Abstract

The capability to image the 3D distribution of melanin in human skin in vivo with absolute quantities and microscopic details will not only enable noninvasive histopathological diagnosis of melanin-related cutaneous disorders, but also make long term treatment assessment possible. In this paper, we demonstrate clinical in vivo imaging of the melanin distribution in human skin with absolute quantities on mass density and with microscopic details by using label-free third-harmonic-generation (THG) enhancement-ratio microscopy. As the dominant absorber in skin, melanin provides the strongest THG nonlinearity in human skin due to resonance enhancement. We show that the THG-enhancement-ratio (erTHG) parameter can be calibrated in vivo and can indicate the melanin mass density. With an unprecedented clinical imaging resolution, our study revealed erTHG-microscopy’s unique capability for long-term treatment assessment and direct clinical observation of melanin’s micro-distribution to shed light into the unknown pathway and regulation mechanism of melanosome transfer and translocation.

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

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2020 (2)

S. Chakraborty, S.-T. Chen, Y.-T. Hsiao, M.-J. Chiu, and C.-K. Sun, “Additive-color multi-harmonic generation microscopy for simultaneous label-free differentiation of plaques, tangles, and neuronal axons,” Biomed. Opt. Express 11(2), 571–585 (2020).
[Crossref]

K.-H. Lin, Y.-H. Liao, M.-L. Wei, and C.-K. Sun, “Comparative analysis of intrinsic skin aging between Caucasian and Asian subjects by slide-free in vivo harmonic generation microscopy,” J. Biophotonics 13(4), e201960063 (2020).
[Crossref]

2019 (3)

J.-H. Lee, Y.-T. Shih, M.-L. Wei, C.-K. Sun, and B.-L. Chiang, “Classification of Established atopic dermatitis in children with the in vivo imaging methods,” J. Biophotonics 12(5), e201800148 (2019).
[Crossref]

C.-K. Sun, W.-M. Liu, and Y.-H. Liao, “Study on melanin enhanced third harmonic generation in a live cell model,” Biomed. Opt. Express 10(11), 5716–5723 (2019).
[Crossref]

Y.-H. Liao, Y.-H. Su, Y.-T. Shih, W.-S. Chen, S.-H. Jee, and C.-K. Sun, “In vivo third-harmonic generation microscopy study on vitiligo patients,” J. Biomed. Opt. 25(1), 014504 (2019).
[Crossref]

2017 (1)

C. Stringari, L. Abdeladim, G. Malkinson, P. Mahou, X. Solinas, I. Lamarre, S. Brizion, J.-B. Galey, W. Supatto, R. Legouis, A.-M. Pena, and E. Beaurepaire, “Multicolor two-photon imaging of endogenous fluorophores in living tissues by wavelength mixing,” Sci. Rep. 7(1), 3792 (2017).
[Crossref]

2016 (2)

W.-H. Weng, Y.-H. Liao, M.-R. Tsai, M.-L. Wei, H.-Y. Huang, and C.-K. Sun, “Differentiating intratumoral melanocytes from Langerhans cells in nonmelanocytic pigmented skin tumors in vivo by label-free third-harmonic generation microscopy,” J. Biomed. Opt. 21(7), 076009 (2016).
[Crossref]

Z. Kmiec, “Book Review of Histological and Histochemical Methods: Theory and Practice,' by J. A. Keirnan,ed.,” Folia Histochem. Cytobiol. 54(1), 58–59 (2016).
[Crossref]

2015 (2)

A. P. Jathoul, J. Laufer, O. Ogunlade, B. Treeby, B. Cox, E. Zhang, P. Johnson, A. R. Pizzey, B. Philip, and T. Marafioti, “Deep in vivo photoacoustic imaging of mammalian tissues using a tyrosinase-based genetic reporter,” Nat. Photonics 9(4), 239–246 (2015).
[Crossref]

Y.-C. Chen, H.-C. Hsu, C.-M. Lee, and C.-K. Sun, “Third-harmonic generation susceptibility spectroscopy in free fatty acids,” J. Biomed. Opt. 20(9), 095013 (2015).
[Crossref]

2014 (4)

Y.-H. Liao, W.-C. Kuo, S.-Y. Chou, C.-S. Tsai, G.-L. Lin, M.-R. Tsai, Y.-T. Shih, G.-G. Lee, and C.-K. Sun, “Quantitative analysis of intrinsic skin aging in dermal papillae by in vivo harmonic generation microscopy,” Biomed. Opt. Express 5(9), 3266–3279 (2014).
[Crossref]

H. Lim, D. Sharoukhov, I. Kassim, Y. Zhang, J. L. Salzer, and C. V. Melendez-Vasquez, “Label-free imaging of Schwann cell myelination by third harmonic generation microscopy,” Proc. Natl. Acad. Sci. 111(50), 18025–18030 (2014).
[Crossref]

K.-B. Sung, K.-W. Shih, F.-W. Hsu, H.-P. Hsieh, M.-J. Chuang, Y.-H. Hsiao, Y.-H. Su, and G.-H. Tien, “Accurate extraction of optical properties and top layer thickness of two-layered mucosal tissue phantoms from spatially resolved reflectance spectra,” J. Biomed. Opt. 19(7), 077002 (2014).
[Crossref]

M.-R. Tsai, Y.-H. Cheng, J.-S. Chen, Y.-S. Sheen, Y.-H. Liao, and C.-K. Sun, “Differential diagnosis of nonmelanoma pigmented skin lesions based on harmonic generation microscopy,” J. Biomed. Opt. 19(3), 036001 (2014).
[Crossref]

2013 (6)

Y.-H. Liao, S.-Y. Chen, S.-Y. Chou, P.-H. Wang, M.-R. Tsai, and C.-K. Sun, “Determination of chronological aging parameters in epidermal keratinocytes by in vivo harmonic generation microscopy,” Biomed. Opt. Express 4(1), 77–88 (2013).
[Crossref]

M. J. Simpson, J. W. Wilson, M. A. Phipps, F. E. Robles, M. A. Selim, and W. S. Warren, “Nonlinear microscopy of eumelanin and pheomelanin with subcellular resolution,” J. Invest. Dermatol. 133(7), 1822–1826 (2013).
[Crossref]

C. Pollefliet, H. Corstjens, S. González, L. Hellemans, L. Declercq, and D. Yarosh, “Morphological characterization of solar lentigines by in vivo reflectance confocal microscopy: a longitudinal approach,” Int. J. Cosmet. Sci. 35(2), 149–155 (2013).
[Crossref]

G. G. Lee, H.-H. Lin, M.-R. Tsai, S.-Y. Chou, W.-J. Lee, Y.-H. Liao, C.-K. Sun, and C.-F. Chen, “Automatic cell segmentation and nuclear-to-cytoplasmic ratio analysis for third harmonic generated microscopy medical images,” IEEE Trans. Biomed. Circuits Syst. 7(2), 158–168 (2013).
[Crossref]

M.-R. Tsai, C.-Y. Lin, Y.-H. Liao, H.-L. Liu, and C.-K. Sun, “Applying tattoo dye as a third-harmonic generation contrast agent for in vivo optical virtual biopsy of human skin,” J. Biomed. Opt. 18(2), 026012 (2013).
[Crossref]

E. Chodurek, M. Zdybel, and B. Pilawa, “Application of EPR spectroscopy to examination of free radicals in melanins from A-375 and G-361 human melanoma malignum cells,” J. Appl. Biomed. 11(3), 173–185 (2013).
[Crossref]

2012 (3)

T. B. Krasieva, C. Stringari, F. Liu, C.-H. Sun, Y. Kong, M. Balu, F. L. Meyskens, E. Gratton, and B. J. Tromberg, “Two-photon excited fluorescence lifetime imaging and spectroscopy of melanins in vitro and in vivo,” J. Biomed. Opt. 18(3), 031107 (2012).
[Crossref]

S. G. Lagarrigue, J. George, E. Questel, C. Lauze, N. Meyer, J. M. Lagarde, M. Simon, A. M. Schmitt, G. Serre, and C. Paul, “In vivo quantification of epidermis pigmentation and dermis papilla density with reflectance confocal microscopy: variations with age and skin phototype,” Exp. Dermatol. 21(4), 281–286 (2012).
[Crossref]

H. Ando, Y. Niki, M. Ito, K. Akiyama, M. S. Matsui, D. B. Yarosh, and M. Ichihashi, “Melanosomes are transferred from melanocytes to keratinocytes through the processes of packaging, release, uptake, and dispersion,” J. Invest. Dermatol. 132(4), 1222–1229 (2012).
[Crossref]

2011 (5)

M.-R. Tsai, S.-Y. Chen, D.-B. Shieh, P.-J. Lou, and C.-K. Sun, “In vivo optical virtual biopsy of human oral mucosa with harmonic generation microscopy,” Biomed. Opt. Express 2(8), 2317–2328 (2011).
[Crossref]

M. J. Farrar, F. W. Wise, J. R. Fetcho, and C. B. Schaffer, “In vivo imaging of myelin in the vertebrate central nervous system using third harmonic generation microscopy,” Biophys. J. 100(5), 1362–1371 (2011).
[Crossref]

D. Yudovsky and L. Pilon, “Retrieving skin properties from in vivo spectral reflectance measurements,” J. Biophotonics 4(5), 305–314 (2011).
[Crossref]

C. P. Favazza, L. V. Wang, O. W. Jassim, and L. A. Cornelius, “In vivo photoacoustic microscopy of human cutaneous microvasculature and a nevus,” J. Biomed. Opt. 16(1), 016015 (2011).
[Crossref]

V. S. Carriel, J. Aneiros-Fernandez, S. Arias-Santiago, I. J. Garzón, M. Alaminos, and A. Campos, “A novel histochemical method for a simultaneous staining of melanin and collagen fibers,” J. Histochem. Cytochem. 59(3), 270–277 (2011).
[Crossref]

2010 (1)

S.-Y. Chen, S.-U. Chen, H.-Y. Wu, W.-J. Lee, Y.-H. Liao, and C.-K. Sun, “In vivo virtual biopsy of human skin by using noninvasive higher harmonic generation microscopy,” IEEE J. Sel. Top. Quantum Electron. 16(3), 478–492 (2010).
[Crossref]

2009 (1)

S.-Y. Chen, H.-Y. Wu, and C.-K. Sun, “In vivo harmonic generation biopsy of human skin,” J. Biomed. Opt. 14(6), 060505 (2009).
[Crossref]

2008 (3)

2007 (1)

J. Y. Lin and D. E. Fisher, “Melanocyte biology and skin pigmentation,” Nature 445(7130), 843–850 (2007).
[Crossref]

2006 (3)

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.-Y. Chen, C.-S. Hsieh, S.-W. Chu, C.-Y. Lin, C.-Y. Ko, Y.-C. Chen, H.-J. Tsai, C.-H. Hu, and C.-K. Sun, “Noninvasive harmonics optical microscopy for long-term observation of embryonic nervous system development in vivo,” J. Biomed. Opt. 11(5), 054022 (2006).
[Crossref]

S.-P. Tai, W.-J. Lee, D.-B. Shieh, P.-C. Wu, H.-Y. Huang, C.-H. Yu, and C.-K. Sun, “In vivo optical biopsy of hamster oral cavity with epi-third-harmonic-generation microscopy,” Opt. Express 14(13), 6178–6187 (2006).
[Crossref]

2004 (3)

C.-K. Sun, S.-W. Chu, S.-Y. Chen, T.-H. Tsai, T.-M. Liu, C.-Y. Lin, and H.-J. Tsai, “Higher harmonic generation microscopy for developmental biology,” J. Struct. Biol. 147(1), 19–30 (2004).
[Crossref]

J. A. Viator, J. Komadina, L. O. Svaasand, G. Aguilar, B. Choi, and J. S. Nelson, “A comparative study of photoacoustic and reflectance methods for determination of epidermal melanin content,” J. Invest. Dermatol. 122(6), 1432–1439 (2004).
[Crossref]

Z. Huang, H. Lui, M. X. Chen, A. Alajlan, D. I. McLean, and H. Zeng, “Raman spectroscopy of in vivo cutaneous melanin,” J. Biomed. Opt. 9(6), 1198–1206 (2004).
[Crossref]

2003 (1)

R. E. Boissy, “Melanosome transfer to and translocation in the keratinocyte,” Exp. Dermatol. 12(s2), 5–12 (2003).
[Crossref]

2002 (2)

J. X. Cheng and X. S. Xie, “Green's function formulation for third-harmonic generation microscopy,” J. Opt. Soc. Am. B 19(7), 1604–1610 (2002).
[Crossref]

I.-H. Chen, S.-W. Chu, C.-K. Sun, P. C. Cheng, and B.-L. Lin, “Wavelength dependent damage in biological multi-photon confocal microscopy: A micro-spectroscopic comparison between femtosecond Ti:sapphire and Cr:forsterite laser sources,” Opt. Quantum Electron. 34(12), 1251–1266 (2002).
[Crossref]

2001 (1)

G. Zonios, J. Bykowski, and N. Kollias, “Skin melanin, hemoglobin, and light scattering properties can be quantitatively assessed in vivo using diffuse reflectance spectroscopy,” J. Invest. Dermatol. 117(6), 1452–1457 (2001).
[Crossref]

1999 (1)

1997 (1)

W. K. Andersen, R. R. Labadie, and J. Bhawan, “Histopathology of solar lentigines of the face: a quantitative study,” J. Am. Acad. Dermatol. 36(3), 444–447 (1997).
[Crossref]

1996 (1)

H. Ozeki, S. Ito, K. Wakamatsu, and A. J. Thody, “Spectrophotometric characterization of eumelanin and pheomelanin in hair,” Pigm. Cell Res. 9(5), 265–270 (1996).
[Crossref]

1995 (1)

M. Rajadhyaksha, M. Grossman, D. Esterowitz, R. H. Webb, and R. R. Anderson, “In vivo confocal scanning laser microscopy of human skin: melanin provides strong contrast,” J. Invest. Dermatol. 104(6), 946–952 (1995).
[Crossref]

1993 (1)

B. S. Larsson, “Interaction between chemicals and melanin,” Pigm. Cell Res. 6(3), 127–133 (1993).
[Crossref]

1986 (1)

A. M. Gown, A. Vogel, D. Hoak, F. Gough, and M. McNutt, “Monoclonal antibodies specific for melanocytic tumors distinguish subpopulations of melanocytes,” The American Journal of Pathology 123(2), 195–203 (1986).

1983 (1)

S. Ito and K. Jimbow, “Quantitative analysis of eumelanin and pheomelanin in hair and melanomas,” J. Invest. Dermatol. 80(4), 268–272 (1983).
[Crossref]

1978 (1)

C. Felix, J. Hyde, T. Sarna, and R. Sealy, “Interactions of melanin with metal ions. Electron spin resonance evidence for chelate complexes of metal ions with free radicals,” J. Am. Chem. Soc. 100(12), 3922–3926 (1978).
[Crossref]

1975 (1)

A. H. Mehregan, “Lentigo senilis and its evolutions,” J. Invest. Dermatol. 65(5), 429–433 (1975).
[Crossref]

Abdeladim, L.

C. Stringari, L. Abdeladim, G. Malkinson, P. Mahou, X. Solinas, I. Lamarre, S. Brizion, J.-B. Galey, W. Supatto, R. Legouis, A.-M. Pena, and E. Beaurepaire, “Multicolor two-photon imaging of endogenous fluorophores in living tissues by wavelength mixing,” Sci. Rep. 7(1), 3792 (2017).
[Crossref]

Aguilar, G.

J. A. Viator, J. Komadina, L. O. Svaasand, G. Aguilar, B. Choi, and J. S. Nelson, “A comparative study of photoacoustic and reflectance methods for determination of epidermal melanin content,” J. Invest. Dermatol. 122(6), 1432–1439 (2004).
[Crossref]

Akiyama, K.

H. Ando, Y. Niki, M. Ito, K. Akiyama, M. S. Matsui, D. B. Yarosh, and M. Ichihashi, “Melanosomes are transferred from melanocytes to keratinocytes through the processes of packaging, release, uptake, and dispersion,” J. Invest. Dermatol. 132(4), 1222–1229 (2012).
[Crossref]

Alajlan, A.

Z. Huang, H. Lui, M. X. Chen, A. Alajlan, D. I. McLean, and H. Zeng, “Raman spectroscopy of in vivo cutaneous melanin,” J. Biomed. Opt. 9(6), 1198–1206 (2004).
[Crossref]

Alaminos, M.

V. S. Carriel, J. Aneiros-Fernandez, S. Arias-Santiago, I. J. Garzón, M. Alaminos, and A. Campos, “A novel histochemical method for a simultaneous staining of melanin and collagen fibers,” J. Histochem. Cytochem. 59(3), 270–277 (2011).
[Crossref]

Andersen, W. K.

W. K. Andersen, R. R. Labadie, and J. Bhawan, “Histopathology of solar lentigines of the face: a quantitative study,” J. Am. Acad. Dermatol. 36(3), 444–447 (1997).
[Crossref]

Anderson, R. R.

M. Rajadhyaksha, M. Grossman, D. Esterowitz, R. H. Webb, and R. R. Anderson, “In vivo confocal scanning laser microscopy of human skin: melanin provides strong contrast,” J. Invest. Dermatol. 104(6), 946–952 (1995).
[Crossref]

Ando, H.

H. Ando, Y. Niki, M. Ito, K. Akiyama, M. S. Matsui, D. B. Yarosh, and M. Ichihashi, “Melanosomes are transferred from melanocytes to keratinocytes through the processes of packaging, release, uptake, and dispersion,” J. Invest. Dermatol. 132(4), 1222–1229 (2012).
[Crossref]

Aneiros-Fernandez, J.

V. S. Carriel, J. Aneiros-Fernandez, S. Arias-Santiago, I. J. Garzón, M. Alaminos, and A. Campos, “A novel histochemical method for a simultaneous staining of melanin and collagen fibers,” J. Histochem. Cytochem. 59(3), 270–277 (2011).
[Crossref]

Arias-Santiago, S.

V. S. Carriel, J. Aneiros-Fernandez, S. Arias-Santiago, I. J. Garzón, M. Alaminos, and A. Campos, “A novel histochemical method for a simultaneous staining of melanin and collagen fibers,” J. Histochem. Cytochem. 59(3), 270–277 (2011).
[Crossref]

Baldeweck, T.

T. Baldeweck, E. Decencière, S. Brizion, S. Koudoro, E. Tancrède, and A.-M. Pena, “3D quantification of melanin in human skin in vivo based on multiphoton microscopy and image processing,” Focus on Microscopy, Maastricht, Netherlands (2013).

Balu, M.

T. B. Krasieva, C. Stringari, F. Liu, C.-H. Sun, Y. Kong, M. Balu, F. L. Meyskens, E. Gratton, and B. J. Tromberg, “Two-photon excited fluorescence lifetime imaging and spectroscopy of melanins in vitro and in vivo,” J. Biomed. Opt. 18(3), 031107 (2012).
[Crossref]

Beaurepaire, E.

C. Stringari, L. Abdeladim, G. Malkinson, P. Mahou, X. Solinas, I. Lamarre, S. Brizion, J.-B. Galey, W. Supatto, R. Legouis, A.-M. Pena, and E. Beaurepaire, “Multicolor two-photon imaging of endogenous fluorophores in living tissues by wavelength mixing,” Sci. Rep. 7(1), 3792 (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]

Bhawan, J.

W. K. Andersen, R. R. Labadie, and J. Bhawan, “Histopathology of solar lentigines of the face: a quantitative study,” J. Am. Acad. Dermatol. 36(3), 444–447 (1997).
[Crossref]

Boissy, R. E.

R. E. Boissy, “Melanosome transfer to and translocation in the keratinocyte,” Exp. Dermatol. 12(s2), 5–12 (2003).
[Crossref]

Bosko, C.

J. Nip, S. Potterf, S. Rocha, S. Vora, and C. Bosko, “The new face of pigmentation and aging,” F. A. Miranda, M. W. Kenneth, and M. I. Howard, eds., Textbook of Aging Skin, 1st edition (Springer, 2010), pp. 509–512.

Brenner, M.

M. Brenner and V. J. Hearing, “The protective role of melanin against UV damage in human skin,” Photochem. Photobiol. 84(3), 539–549 (2008).
[Crossref]

Brizion, S.

C. Stringari, L. Abdeladim, G. Malkinson, P. Mahou, X. Solinas, I. Lamarre, S. Brizion, J.-B. Galey, W. Supatto, R. Legouis, A.-M. Pena, and E. Beaurepaire, “Multicolor two-photon imaging of endogenous fluorophores in living tissues by wavelength mixing,” Sci. Rep. 7(1), 3792 (2017).
[Crossref]

T. Baldeweck, E. Decencière, S. Brizion, S. Koudoro, E. Tancrède, and A.-M. Pena, “3D quantification of melanin in human skin in vivo based on multiphoton microscopy and image processing,” Focus on Microscopy, Maastricht, Netherlands (2013).

Bykowski, J.

G. Zonios, J. Bykowski, and N. Kollias, “Skin melanin, hemoglobin, and light scattering properties can be quantitatively assessed in vivo using diffuse reflectance spectroscopy,” J. Invest. Dermatol. 117(6), 1452–1457 (2001).
[Crossref]

Campos, A.

V. S. Carriel, J. Aneiros-Fernandez, S. Arias-Santiago, I. J. Garzón, M. Alaminos, and A. Campos, “A novel histochemical method for a simultaneous staining of melanin and collagen fibers,” J. Histochem. Cytochem. 59(3), 270–277 (2011).
[Crossref]

Carriel, V. S.

V. S. Carriel, J. Aneiros-Fernandez, S. Arias-Santiago, I. J. Garzón, M. Alaminos, and A. Campos, “A novel histochemical method for a simultaneous staining of melanin and collagen fibers,” J. Histochem. Cytochem. 59(3), 270–277 (2011).
[Crossref]

Chakraborty, S.

Chan, Y.-F.

Chen, C.-F.

G. G. Lee, H.-H. Lin, M.-R. Tsai, S.-Y. Chou, W.-J. Lee, Y.-H. Liao, C.-K. Sun, and C.-F. Chen, “Automatic cell segmentation and nuclear-to-cytoplasmic ratio analysis for third harmonic generated microscopy medical images,” IEEE Trans. Biomed. Circuits Syst. 7(2), 158–168 (2013).
[Crossref]

Chen, I.-H.

I.-H. Chen, S.-W. Chu, C.-K. Sun, P. C. Cheng, and B.-L. Lin, “Wavelength dependent damage in biological multi-photon confocal microscopy: A micro-spectroscopic comparison between femtosecond Ti:sapphire and Cr:forsterite laser sources,” Opt. Quantum Electron. 34(12), 1251–1266 (2002).
[Crossref]

Chen, J.-S.

M.-R. Tsai, Y.-H. Cheng, J.-S. Chen, Y.-S. Sheen, Y.-H. Liao, and C.-K. Sun, “Differential diagnosis of nonmelanoma pigmented skin lesions based on harmonic generation microscopy,” J. Biomed. Opt. 19(3), 036001 (2014).
[Crossref]

Chen, M. X.

Z. Huang, H. Lui, M. X. Chen, A. Alajlan, D. I. McLean, and H. Zeng, “Raman spectroscopy of in vivo cutaneous melanin,” J. Biomed. Opt. 9(6), 1198–1206 (2004).
[Crossref]

Chen, S.-T.

Chen, S.-U.

S.-Y. Chen, S.-U. Chen, H.-Y. Wu, W.-J. Lee, Y.-H. Liao, and C.-K. Sun, “In vivo virtual biopsy of human skin by using noninvasive higher harmonic generation microscopy,” IEEE J. Sel. Top. Quantum Electron. 16(3), 478–492 (2010).
[Crossref]

C.-S. Hsieh, S.-U. Chen, Y.-W. Lee, Y.-S. Yang, and C.-K. Sun, “Higher harmonic generation microscopy of in vitro cultured mammal oocytes and embryos,” Opt. Express 16(15), 11574–11588 (2008).

Chen, S.-Y.

Y.-H. Liao, S.-Y. Chen, S.-Y. Chou, P.-H. Wang, M.-R. Tsai, and C.-K. Sun, “Determination of chronological aging parameters in epidermal keratinocytes by in vivo harmonic generation microscopy,” Biomed. Opt. Express 4(1), 77–88 (2013).
[Crossref]

M.-R. Tsai, S.-Y. Chen, D.-B. Shieh, P.-J. Lou, and C.-K. Sun, “In vivo optical virtual biopsy of human oral mucosa with harmonic generation microscopy,” Biomed. Opt. Express 2(8), 2317–2328 (2011).
[Crossref]

S.-Y. Chen, S.-U. Chen, H.-Y. Wu, W.-J. Lee, Y.-H. Liao, and C.-K. Sun, “In vivo virtual biopsy of human skin by using noninvasive higher harmonic generation microscopy,” IEEE J. Sel. Top. Quantum Electron. 16(3), 478–492 (2010).
[Crossref]

S.-Y. Chen, H.-Y. Wu, and C.-K. Sun, “In vivo harmonic generation biopsy of human skin,” J. Biomed. Opt. 14(6), 060505 (2009).
[Crossref]

S.-Y. Chen, C.-S. Hsieh, S.-W. Chu, C.-Y. Lin, C.-Y. Ko, Y.-C. Chen, H.-J. Tsai, C.-H. Hu, and C.-K. Sun, “Noninvasive harmonics optical microscopy for long-term observation of embryonic nervous system development in vivo,” J. Biomed. Opt. 11(5), 054022 (2006).
[Crossref]

C.-K. Sun, S.-W. Chu, S.-Y. Chen, T.-H. Tsai, T.-M. Liu, C.-Y. Lin, and H.-J. Tsai, “Higher harmonic generation microscopy for developmental biology,” J. Struct. Biol. 147(1), 19–30 (2004).
[Crossref]

Chen, W.-S.

Y.-H. Liao, Y.-H. Su, Y.-T. Shih, W.-S. Chen, S.-H. Jee, and C.-K. Sun, “In vivo third-harmonic generation microscopy study on vitiligo patients,” J. Biomed. Opt. 25(1), 014504 (2019).
[Crossref]

Chen, Y.-C.

Y.-C. Chen, H.-C. Hsu, C.-M. Lee, and C.-K. Sun, “Third-harmonic generation susceptibility spectroscopy in free fatty acids,” J. Biomed. Opt. 20(9), 095013 (2015).
[Crossref]

S.-Y. Chen, C.-S. Hsieh, S.-W. Chu, C.-Y. Lin, C.-Y. Ko, Y.-C. Chen, H.-J. Tsai, C.-H. Hu, and C.-K. Sun, “Noninvasive harmonics optical microscopy for long-term observation of embryonic nervous system development in vivo,” J. Biomed. Opt. 11(5), 054022 (2006).
[Crossref]

Cheng, J. X.

Cheng, P. C.

I.-H. Chen, S.-W. Chu, C.-K. Sun, P. C. Cheng, and B.-L. Lin, “Wavelength dependent damage in biological multi-photon confocal microscopy: A micro-spectroscopic comparison between femtosecond Ti:sapphire and Cr:forsterite laser sources,” Opt. Quantum Electron. 34(12), 1251–1266 (2002).
[Crossref]

Cheng, Y.-H.

M.-R. Tsai, Y.-H. Cheng, J.-S. Chen, Y.-S. Sheen, Y.-H. Liao, and C.-K. Sun, “Differential diagnosis of nonmelanoma pigmented skin lesions based on harmonic generation microscopy,” J. Biomed. Opt. 19(3), 036001 (2014).
[Crossref]

Chiang, B.-L.

J.-H. Lee, Y.-T. Shih, M.-L. Wei, C.-K. Sun, and B.-L. Chiang, “Classification of Established atopic dermatitis in children with the in vivo imaging methods,” J. Biophotonics 12(5), e201800148 (2019).
[Crossref]

Chiu, M.-J.

Chodurek, E.

E. Chodurek, M. Zdybel, and B. Pilawa, “Application of EPR spectroscopy to examination of free radicals in melanins from A-375 and G-361 human melanoma malignum cells,” J. Appl. Biomed. 11(3), 173–185 (2013).
[Crossref]

Choi, B.

J. A. Viator, J. Komadina, L. O. Svaasand, G. Aguilar, B. Choi, and J. S. Nelson, “A comparative study of photoacoustic and reflectance methods for determination of epidermal melanin content,” J. Invest. Dermatol. 122(6), 1432–1439 (2004).
[Crossref]

Chou, S.-Y.

Chu, S.-W.

S.-Y. Chen, C.-S. Hsieh, S.-W. Chu, C.-Y. Lin, C.-Y. Ko, Y.-C. Chen, H.-J. Tsai, C.-H. Hu, and C.-K. Sun, “Noninvasive harmonics optical microscopy for long-term observation of embryonic nervous system development in vivo,” J. Biomed. Opt. 11(5), 054022 (2006).
[Crossref]

C.-K. Sun, S.-W. Chu, S.-Y. Chen, T.-H. Tsai, T.-M. Liu, C.-Y. Lin, and H.-J. Tsai, “Higher harmonic generation microscopy for developmental biology,” J. Struct. Biol. 147(1), 19–30 (2004).
[Crossref]

I.-H. Chen, S.-W. Chu, C.-K. Sun, P. C. Cheng, and B.-L. Lin, “Wavelength dependent damage in biological multi-photon confocal microscopy: A micro-spectroscopic comparison between femtosecond Ti:sapphire and Cr:forsterite laser sources,” Opt. Quantum Electron. 34(12), 1251–1266 (2002).
[Crossref]

Chuang, M.-J.

K.-B. Sung, K.-W. Shih, F.-W. Hsu, H.-P. Hsieh, M.-J. Chuang, Y.-H. Hsiao, Y.-H. Su, and G.-H. Tien, “Accurate extraction of optical properties and top layer thickness of two-layered mucosal tissue phantoms from spatially resolved reflectance spectra,” J. Biomed. Opt. 19(7), 077002 (2014).
[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]

Cornelius, L. A.

C. P. Favazza, L. V. Wang, O. W. Jassim, and L. A. Cornelius, “In vivo photoacoustic microscopy of human cutaneous microvasculature and a nevus,” J. Biomed. Opt. 16(1), 016015 (2011).
[Crossref]

Corstjens, H.

C. Pollefliet, H. Corstjens, S. González, L. Hellemans, L. Declercq, and D. Yarosh, “Morphological characterization of solar lentigines by in vivo reflectance confocal microscopy: a longitudinal approach,” Int. J. Cosmet. Sci. 35(2), 149–155 (2013).
[Crossref]

Cox, B.

A. P. Jathoul, J. Laufer, O. Ogunlade, B. Treeby, B. Cox, E. Zhang, P. Johnson, A. R. Pizzey, B. Philip, and T. Marafioti, “Deep in vivo photoacoustic imaging of mammalian tissues using a tyrosinase-based genetic reporter,” Nat. Photonics 9(4), 239–246 (2015).
[Crossref]

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).
[Crossref]

Decencière, E.

T. Baldeweck, E. Decencière, S. Brizion, S. Koudoro, E. Tancrède, and A.-M. Pena, “3D quantification of melanin in human skin in vivo based on multiphoton microscopy and image processing,” Focus on Microscopy, Maastricht, Netherlands (2013).

Declercq, L.

C. Pollefliet, H. Corstjens, S. González, L. Hellemans, L. Declercq, and D. Yarosh, “Morphological characterization of solar lentigines by in vivo reflectance confocal microscopy: a longitudinal approach,” Int. J. Cosmet. Sci. 35(2), 149–155 (2013).
[Crossref]

Esterowitz, D.

M. Rajadhyaksha, M. Grossman, D. Esterowitz, R. H. Webb, and R. R. Anderson, “In vivo confocal scanning laser microscopy of human skin: melanin provides strong contrast,” J. Invest. Dermatol. 104(6), 946–952 (1995).
[Crossref]

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).
[Crossref]

Farrar, M. J.

M. J. Farrar, F. W. Wise, J. R. Fetcho, and C. B. Schaffer, “In vivo imaging of myelin in the vertebrate central nervous system using third harmonic generation microscopy,” Biophys. J. 100(5), 1362–1371 (2011).
[Crossref]

Favazza, C. P.

C. P. Favazza, L. V. Wang, O. W. Jassim, and L. A. Cornelius, “In vivo photoacoustic microscopy of human cutaneous microvasculature and a nevus,” J. Biomed. Opt. 16(1), 016015 (2011).
[Crossref]

Felix, C.

C. Felix, J. Hyde, T. Sarna, and R. Sealy, “Interactions of melanin with metal ions. Electron spin resonance evidence for chelate complexes of metal ions with free radicals,” J. Am. Chem. Soc. 100(12), 3922–3926 (1978).
[Crossref]

Fetcho, J. R.

M. J. Farrar, F. W. Wise, J. R. Fetcho, and C. B. Schaffer, “In vivo imaging of myelin in the vertebrate central nervous system using third harmonic generation microscopy,” Biophys. J. 100(5), 1362–1371 (2011).
[Crossref]

Fisher, D. E.

J. Y. Lin and D. E. Fisher, “Melanocyte biology and skin pigmentation,” Nature 445(7130), 843–850 (2007).
[Crossref]

Fitzpatrick, T. B.

M. A. Pathak, K. Jimbow, G. Szabo, and T. B. Fitzpatrick, “Sunlight and melanin pigmentation,” in Photochemical and Photobiological Reviews (Springer, 1976), pp. 211–239.

Galey, J.-B.

C. Stringari, L. Abdeladim, G. Malkinson, P. Mahou, X. Solinas, I. Lamarre, S. Brizion, J.-B. Galey, W. Supatto, R. Legouis, A.-M. Pena, and E. Beaurepaire, “Multicolor two-photon imaging of endogenous fluorophores in living tissues by wavelength mixing,” Sci. Rep. 7(1), 3792 (2017).
[Crossref]

Garzón, I. J.

V. S. Carriel, J. Aneiros-Fernandez, S. Arias-Santiago, I. J. Garzón, M. Alaminos, and A. Campos, “A novel histochemical method for a simultaneous staining of melanin and collagen fibers,” J. Histochem. Cytochem. 59(3), 270–277 (2011).
[Crossref]

George, J.

S. G. Lagarrigue, J. George, E. Questel, C. Lauze, N. Meyer, J. M. Lagarde, M. Simon, A. M. Schmitt, G. Serre, and C. Paul, “In vivo quantification of epidermis pigmentation and dermis papilla density with reflectance confocal microscopy: variations with age and skin phototype,” Exp. Dermatol. 21(4), 281–286 (2012).
[Crossref]

González, S.

C. Pollefliet, H. Corstjens, S. González, L. Hellemans, L. Declercq, and D. Yarosh, “Morphological characterization of solar lentigines by in vivo reflectance confocal microscopy: a longitudinal approach,” Int. J. Cosmet. Sci. 35(2), 149–155 (2013).
[Crossref]

Gough, F.

A. M. Gown, A. Vogel, D. Hoak, F. Gough, and M. McNutt, “Monoclonal antibodies specific for melanocytic tumors distinguish subpopulations of melanocytes,” The American Journal of Pathology 123(2), 195–203 (1986).

Gown, A. M.

A. M. Gown, A. Vogel, D. Hoak, F. Gough, and M. McNutt, “Monoclonal antibodies specific for melanocytic tumors distinguish subpopulations of melanocytes,” The American Journal of Pathology 123(2), 195–203 (1986).

Gratton, E.

T. B. Krasieva, C. Stringari, F. Liu, C.-H. Sun, Y. Kong, M. Balu, F. L. Meyskens, E. Gratton, and B. J. Tromberg, “Two-photon excited fluorescence lifetime imaging and spectroscopy of melanins in vitro and in vivo,” J. Biomed. Opt. 18(3), 031107 (2012).
[Crossref]

Grossman, M.

M. Rajadhyaksha, M. Grossman, D. Esterowitz, R. H. Webb, and R. R. Anderson, “In vivo confocal scanning laser microscopy of human skin: melanin provides strong contrast,” J. Invest. Dermatol. 104(6), 946–952 (1995).
[Crossref]

Hearing, V. J.

M. Brenner and V. J. Hearing, “The protective role of melanin against UV damage in human skin,” Photochem. Photobiol. 84(3), 539–549 (2008).
[Crossref]

Hellemans, L.

C. Pollefliet, H. Corstjens, S. González, L. Hellemans, L. Declercq, and D. Yarosh, “Morphological characterization of solar lentigines by in vivo reflectance confocal microscopy: a longitudinal approach,” Int. J. Cosmet. Sci. 35(2), 149–155 (2013).
[Crossref]

Hoak, D.

A. M. Gown, A. Vogel, D. Hoak, F. Gough, and M. McNutt, “Monoclonal antibodies specific for melanocytic tumors distinguish subpopulations of melanocytes,” The American Journal of Pathology 123(2), 195–203 (1986).

Hsiao, Y.-H.

K.-B. Sung, K.-W. Shih, F.-W. Hsu, H.-P. Hsieh, M.-J. Chuang, Y.-H. Hsiao, Y.-H. Su, and G.-H. Tien, “Accurate extraction of optical properties and top layer thickness of two-layered mucosal tissue phantoms from spatially resolved reflectance spectra,” J. Biomed. Opt. 19(7), 077002 (2014).
[Crossref]

Hsiao, Y.-T.

Hsieh, C.-S.

C.-S. Hsieh, S.-U. Chen, Y.-W. Lee, Y.-S. Yang, and C.-K. Sun, “Higher harmonic generation microscopy of in vitro cultured mammal oocytes and embryos,” Opt. Express 16(15), 11574–11588 (2008).

S.-Y. Chen, C.-S. Hsieh, S.-W. Chu, C.-Y. Lin, C.-Y. Ko, Y.-C. Chen, H.-J. Tsai, C.-H. Hu, and C.-K. Sun, “Noninvasive harmonics optical microscopy for long-term observation of embryonic nervous system development in vivo,” J. Biomed. Opt. 11(5), 054022 (2006).
[Crossref]

Hsieh, H.-P.

K.-B. Sung, K.-W. Shih, F.-W. Hsu, H.-P. Hsieh, M.-J. Chuang, Y.-H. Hsiao, Y.-H. Su, and G.-H. Tien, “Accurate extraction of optical properties and top layer thickness of two-layered mucosal tissue phantoms from spatially resolved reflectance spectra,” J. Biomed. Opt. 19(7), 077002 (2014).
[Crossref]

Hsu, F.-W.

K.-B. Sung, K.-W. Shih, F.-W. Hsu, H.-P. Hsieh, M.-J. Chuang, Y.-H. Hsiao, Y.-H. Su, and G.-H. Tien, “Accurate extraction of optical properties and top layer thickness of two-layered mucosal tissue phantoms from spatially resolved reflectance spectra,” J. Biomed. Opt. 19(7), 077002 (2014).
[Crossref]

Hsu, H.-C.

Y.-C. Chen, H.-C. Hsu, C.-M. Lee, and C.-K. Sun, “Third-harmonic generation susceptibility spectroscopy in free fatty acids,” J. Biomed. Opt. 20(9), 095013 (2015).
[Crossref]

Hu, C.-H.

S.-Y. Chen, C.-S. Hsieh, S.-W. Chu, C.-Y. Lin, C.-Y. Ko, Y.-C. Chen, H.-J. Tsai, C.-H. Hu, and C.-K. Sun, “Noninvasive harmonics optical microscopy for long-term observation of embryonic nervous system development in vivo,” J. Biomed. Opt. 11(5), 054022 (2006).
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S. G. Lagarrigue, J. George, E. Questel, C. Lauze, N. Meyer, J. M. Lagarde, M. Simon, A. M. Schmitt, G. Serre, and C. Paul, “In vivo quantification of epidermis pigmentation and dermis papilla density with reflectance confocal microscopy: variations with age and skin phototype,” Exp. Dermatol. 21(4), 281–286 (2012).
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H. Lim, D. Sharoukhov, I. Kassim, Y. Zhang, J. L. Salzer, and C. V. Melendez-Vasquez, “Label-free imaging of Schwann cell myelination by third harmonic generation microscopy,” Proc. Natl. Acad. Sci. 111(50), 18025–18030 (2014).
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S. G. Lagarrigue, J. George, E. Questel, C. Lauze, N. Meyer, J. M. Lagarde, M. Simon, A. M. Schmitt, G. Serre, and C. Paul, “In vivo quantification of epidermis pigmentation and dermis papilla density with reflectance confocal microscopy: variations with age and skin phototype,” Exp. Dermatol. 21(4), 281–286 (2012).
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M. J. Simpson, J. W. Wilson, M. A. Phipps, F. E. Robles, M. A. Selim, and W. S. Warren, “Nonlinear microscopy of eumelanin and pheomelanin with subcellular resolution,” J. Invest. Dermatol. 133(7), 1822–1826 (2013).
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M.-R. Tsai, Y.-H. Cheng, J.-S. Chen, Y.-S. Sheen, Y.-H. Liao, and C.-K. Sun, “Differential diagnosis of nonmelanoma pigmented skin lesions based on harmonic generation microscopy,” J. Biomed. Opt. 19(3), 036001 (2014).
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Shih, K.-W.

K.-B. Sung, K.-W. Shih, F.-W. Hsu, H.-P. Hsieh, M.-J. Chuang, Y.-H. Hsiao, Y.-H. Su, and G.-H. Tien, “Accurate extraction of optical properties and top layer thickness of two-layered mucosal tissue phantoms from spatially resolved reflectance spectra,” J. Biomed. Opt. 19(7), 077002 (2014).
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Y.-H. Liao, Y.-H. Su, Y.-T. Shih, W.-S. Chen, S.-H. Jee, and C.-K. Sun, “In vivo third-harmonic generation microscopy study on vitiligo patients,” J. Biomed. Opt. 25(1), 014504 (2019).
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Y.-H. Liao, W.-C. Kuo, S.-Y. Chou, C.-S. Tsai, G.-L. Lin, M.-R. Tsai, Y.-T. Shih, G.-G. Lee, and C.-K. Sun, “Quantitative analysis of intrinsic skin aging in dermal papillae by in vivo harmonic generation microscopy,” Biomed. Opt. Express 5(9), 3266–3279 (2014).
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Simon, M.

S. G. Lagarrigue, J. George, E. Questel, C. Lauze, N. Meyer, J. M. Lagarde, M. Simon, A. M. Schmitt, G. Serre, and C. Paul, “In vivo quantification of epidermis pigmentation and dermis papilla density with reflectance confocal microscopy: variations with age and skin phototype,” Exp. Dermatol. 21(4), 281–286 (2012).
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M. J. Simpson, J. W. Wilson, M. A. Phipps, F. E. Robles, M. A. Selim, and W. S. Warren, “Nonlinear microscopy of eumelanin and pheomelanin with subcellular resolution,” J. Invest. Dermatol. 133(7), 1822–1826 (2013).
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Y.-H. Liao, Y.-H. Su, Y.-T. Shih, W.-S. Chen, S.-H. Jee, and C.-K. Sun, “In vivo third-harmonic generation microscopy study on vitiligo patients,” J. Biomed. Opt. 25(1), 014504 (2019).
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K.-B. Sung, K.-W. Shih, F.-W. Hsu, H.-P. Hsieh, M.-J. Chuang, Y.-H. Hsiao, Y.-H. Su, and G.-H. Tien, “Accurate extraction of optical properties and top layer thickness of two-layered mucosal tissue phantoms from spatially resolved reflectance spectra,” J. Biomed. Opt. 19(7), 077002 (2014).
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K.-H. Lin, Y.-H. Liao, M.-L. Wei, and C.-K. Sun, “Comparative analysis of intrinsic skin aging between Caucasian and Asian subjects by slide-free in vivo harmonic generation microscopy,” J. Biophotonics 13(4), e201960063 (2020).
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S. Chakraborty, S.-T. Chen, Y.-T. Hsiao, M.-J. Chiu, and C.-K. Sun, “Additive-color multi-harmonic generation microscopy for simultaneous label-free differentiation of plaques, tangles, and neuronal axons,” Biomed. Opt. Express 11(2), 571–585 (2020).
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[Crossref]

W.-H. Weng, Y.-H. Liao, M.-R. Tsai, M.-L. Wei, H.-Y. Huang, and C.-K. Sun, “Differentiating intratumoral melanocytes from Langerhans cells in nonmelanocytic pigmented skin tumors in vivo by label-free third-harmonic generation microscopy,” J. Biomed. Opt. 21(7), 076009 (2016).
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Y.-H. Liao, S.-Y. Chen, S.-Y. Chou, P.-H. Wang, M.-R. Tsai, and C.-K. Sun, “Determination of chronological aging parameters in epidermal keratinocytes by in vivo harmonic generation microscopy,” Biomed. Opt. Express 4(1), 77–88 (2013).
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Tsai, H.-J.

S.-Y. Chen, C.-S. Hsieh, S.-W. Chu, C.-Y. Lin, C.-Y. Ko, Y.-C. Chen, H.-J. Tsai, C.-H. Hu, and C.-K. Sun, “Noninvasive harmonics optical microscopy for long-term observation of embryonic nervous system development in vivo,” J. Biomed. Opt. 11(5), 054022 (2006).
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C.-K. Sun, S.-W. Chu, S.-Y. Chen, T.-H. Tsai, T.-M. Liu, C.-Y. Lin, and H.-J. Tsai, “Higher harmonic generation microscopy for developmental biology,” J. Struct. Biol. 147(1), 19–30 (2004).
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W.-H. Weng, Y.-H. Liao, M.-R. Tsai, M.-L. Wei, H.-Y. Huang, and C.-K. Sun, “Differentiating intratumoral melanocytes from Langerhans cells in nonmelanocytic pigmented skin tumors in vivo by label-free third-harmonic generation microscopy,” J. Biomed. Opt. 21(7), 076009 (2016).
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Y.-H. Liao, W.-C. Kuo, S.-Y. Chou, C.-S. Tsai, G.-L. Lin, M.-R. Tsai, Y.-T. Shih, G.-G. Lee, and C.-K. Sun, “Quantitative analysis of intrinsic skin aging in dermal papillae by in vivo harmonic generation microscopy,” Biomed. Opt. Express 5(9), 3266–3279 (2014).
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Y.-H. Liao, S.-Y. Chen, S.-Y. Chou, P.-H. Wang, M.-R. Tsai, and C.-K. Sun, “Determination of chronological aging parameters in epidermal keratinocytes by in vivo harmonic generation microscopy,” Biomed. Opt. Express 4(1), 77–88 (2013).
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M.-R. Tsai, S.-Y. Chen, D.-B. Shieh, P.-J. Lou, and C.-K. Sun, “In vivo optical virtual biopsy of human oral mucosa with harmonic generation microscopy,” Biomed. Opt. Express 2(8), 2317–2328 (2011).
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H. Ozeki, S. Ito, K. Wakamatsu, and A. J. Thody, “Spectrophotometric characterization of eumelanin and pheomelanin in hair,” Pigm. Cell Res. 9(5), 265–270 (1996).
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Figures (7)

Fig. 1.
Fig. 1. Energy level diagram and histology verification. (a) The quantum mechanical energy diagram showing the three-photon and two-photon resonance enhanced THG with the melanin absorption levels at the corresponding photon energy. With an excitation light located out of the absorption band of melanin, the single photon level is a virtual level. For THG, ν3=3ν1. (b). and (c). Ex vivo epi-HGM images of a human face skin sample. Images were optically sectioned in the transverse direction. (d). and (e). Corresponding histology sections with Fontana-Masson staining for melanin. Epi-SHG and epi-THG are represented by green and magenta pseudo-colors. Scale bar: 50 µm.
Fig. 2.
Fig. 2. Processing the third-harmonic generation microscopy images acquired in human skin. (a). The flow chart demonstrates the process of the quantification of melanin mass density in basal cell cytoplasm at the dermal epidermal junction in human skin. (b). The THG and SHG image acquired at the dermal-epidermal junction. (Green: SHG; Magenta: THG) (c). Collagen fiber segmentation based on the SHG contrast. Segmented collagen fiber after manual modification is masked white. (d). Cytoplasm segmentation based on the THG contrast. The segmented cell nuclei were masked solid white while the outlines of the cells were also marked. (e) erTHG image of the segmented cell cytoplasm as calculated following Eq. (3). (f). MMD image of cytoplasmic segmentation, calculated from the erTHG image following Eqs. (1) and (2). (g) Example THG image acquired at the dermal-epidermal junction showing unclear outlines of basal cells. This type of THG images were not processed. erTHG and MMD images are color coded based on their values.
Fig. 3.
Fig. 3. Examples of MMD and erTHG images. (a). The slide-free in vivo HGM images en-face optically sectioned underneath the skins of dorsal forearm, ventral forearm, ankle, dorsum of hand, and face of different volunteers. (b). The corresponding erTHG images of the segmented cell cytoplasm. (c). The corresponding MMD distribution images inside the cytoplasm of basal cells. (d). MMD distribution images shown in a different scale limited to 10 mg/ml. Imaging depths beneath the skin surface and MMD mean values are provided. Unit of MMD and AMMD images is mg/ml. Epi-SHG and epi-THG are represented by green and magenta pseudo-colors. erTHG, MMD, and A-MMD distribution images are color coded. A-MMD: amplified MMD.
Fig. 4.
Fig. 4. Obtaining the IMMD values. (a) In vivo THG/SHG image of SL lesion. (b) The corresponding MMD image of (a). Mean MMD value of all selected areas is 14.4 mg/ml. The IMMD value is 49.6%. (c) The IMMD value of one selected cell in (b) is 36.9%. (d) In vivo THG/SHG image of normal region next to the SL lesion in (a). (e) The corresponding MMD image of (d). Mean MMD value of all selected areas is 10.7 mg/ml. The IMMD value is 23.9%. (f) The IMMD value of one selected cell in (e) is 21.8%. IMMD: Inhomogeneity of melanin mass density.
Fig. 5.
Fig. 5. Assessing the laser treatment of Solar Lentigine. (a), (b), (c). The representative in vivo HGM images acquired at the facial skins of the normal region before laser treatment, the lesioned region before laser treatment, and the lesioned region after laser treatment of three patients. Slide-free images were en face optically sectioned. The corresponding MMD distribution images inside the cytoplasm of basal cells at the DEJ are also provided. In some cases, increased MMD mean value in lesion was observed after the laser treatment. It is noted that low THG intensity in deep layers might not correspond to low melanin density. Epi-SHG and epi-THG are represented by green and magenta pseudo-colors. MMD distribution image is color coded. Imaging depths beneath the skin surface, MMD mean, and IMMD values of the images are provided.
Fig. 6.
Fig. 6. Laser treatment effect on Solar Lentigine. Paired T-test (two-sided) showing difference not only in (a) MMD mean but also (b) IMMD values in basal cells between normal region and SL lesions on face. No significant change in the lesion was observed after treatment. *p=0.0316; ** p=0.0023. n=7. N: normal; SL: Solar lentigine before treatment; SLAT: Solar lentigine after treatment.
Fig. 7.
Fig. 7. In vivo erTHG microscopy images repeatedly measured in the ventral forearm skin of one healthy volunteer at the fixed depth of DEJ for a period of 1 minute. The acquired MMD distribution images inside the cytoplasm of basal cells at the DEJ are provided at the exposure time of 0.77, 1.1, 29.4 and 57.6 seconds. All images were segmented by the program and no manual selection was applied. The differences between the basal cell distribution and the MMD mean value are attributed to the minute movement of the volunteer during the measurement period. MMD distribution image is color coded. MMD mean values of the images are provided.

Equations (4)

Equations on this page are rendered with MathJax. Learn more.

= 1.19 × 10 3 × M M D 3.47 + 1.0 , ( MMD < 11.0 )
= 5.04 × 10 1 × M M D 0.95 + 1.0. ( MMD > 11.0 )
erTHG = T H G C y t o p l a s m N o i s e T H G C o l l a g e n N o i s e × 1 1.106
IMMD = Standard deviation of MMD of segmented cytoplasm Mean MMD of segmented cytoplasm × 100 % .