Su, Y. C. Ahn, B. J. Tromberg, and Z. Chen, “Design and implementation of fiber-based multiphoton endoscopy with microelectromechanical systems scanning,” J. Biomed. Opt. 14(3), 034005 (2009).
[Crossref]

2007 (1)

A. D. Bristow, N. Rotenberg, and H. M. Van Driel, “Two-photon absorption and Kerr coefficients of silicon for 850–2200 nm,” Appl. Phys. Lett. 90(19), 191104 (2007).
[Crossref]

2006 (2)

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).
[Crossref]

S. J. Lin, S. H. Jee, C. J. Kuo, R. J. Wu, W. C. Lin, J. S. Chen, Y. H. Liao, C. J. Hsu, T. F. Tsai, and Y. F. Chen, “Discrimination of basal cell carcinoma from normal dermal stroma by quantitative multiphoton imaging,” Opt. Lett. 31(18), 2756–2758 (2006).
[Crossref]

2004 (2)

M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol. 91(4), 1908–1912 (2004).
[Crossref]

D. Oron, D. Yelin, E. Tal, S. Raz, R. Fachima, and Y. Silberberg, “Depth-resolved structural imaging by third-harmonic generation microscopy,” J. Struct. Biol. 147(1), 3–11 (2004).
[Crossref]

2003 (3)

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
[Crossref]

P. J. Campagnola and L. M. Loew, “Second-harmonic imaging microscopy for visualizing biomolecular arrays in cells, tissues and organisms,” Nat. Biotechnol. 21(11), 1356–1360 (2003).
[Crossref]

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U. S. A. 100(12), 7075–7080 (2003).
[Crossref]

2002 (1)

A. Zoumi, A. Yeh, and B. J. Tromberg, “Imaging cells and extracellular matrix in vivo by using second-harmonic generation and two-photon excited fluorescence,” Proc. Natl. Acad. Sci. U. S. A. 99(17), 11014–11019 (2002).
[Crossref]

1999 (1)

P. J. Campagnola, A. Lewis, and L. M. Loew, “High-resolution nonlinear optical imaging of live cells by second harmonic generation,” Biophys. J. 77(6), 3341–3349 (1999).
[Crossref]

1997 (1)

Y. Barad, H. Eisenberg, M. Horowitz, and Y. Silberberg, “Nonlinear scanning laser microscopy by third harmonic generation,” Appl. Phys. Lett. 70(8), 922–924 (1997).
[Crossref]

1996 (1)

C. Xu, W. Zipfel, J. B. Shear, R. M. Williams, and W. W. Webb, “Multiphoton fluorescence excitation: new spectral windows for biological nonlinear microscopy,” Proc. Natl. Acad. Sci. U. S. A. 93(20), 10763–10768 (1996).
[Crossref]

1990 (1)

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

Ahn, Y. C.

S. Tang, W. Jung, D. McCormick, T. Xie, J. Su, Y. C. Ahn, B. J. Tromberg, and Z. Chen, “Design and implementation of fiber-based multiphoton endoscopy with microelectromechanical systems scanning,” J. Biomed. Opt. 14(3), 034005 (2009).
[Crossref]

Akhoundi, F.

Armani, A.

A. Filippi, E. Dal Sasso, L. Iop, A. Armani, M. Gintoli, M. Sandri, G. Gerosa, F. Romanato, and G. Borile, “Multimodal label-free ex vivo imaging using a dual-wavelength microscope with axial chromatic aberration compensation,” J. Biomed. Opt. 23(9), 1–9 (2018).
[Crossref]

Bakker, G. J.

B. Weigelin, G. J. Bakker, and P. Friedl, “Intravital third harmonic generation microscopy of collective melanoma cell invasion: principles of interface guidance and microvesicle dynamics,” IntraVital 1(1), 32–43 (2012).
[Crossref]

Bala, Y.

R. Genthial, E. Beaurepaire, M. C. Schanne-Klein, F. Peyrin, D. Farlay, C. Olivier, Y. Bala, G. Boivin, J. C. Vial, and D. Débarre, “Label-free imaging of bone multiscale porosity and interfaces using third-harmonic generation microscopy,” Sci. Rep. 7(1), 3419 (2017).
[Crossref]

Barad, Y.

Y. Barad, H. Eisenberg, M. Horowitz, and Y. Silberberg, “Nonlinear scanning laser microscopy by third harmonic generation,” Appl. Phys. Lett. 70(8), 922–924 (1997).
[Crossref]

Bartels, R. A.

M. D. Young, J. J. Field, K. E. Sheetz, R. A. Bartels, and J. Squier, “A pragmatic guide to multiphoton microscope design,” Adv. Opt. Photonics 7(2), 276–378 (2015).
[Crossref]

Barton, J. K.

Beaurepaire, E.

R. Genthial, E. Beaurepaire, M. C. Schanne-Klein, F. Peyrin, D. Farlay, C. Olivier, Y. Bala, G. Boivin, J. C. Vial, and D. Débarre, “Label-free imaging of bone multiscale porosity and interfaces using third-harmonic generation microscopy,” Sci. Rep. 7(1), 3419 (2017).
[Crossref]

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).
[Crossref]

Boivin, G.

R. Genthial, E. Beaurepaire, M. C. Schanne-Klein, F. Peyrin, D. Farlay, C. Olivier, Y. Bala, G. Boivin, J. C. Vial, and D. Débarre, “Label-free imaging of bone multiscale porosity and interfaces using third-harmonic generation microscopy,” Sci. Rep. 7(1), 3419 (2017).
[Crossref]

Borile, G.

A. Filippi, E. Dal Sasso, L. Iop, A. Armani, M. Gintoli, M. Sandri, G. Gerosa, F. Romanato, and G. Borile, “Multimodal label-free ex vivo imaging using a dual-wavelength microscope with axial chromatic aberration compensation,” J. Biomed. Opt. 23(9), 1–9 (2018).
[Crossref]

Born, M.

M. Born and E. Wolf, Principles of Optics: Electromagnetic Theory of Propagation, Interference and Diffraction of Light (Elsevier, 2013).

Bourgine, P.

N. Olivier, M. A. Luengo-Oroz, L. Duloquin, E. Faure, T. Savy, I. Veilleux, X. Solinas, D. Débarre, P. Bourgine, and A. Santos, “Cell lineage reconstruction of early zebrafish embryos using label-free nonlinear microscopy,” Science 329(5994), 967–971 (2010).
[Crossref]

Boyd, R. W.

R. W. Boyd, Nonlinear Optics (Academic Press, 2003).

Brändli, A. W.

S. Dietzel, J. Pircher, A. K. Nekolla, M. Gull, A. W. Brändli, U. Pohl, and M. Rehberg, “Label-free determination of hemodynamic parameters in the microcirculaton with third harmonic generation microscopy,” PLoS One 9(6), e99615 (2014).
[Crossref]

Bristow, A. D.

A. D. Bristow, N. Rotenberg, and H. M. Van Driel, “Two-photon absorption and Kerr coefficients of silicon for 850–2200 nm,” Appl. Phys. Lett. 90(19), 191104 (2007).
[Crossref]

Campagnola, P. J.

P. J. Campagnola and L. M. Loew, “Second-harmonic imaging microscopy for visualizing biomolecular arrays in cells, tissues and organisms,” Nat. Biotechnol. 21(11), 1356–1360 (2003).
[Crossref]

P. J. Campagnola, A. Lewis, and L. M. Loew, “High-resolution nonlinear optical imaging of live cells by second harmonic generation,” Biophys. J. 77(6), 3341–3349 (1999).
[Crossref]

Chen, J. S.

Chen, Y. F.

Chen, Z.

S. Tang, W. Jung, D. McCormick, T. Xie, J. Su, Y. C. Ahn, B. J. Tromberg, and Z. Chen, “Design and implementation of fiber-based multiphoton endoscopy with microelectromechanical systems scanning,” J. Biomed. Opt. 14(3), 034005 (2009).
[Crossref]

Cheng, Y. T.

D. G. Ouzounov, T. Wang, M. Wang, D. D. Feng, N. G. Horton, J. C. Cruz-Hernández, Y. T. Cheng, J. Reimer, A. S. Tolias, and N. Nishimura, “In vivo three-photon imaging of activity of GCaMP6-labeled neurons deep in intact mouse brain,” Nat. Methods 14(4), 388–390 (2017).
[Crossref]

Choi, M.

J. H. Yu, S. H. Kwon, Z. Petrášek, O. K. Park, S. W. Jun, K. Shin, M. Choi, Y. I. Park, K. Park, and H. B. Na, “High-resolution three-photon biomedical imaging using doped ZnS nanocrystals,” Nat. Mater. 12(4), 359–366 (2013).
[Crossref]

Christie, R.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U. S. A. 100(12), 7075–7080 (2003).
[Crossref]

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).
[Crossref]

Cruz-Hernández, J. C.

D. G. Ouzounov, T. Wang, M. Wang, D. D. Feng, N. G. Horton, J. C. Cruz-Hernández, Y. T. Cheng, J. Reimer, A. S. Tolias, and N. Nishimura, “In vivo three-photon imaging of activity of GCaMP6-labeled neurons deep in intact mouse brain,” Nat. Methods 14(4), 388–390 (2017).
[Crossref]

Dal Sasso, E.

A. Filippi, E. Dal Sasso, L. Iop, A. Armani, M. Gintoli, M. Sandri, G. Gerosa, F. Romanato, and G. Borile, “Multimodal label-free ex vivo imaging using a dual-wavelength microscope with axial chromatic aberration compensation,” J. Biomed. Opt. 23(9), 1–9 (2018).
[Crossref]

Davies, C. L.

Débarre, D.

R. Genthial, E. Beaurepaire, M. C. Schanne-Klein, F. Peyrin, D. Farlay, C. Olivier, Y. Bala, G. Boivin, J. C. Vial, and D. Débarre, “Label-free imaging of bone multiscale porosity and interfaces using third-harmonic generation microscopy,” Sci. Rep. 7(1), 3419 (2017).
[Crossref]

N. Olivier, M. A. Luengo-Oroz, L. Duloquin, E. Faure, T. Savy, I. Veilleux, X. Solinas, D. Débarre, P. Bourgine, and A. Santos, “Cell lineage reconstruction of early zebrafish embryos using label-free nonlinear microscopy,” Science 329(5994), 967–971 (2010).
[Crossref]

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).
[Crossref]

Denk, W.

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

Dietzel, S.

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D. G. Ouzounov, T. Wang, M. Wang, D. D. Feng, N. G. Horton, J. C. Cruz-Hernández, Y. T. Cheng, J. Reimer, A. S. Tolias, and N. Nishimura, “In vivo three-photon imaging of activity of GCaMP6-labeled neurons deep in intact mouse brain,” Nat. Methods 14(4), 388–390 (2017).
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M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol. 91(4), 1908–1912 (2004).
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W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
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W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U. S. A. 100(12), 7075–7080 (2003).
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C. Xu, W. Zipfel, J. B. Shear, R. M. Williams, and W. W. Webb, “Multiphoton fluorescence excitation: new spectral windows for biological nonlinear microscopy,” Proc. Natl. Acad. Sci. U. S. A. 93(20), 10763–10768 (1996).
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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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Weigelin, B.

B. Weigelin, G. J. Bakker, and P. Friedl, “Intravital third harmonic generation microscopy of collective melanoma cell invasion: principles of interface guidance and microvesicle dynamics,” IntraVital 1(1), 32–43 (2012).
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W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U. S. A. 100(12), 7075–7080 (2003).
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W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
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C. Xu, W. Zipfel, J. B. Shear, R. M. Williams, and W. W. Webb, “Multiphoton fluorescence excitation: new spectral windows for biological nonlinear microscopy,” Proc. Natl. Acad. Sci. U. S. A. 93(20), 10763–10768 (1996).
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M. Born and E. Wolf, Principles of Optics: Electromagnetic Theory of Propagation, Interference and Diffraction of Light (Elsevier, 2013).

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S. Tang, W. Jung, D. McCormick, T. Xie, J. Su, Y. C. Ahn, B. J. Tromberg, and Z. Chen, “Design and implementation of fiber-based multiphoton endoscopy with microelectromechanical systems scanning,” J. Biomed. Opt. 14(3), 034005 (2009).
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K. Wang, T. M. Liu, J. Wu, N. G. Horton, C. P. Lin, and C. Xu, “Three-color femtosecond source for simultaneous excitation of three fluorescent proteins in two-photon fluorescence microscopy,” Biomed. Opt. Express 3(9), 1972–1977 (2012).
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C. Xu, W. Zipfel, J. B. Shear, R. M. Williams, and W. W. Webb, “Multiphoton fluorescence excitation: new spectral windows for biological nonlinear microscopy,” Proc. Natl. Acad. Sci. U. S. A. 93(20), 10763–10768 (1996).
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A. Zoumi, A. Yeh, and B. J. Tromberg, “Imaging cells and extracellular matrix in vivo by using second-harmonic generation and two-photon excited fluorescence,” Proc. Natl. Acad. Sci. U. S. A. 99(17), 11014–11019 (2002).
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D. Oron, D. Yelin, E. Tal, S. Raz, R. Fachima, and Y. Silberberg, “Depth-resolved structural imaging by third-harmonic generation microscopy,” J. Struct. Biol. 147(1), 3–11 (2004).
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M. D. Young, J. J. Field, K. E. Sheetz, R. A. Bartels, and J. Squier, “A pragmatic guide to multiphoton microscope design,” Adv. Opt. Photonics 7(2), 276–378 (2015).
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J. H. Yu, S. H. Kwon, Z. Petrášek, O. K. Park, S. W. Jun, K. Shin, M. Choi, Y. I. Park, K. Park, and H. B. Na, “High-resolution three-photon biomedical imaging using doped ZnS nanocrystals,” Nat. Mater. 12(4), 359–366 (2013).
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L. Huang, X. Zhou, and S. Tang, “Optimization of frequency-doubled Er-doped fiber laser for miniature multiphoton endoscopy,” J. Biomed. Opt. 23(12), 1–12 (2018).
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C. Xu, W. Zipfel, J. B. Shear, R. M. Williams, and W. W. Webb, “Multiphoton fluorescence excitation: new spectral windows for biological nonlinear microscopy,” Proc. Natl. Acad. Sci. U. S. A. 93(20), 10763–10768 (1996).
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W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
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W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U. S. A. 100(12), 7075–7080 (2003).
[Crossref]

Zoumi, A.

A. Zoumi, A. Yeh, and B. J. Tromberg, “Imaging cells and extracellular matrix in vivo by using second-harmonic generation and two-photon excited fluorescence,” Proc. Natl. Acad. Sci. U. S. A. 99(17), 11014–11019 (2002).
[Crossref]

Adv. Opt. Photonics (1)

M. D. Young, J. J. Field, K. E. Sheetz, R. A. Bartels, and J. Squier, “A pragmatic guide to multiphoton microscope design,” Adv. Opt. Photonics 7(2), 276–378 (2015).
[Crossref]

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[Crossref]

Biomed. Opt. Express (6)

Biophys. J. (1)

P. J. Campagnola, A. Lewis, and L. M. Loew, “High-resolution nonlinear optical imaging of live cells by second harmonic generation,” Biophys. J. 77(6), 3341–3349 (1999).
[Crossref]

IntraVital (1)

B. Weigelin, G. J. Bakker, and P. Friedl, “Intravital third harmonic generation microscopy of collective melanoma cell invasion: principles of interface guidance and microvesicle dynamics,” IntraVital 1(1), 32–43 (2012).
[Crossref]

J. Anat. (1)

J. C. Mansfield and C. Peter Winlove, “A multi-modal multiphoton investigation of microstructure in the deep zone and calcified cartilage,” J. Anat. 220(4), 405–416 (2012).
[Crossref]

J. Biomed. Opt. (3)

S. Tang, W. Jung, D. McCormick, T. Xie, J. Su, Y. C. Ahn, B. J. Tromberg, and Z. Chen, “Design and implementation of fiber-based multiphoton endoscopy with microelectromechanical systems scanning,” J. Biomed. Opt. 14(3), 034005 (2009).
[Crossref]

A. Filippi, E. Dal Sasso, L. Iop, A. Armani, M. Gintoli, M. Sandri, G. Gerosa, F. Romanato, and G. Borile, “Multimodal label-free ex vivo imaging using a dual-wavelength microscope with axial chromatic aberration compensation,” J. Biomed. Opt. 23(9), 1–9 (2018).
[Crossref]

L. Huang, X. Zhou, and S. Tang, “Optimization of frequency-doubled Er-doped fiber laser for miniature multiphoton endoscopy,” J. Biomed. Opt. 23(12), 1–12 (2018).
[Crossref]

J. Neurophysiol. (1)

M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol. 91(4), 1908–1912 (2004).
[Crossref]

J. Struct. Biol. (1)

D. Oron, D. Yelin, E. Tal, S. Raz, R. Fachima, and Y. Silberberg, “Depth-resolved structural imaging by third-harmonic generation microscopy,” J. Struct. Biol. 147(1), 3–11 (2004).
[Crossref]

Nat. Biotechnol. (2)

P. J. Campagnola and L. M. Loew, “Second-harmonic imaging microscopy for visualizing biomolecular arrays in cells, tissues and organisms,” Nat. Biotechnol. 21(11), 1356–1360 (2003).
[Crossref]

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21(11), 1369–1377 (2003).
[Crossref]

Nat. Mater. (1)

J. H. Yu, S. H. Kwon, Z. Petrášek, O. K. Park, S. W. Jun, K. Shin, M. Choi, Y. I. Park, K. Park, and H. B. Na, “High-resolution three-photon biomedical imaging using doped ZnS nanocrystals,” Nat. Mater. 12(4), 359–366 (2013).
[Crossref]

Nat. Methods (2)

D. G. Ouzounov, T. Wang, M. Wang, D. D. Feng, N. G. Horton, J. C. Cruz-Hernández, Y. T. Cheng, J. Reimer, A. S. Tolias, and N. Nishimura, “In vivo three-photon imaging of activity of GCaMP6-labeled neurons deep in intact mouse brain,” Nat. Methods 14(4), 388–390 (2017).
[Crossref]

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).
[Crossref]

Opt. Lett. (1)

PLoS One (1)

S. Dietzel, J. Pircher, A. K. Nekolla, M. Gull, A. W. Brändli, U. Pohl, and M. Rehberg, “Label-free determination of hemodynamic parameters in the microcirculaton with third harmonic generation microscopy,” PLoS One 9(6), e99615 (2014).
[Crossref]

Proc. Natl. Acad. Sci. U. S. A. (3)

C. Xu, W. Zipfel, J. B. Shear, R. M. Williams, and W. W. Webb, “Multiphoton fluorescence excitation: new spectral windows for biological nonlinear microscopy,” Proc. Natl. Acad. Sci. U. S. A. 93(20), 10763–10768 (1996).
[Crossref]

A. Zoumi, A. Yeh, and B. J. Tromberg, “Imaging cells and extracellular matrix in vivo by using second-harmonic generation and two-photon excited fluorescence,” Proc. Natl. Acad. Sci. U. S. A. 99(17), 11014–11019 (2002).
[Crossref]

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U. S. A. 100(12), 7075–7080 (2003).
[Crossref]

Sci. Rep. (1)

R. Genthial, E. Beaurepaire, M. C. Schanne-Klein, F. Peyrin, D. Farlay, C. Olivier, Y. Bala, G. Boivin, J. C. Vial, and D. Débarre, “Label-free imaging of bone multiscale porosity and interfaces using third-harmonic generation microscopy,” Sci. Rep. 7(1), 3419 (2017).
[Crossref]

Science (2)

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

N. Olivier, M. A. Luengo-Oroz, L. Duloquin, E. Faure, T. Savy, I. Veilleux, X. Solinas, D. Débarre, P. Bourgine, and A. Santos, “Cell lineage reconstruction of early zebrafish embryos using label-free nonlinear microscopy,” Science 329(5994), 967–971 (2010).
[Crossref]

Other (5)

R. W. Boyd, Nonlinear Optics (Academic Press, 2003).

A. M. Weiner, Ultrafast Optics (Wiley, 2009).

W. Nagourney, Quantum Electronics for Atomic Physics and Telecommunication (OUP, 2014).

B. E. Saleh, M. C. Teich, and B. E. Saleh, Fundamentals of Photonics (Wiley, 1991), Vol. 22.

M. Born and E. Wolf, Principles of Optics: Electromagnetic Theory of Propagation, Interference and Diffraction of Light (Elsevier, 2013).

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Figures (9)

Fig. 1.
Fig. 1. Schematic of the miniaturized multimodal 2PM and 3PM with a dual-wavelength EDF laser. SMF: single mode fiber; CL: collimating lens; HWP: half-wave plate; QWP: quarter-wave plate; L: lens; SL: scan lens; TL: tube lens; PPLN: periodically poled MgO:LiNbO3 crystal; F: filter; MEMS: micro-electro-mechanical scanning mirror; DM: Dichroic mirror; OBJ: objective lens; MMF: multimode fiber; PMT: photomultiplier tube.
Fig. 2.
Fig. 2. Illustration of the spectral relationship of the excitation and emission wavelengths involved in the multimodal 2PM and 3PM imaging. Top left insert shows the energy diagrams of SHG, TPEF, and THG processes. Top right insert shows the measured spectrum of the dual-wavelength EDF laser with frequency doubling.
Fig. 3.
Fig. 3. Gaussian beam width versus the axial distance to the focal plane of the collimation lens for the 1580-nm (blue) and the 790-nm (red) beams, respectively.
Fig. 4.
Fig. 4. Zemax simulation of focal shift. (a) Optical layout of the scan lens, tube lens, and objective lens. (b) Simulated focal shift versus wavelength from 400 nm to 1580 nm.
Fig. 5.
Fig. 5. (a) and (c) are the Zemax simulation of the spot diagrams at the center and edges of the FOV at 790 nm and 1580 nm, respectively. Scale bar is 150 µm. (b) and (d) are the RMS spot radius at different distances from the center of the FOV at 790 nm and 1580 nm, respectively. The left and right Y-axes show the RMS spot radius for one-photon and 2PM (or 3PM) signals, respectively. The corresponding radius of the Airy disc is shown as the dashed line.
Fig. 6.
Fig. 6. (a) Layout of the silicon nano-chip. (b-e) Multimodal MPM imaging of the silicon nano-chip. (b) TPEF image. (c) SHG image. (d) THG image. (e) Merged image. Pseudocolor: TPEF in red, SHG in green, THG in blue. Scale bar is 50 µm.
Fig. 7.
Fig. 7. (a) Signal intensity of TPEF, SHG, and THG respectively versus excitation power. (b) Intensity line profile of TPEF, SHG, and THG respectively measured across a nano-waveguide. The dashed lines are the corresponding Gaussian fitting.
Fig. 8.
Fig. 8. Multimodal MPM imaging of the inner surface (top) and outer surface (bottom) of murine femur bone. Pseudocolor: TPEF in red, SHG in green, THG in blue. Scale bar is 50 µm.
Fig. 9.
Fig. 9. Multimodal MPM imaging of the inner surface of porcine femur bone. Pseudocolor: TPEF in red, SHG in green, THG in blue. Scale bar is 50 µm.

Tables (2)

Tables Icon

Table 1. Specifications of the dual-wavelength EDF laser source.

Tables Icon

Table 2. Comparison of the specifications of the 2PM and 3PM.

Equations (4)

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w0(2ω)=w0(ω)2
w0=λfπw0
w0(2ω)=w0(ω)2
θ=λπw0

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