Abstract

Chronological skin aging is associated with flattening of the dermal-epidermal junction (DEJ), but to date no quantitative analysis focusing on the aging changes in the dermal papillae (DP) has been performed. The aim of the study is to determine the architectural changes and the collagen density related to chronological aging in the dermal papilla zone (DPZ) by in vivo harmonic generation microscopy (HGM) with a sub-femtoliter spatial resolution. We recruited 48 Asian subjects and obtained in vivo images on the sun-protected volar forearm. Six parameters were defined to quantify 3D morphological changes of the DPZ, which we analyzed both manually and computationally to study their correlation with age. The depth of DPZ, the average height of isolated DP, and the 3D interdigitation index decreased with age, while DP number density, DP volume, and the collagen density in DP remained constant over time. In vivo high-resolution HGM technology has uncovered chronological aging-related variations in DP, and sheds light on real-time quantitative skin fragility assessment and disease diagnostics based on collagen density and morphology.

© 2014 Optical Society of America

Full Article  |  PDF Article
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References

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2013 (4)

C. Longo, A. Casari, F. Beretti, A. M. Cesinaro, and G. Pellacani, “Skin aging: in vivo microscopic assessment of epidermal and dermal changes by means of confocal microscopy,” J. Am. Acad. Dermatol. 68(3), e73–e82 (2013).
[Crossref] [PubMed]

T. Yasui, M. Yonetsu, R. Tanaka, Y. Tanaka, S. Fukushima, T. Yamashita, Y. Ogura, T. Hirao, H. Murota, and T. Araki, “In vivo observation of age-related structural changes of dermal collagen in human facial skin using collagen-sensitive second harmonic generation microscope equipped with 1250-nm mode-locked Cr:Forsterite laser,” J. Biomed. Opt. 18(3), 031108 (2013).
[Crossref] [PubMed]

E. Decencière, E. Tancrède-Bohin, P. Dokládal, S. Koudoro, A. M. Pena, and T. Baldeweck, “Automatic 3D segmentation of multiphoton images: a key step for the quantification of human skin,” Skin Res. Technol. 19(2), 115–124 (2013).
[Crossref] [PubMed]

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] [PubMed]

2012 (4)

R. Archid, A. Patzelt, B. Lange-Asschenfeldt, S. S. Ahmad, M. Ulrich, E. Stockfleth, S. Philipp, W. Sterry, and J. Lademann, “Confocal laser-scanning microscopy of capillaries in normal and psoriatic skin,” J. Biomed. Opt. 17(10), 101511 (2012).
[Crossref] [PubMed]

S. Puschmann, C. D. Rahn, H. Wenck, S. Gallinat, and F. Fischer, “Approach to quantify human dermal skin aging using multiphoton laser scanning microscopy,” J. Biomed. Opt. 17(3), 036005 (2012).
[Crossref] [PubMed]

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] [PubMed]

E. M. Wurm, C. Longo, C. Curchin, H. P. Soyer, T. W. Prow, and G. Pellacani, “In vivo assessment of chronological ageing and photoageing in forearm skin using reflectance confocal microscopy,” Br. J. Dermatol. 167(2), 270–279 (2012).
[Crossref] [PubMed]

2011 (1)

M. J. Koehler, S. Zimmermann, S. Springer, P. Elsner, K. König, and M. Kaatz, “Keratinocyte morphology of human skin evaluated by in vivo multiphoton laser tomography,” Skin Res. Technol. 17(4), 479–486 (2011).
[Crossref] [PubMed]

2010 (2)

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]

A. Giangreco, S. J. Goldie, V. Failla, G. Saintigny, and F. M. Watt, “Human skin aging is associated with reduced expression of the stem cell markers beta1 integrin and MCSP,” J. Invest. Dermatol. 130(2), 604–608 (2010).
[Crossref] [PubMed]

2009 (2)

M. A. Farage, K. W. Miller, E. Berardesca, and H. I. Maibach, “Clinical implications of aging skin: cutaneous disorders in the elderly,” Am. J. Clin. Dermatol. 10(2), 73–86 (2009).
[Crossref] [PubMed]

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] [PubMed]

2008 (2)

C.-S. Hsieh, C.-Y. Ko, S.-Y. Chen, T.-M. Liu, J.-S. Wu, C.-H. Hu, and C.-K. Sun, “In vivo long-term continuous observation of gene expression in zebrafish embryo nerve systems by using harmonic generation microscopy and morphant technology,” J. Biomed. Opt. 13(6), 064041 (2008).
[Crossref] [PubMed]

M. A. Farage, K. W. Miller, P. Elsner, and H. I. Maibach, “Intrinsic and extrinsic factors in skin ageing: a review,” Int. J. Cosmet. Sci. 30(2), 87–95 (2008).
[Crossref] [PubMed]

2007 (1)

2006 (3)

D. Harman, “Free radical theory of aging: an update: increasing the functional life span,” Ann. N. Y. Acad. Sci. 1067(1), 10–21 (2006).
[Crossref] [PubMed]

J. Varani, M. K. Dame, L. Rittie, S. E. G. Fligiel, S. Kang, G. J. Fisher, and J. J. Voorhees, “Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation,” Am. J. Pathol. 168(6), 1861–1868 (2006).
[Crossref] [PubMed]

M. J. Koehler, K. König, P. Elsner, R. Bückle, and M. Kaatz, “In vivo assessment of human skin aging by multiphoton laser scanning tomography,” Opt. Lett. 31(19), 2879–2881 (2006).
[Crossref] [PubMed]

2005 (1)

2004 (1)

S. Neerken, G. W. Lucassen, M. A. Bisschop, E. Lenderink, and T. A. Nuijs, “Characterization of age-related effects in human skin: A comparative study that applies confocal laser scanning microscopy and optical coherence tomography,” J. Biomed. Opt. 9(2), 274–281 (2004).
[Crossref] [PubMed]

2003 (2)

S.-W. Chu, S.-Y. Chen, T.-H. Tsai, T.-M. Liu, C.-Y. Lin, H.-J. Tsai, and C.-K. Sun, “In vivo developmental biology study using noninvasive multi-harmonic generation microscopy,” Opt. Express 11(23), 3093–3099 (2003).
[Crossref] [PubMed]

C. Boote, S. Dennis, R. H. Newton, H. Puri, and K. M. Meek, “Collagen fibrils appear more closely packed in the prepupillary cornea: optical and biomechanical implications,” Invest. Ophthalmol. Vis. Sci. 44(7), 2941–2948 (2003).
[Crossref] [PubMed]

2002 (1)

K. Sauermann, S. Clemann, S. Jaspers, T. Gambichler, P. Altmeyer, K. Hoffmann, and J. Ennen, “Age related changes of human skin investigated with histometric measurements by confocal laser scanning microscopy in vivo,” Skin Res. Technol. 8(1), 52–56 (2002).
[Crossref] [PubMed]

2001 (2)

M. Gniadecka, “Effects of ageing on dermal echogenicity,” Skin Res. Technol. 7(3), 204–207 (2001).
[Crossref] [PubMed]

I. Eltoum, J. Fredenburgh, R. B. Myers, and W. E. Grizzle, “Introduction to the theory and practice of fixation of tissues,” J. Histotechnol. 24(3), 173–190 (2001).
[Crossref]

2000 (2)

F. Timár, G. Soós, B. Szende, and A. Horváth, “Interdigitation index - a parameter for differentiating between young and older skin specimens,” Skin Res. Technol. 6(1), 17–20 (2000).
[Crossref] [PubMed]

M. P. Goldman, N. Marchell, and R. E. Fitzpatrick, “Laser skin resurfacing of the face with a combined CO2/Er:YAG laser,” Dermatol. Surg. 26(2), 102–104 (2000).
[Crossref] [PubMed]

1998 (3)

A. F. Frangi, W. J. Niessen, and K. L. Vincken, “Multiscale vessel enhancement filtering,” Med. Image Comput. Comput. Assist. Interv. 1496, 130–137 (1998).

J. McGough-Csarny and C. A. Kopac, “Skin tears in institutionalized elderly: an epidemiological study,” Ostomy Wound Manage. 44(3ASuppl), 14S–24S (1998).
[PubMed]

M. Gniadecka and G. B. Jemec, “Quantitative evaluation of chronological ageing and photoageing in vivo: studies on skin echogenicity and thickness,” Br. J. Dermatol. 139(5), 815–821 (1998).
[Crossref] [PubMed]

1996 (1)

B. R. Nelson, R. D. Metz, G. Majmudar, T. A. Hamilton, M. O. Gillard, D. Railan, C. E. Griffiths, and T. M. Johnson, “A comparison of wire brush and diamond fraise superficial dermabrasion for photoaged skin. A clinical, immunohistologic, and biochemical study,” J. Am. Acad. Dermatol. 34(2 Pt 1), 235–243 (1996).
[Crossref] [PubMed]

1993 (1)

C. E. Griffiths, A. N. Russman, G. Majmudar, R. S. Singer, T. A. Hamilton, and J. J. Voorhees, “Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid),” N. Engl. J. Med. 329(8), 530–535 (1993).
[Crossref] [PubMed]

1987 (1)

R. M. Lavker, P. S. Zheng, and G. Dong, “Aged skin: a study by light, transmission electron, and scanning electron microscopy,” J. Invest. Dermatol. 88(S3), 44s–51s (1987).
[Crossref] [PubMed]

1982 (2)

B. A. Gilchrest, “Age-associated changes in the skin,” J. Am. Geriatr. Soc. 30(2), 139–143 (1982).
[PubMed]

B. A. Gilchrest, “Age-associated changes in the skin,” J. Am. Geriatr. Soc. 30(2), 139–143 (1982).
[PubMed]

1979 (3)

W. Montagna and K. Carlisle, “Structural changes in aging human skin,” J. Invest. Dermatol. 73(1), 47–53 (1979).
[Crossref] [PubMed]

R. M. Lavker, “Structural alterations in exposed and unexposed aged skin,” J. Invest. Dermatol. 73(1), 59–66 (1979).
[Crossref] [PubMed]

N. Otsu, “A threshold selection method from gray-level histograms,” IEEE Trans. Syst., Man. Cybernet. SMC-9(1), 62–66 (1979).

1975 (1)

S. A. M. Shuster, M. M. Black, and E. McVitie, “The influence of age and sex on skin thickness, skin collagen and density,” Br. J. Dermatol. 93(6), 639–643 (1975).
[Crossref] [PubMed]

Ahmad, S. S.

R. Archid, A. Patzelt, B. Lange-Asschenfeldt, S. S. Ahmad, M. Ulrich, E. Stockfleth, S. Philipp, W. Sterry, and J. Lademann, “Confocal laser-scanning microscopy of capillaries in normal and psoriatic skin,” J. Biomed. Opt. 17(10), 101511 (2012).
[Crossref] [PubMed]

Altmeyer, P.

K. Sauermann, S. Clemann, S. Jaspers, T. Gambichler, P. Altmeyer, K. Hoffmann, and J. Ennen, “Age related changes of human skin investigated with histometric measurements by confocal laser scanning microscopy in vivo,” Skin Res. Technol. 8(1), 52–56 (2002).
[Crossref] [PubMed]

Araki, T.

T. Yasui, M. Yonetsu, R. Tanaka, Y. Tanaka, S. Fukushima, T. Yamashita, Y. Ogura, T. Hirao, H. Murota, and T. Araki, “In vivo observation of age-related structural changes of dermal collagen in human facial skin using collagen-sensitive second harmonic generation microscope equipped with 1250-nm mode-locked Cr:Forsterite laser,” J. Biomed. Opt. 18(3), 031108 (2013).
[Crossref] [PubMed]

Archid, R.

R. Archid, A. Patzelt, B. Lange-Asschenfeldt, S. S. Ahmad, M. Ulrich, E. Stockfleth, S. Philipp, W. Sterry, and J. Lademann, “Confocal laser-scanning microscopy of capillaries in normal and psoriatic skin,” J. Biomed. Opt. 17(10), 101511 (2012).
[Crossref] [PubMed]

Baldeweck, T.

E. Decencière, E. Tancrède-Bohin, P. Dokládal, S. Koudoro, A. M. Pena, and T. Baldeweck, “Automatic 3D segmentation of multiphoton images: a key step for the quantification of human skin,” Skin Res. Technol. 19(2), 115–124 (2013).
[Crossref] [PubMed]

Berardesca, E.

M. A. Farage, K. W. Miller, E. Berardesca, and H. I. Maibach, “Clinical implications of aging skin: cutaneous disorders in the elderly,” Am. J. Clin. Dermatol. 10(2), 73–86 (2009).
[Crossref] [PubMed]

Beretti, F.

C. Longo, A. Casari, F. Beretti, A. M. Cesinaro, and G. Pellacani, “Skin aging: in vivo microscopic assessment of epidermal and dermal changes by means of confocal microscopy,” J. Am. Acad. Dermatol. 68(3), e73–e82 (2013).
[Crossref] [PubMed]

Bille, J.

Bisschop, M. A.

S. Neerken, G. W. Lucassen, M. A. Bisschop, E. Lenderink, and T. A. Nuijs, “Characterization of age-related effects in human skin: A comparative study that applies confocal laser scanning microscopy and optical coherence tomography,” J. Biomed. Opt. 9(2), 274–281 (2004).
[Crossref] [PubMed]

Black, M. M.

S. A. M. Shuster, M. M. Black, and E. McVitie, “The influence of age and sex on skin thickness, skin collagen and density,” Br. J. Dermatol. 93(6), 639–643 (1975).
[Crossref] [PubMed]

Boote, C.

C. Boote, S. Dennis, R. H. Newton, H. Puri, and K. M. Meek, “Collagen fibrils appear more closely packed in the prepupillary cornea: optical and biomechanical implications,” Invest. Ophthalmol. Vis. Sci. 44(7), 2941–2948 (2003).
[Crossref] [PubMed]

Bückle, R.

Carlisle, K.

W. Montagna and K. Carlisle, “Structural changes in aging human skin,” J. Invest. Dermatol. 73(1), 47–53 (1979).
[Crossref] [PubMed]

Casari, A.

C. Longo, A. Casari, F. Beretti, A. M. Cesinaro, and G. Pellacani, “Skin aging: in vivo microscopic assessment of epidermal and dermal changes by means of confocal microscopy,” J. Am. Acad. Dermatol. 68(3), e73–e82 (2013).
[Crossref] [PubMed]

Cesinaro, A. M.

C. Longo, A. Casari, F. Beretti, A. M. Cesinaro, and G. Pellacani, “Skin aging: in vivo microscopic assessment of epidermal and dermal changes by means of confocal microscopy,” J. Am. Acad. Dermatol. 68(3), e73–e82 (2013).
[Crossref] [PubMed]

Chan, Y. F.

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]

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] [PubMed]

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] [PubMed]

C.-S. Hsieh, C.-Y. Ko, S.-Y. Chen, T.-M. Liu, J.-S. Wu, C.-H. Hu, and C.-K. Sun, “In vivo long-term continuous observation of gene expression in zebrafish embryo nerve systems by using harmonic generation microscopy and morphant technology,” J. Biomed. Opt. 13(6), 064041 (2008).
[Crossref] [PubMed]

S.-W. Chu, S.-Y. Chen, T.-H. Tsai, T.-M. Liu, C.-Y. Lin, H.-J. Tsai, and C.-K. Sun, “In vivo developmental biology study using noninvasive multi-harmonic generation microscopy,” Opt. Express 11(23), 3093–3099 (2003).
[Crossref] [PubMed]

Chou, S.-Y.

Chu, S.-W.

Clemann, S.

K. Sauermann, S. Clemann, S. Jaspers, T. Gambichler, P. Altmeyer, K. Hoffmann, and J. Ennen, “Age related changes of human skin investigated with histometric measurements by confocal laser scanning microscopy in vivo,” Skin Res. Technol. 8(1), 52–56 (2002).
[Crossref] [PubMed]

Curchin, C.

E. M. Wurm, C. Longo, C. Curchin, H. P. Soyer, T. W. Prow, and G. Pellacani, “In vivo assessment of chronological ageing and photoageing in forearm skin using reflectance confocal microscopy,” Br. J. Dermatol. 167(2), 270–279 (2012).
[Crossref] [PubMed]

Dame, M. K.

J. Varani, M. K. Dame, L. Rittie, S. E. G. Fligiel, S. Kang, G. J. Fisher, and J. J. Voorhees, “Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation,” Am. J. Pathol. 168(6), 1861–1868 (2006).
[Crossref] [PubMed]

Decencière, E.

E. Decencière, E. Tancrède-Bohin, P. Dokládal, S. Koudoro, A. M. Pena, and T. Baldeweck, “Automatic 3D segmentation of multiphoton images: a key step for the quantification of human skin,” Skin Res. Technol. 19(2), 115–124 (2013).
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C. Boote, S. Dennis, R. H. Newton, H. Puri, and K. M. Meek, “Collagen fibrils appear more closely packed in the prepupillary cornea: optical and biomechanical implications,” Invest. Ophthalmol. Vis. Sci. 44(7), 2941–2948 (2003).
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Dokládal, P.

E. Decencière, E. Tancrède-Bohin, P. Dokládal, S. Koudoro, A. M. Pena, and T. Baldeweck, “Automatic 3D segmentation of multiphoton images: a key step for the quantification of human skin,” Skin Res. Technol. 19(2), 115–124 (2013).
[Crossref] [PubMed]

Dong, G.

R. M. Lavker, P. S. Zheng, and G. Dong, “Aged skin: a study by light, transmission electron, and scanning electron microscopy,” J. Invest. Dermatol. 88(S3), 44s–51s (1987).
[Crossref] [PubMed]

Elsner, P.

M. J. Koehler, S. Zimmermann, S. Springer, P. Elsner, K. König, and M. Kaatz, “Keratinocyte morphology of human skin evaluated by in vivo multiphoton laser tomography,” Skin Res. Technol. 17(4), 479–486 (2011).
[Crossref] [PubMed]

M. A. Farage, K. W. Miller, P. Elsner, and H. I. Maibach, “Intrinsic and extrinsic factors in skin ageing: a review,” Int. J. Cosmet. Sci. 30(2), 87–95 (2008).
[Crossref] [PubMed]

M. J. Koehler, K. König, P. Elsner, R. Bückle, and M. Kaatz, “In vivo assessment of human skin aging by multiphoton laser scanning tomography,” Opt. Lett. 31(19), 2879–2881 (2006).
[Crossref] [PubMed]

Eltoum, I.

I. Eltoum, J. Fredenburgh, R. B. Myers, and W. E. Grizzle, “Introduction to the theory and practice of fixation of tissues,” J. Histotechnol. 24(3), 173–190 (2001).
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Ennen, J.

K. Sauermann, S. Clemann, S. Jaspers, T. Gambichler, P. Altmeyer, K. Hoffmann, and J. Ennen, “Age related changes of human skin investigated with histometric measurements by confocal laser scanning microscopy in vivo,” Skin Res. Technol. 8(1), 52–56 (2002).
[Crossref] [PubMed]

Failla, V.

A. Giangreco, S. J. Goldie, V. Failla, G. Saintigny, and F. M. Watt, “Human skin aging is associated with reduced expression of the stem cell markers beta1 integrin and MCSP,” J. Invest. Dermatol. 130(2), 604–608 (2010).
[Crossref] [PubMed]

Farage, M. A.

M. A. Farage, K. W. Miller, E. Berardesca, and H. I. Maibach, “Clinical implications of aging skin: cutaneous disorders in the elderly,” Am. J. Clin. Dermatol. 10(2), 73–86 (2009).
[Crossref] [PubMed]

M. A. Farage, K. W. Miller, P. Elsner, and H. I. Maibach, “Intrinsic and extrinsic factors in skin ageing: a review,” Int. J. Cosmet. Sci. 30(2), 87–95 (2008).
[Crossref] [PubMed]

Fischer, F.

S. Puschmann, C. D. Rahn, H. Wenck, S. Gallinat, and F. Fischer, “Approach to quantify human dermal skin aging using multiphoton laser scanning microscopy,” J. Biomed. Opt. 17(3), 036005 (2012).
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Fisher, G. J.

J. Varani, M. K. Dame, L. Rittie, S. E. G. Fligiel, S. Kang, G. J. Fisher, and J. J. Voorhees, “Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation,” Am. J. Pathol. 168(6), 1861–1868 (2006).
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Fitzpatrick, R. E.

M. P. Goldman, N. Marchell, and R. E. Fitzpatrick, “Laser skin resurfacing of the face with a combined CO2/Er:YAG laser,” Dermatol. Surg. 26(2), 102–104 (2000).
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Fligiel, S. E. G.

J. Varani, M. K. Dame, L. Rittie, S. E. G. Fligiel, S. Kang, G. J. Fisher, and J. J. Voorhees, “Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation,” Am. J. Pathol. 168(6), 1861–1868 (2006).
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A. F. Frangi, W. J. Niessen, and K. L. Vincken, “Multiscale vessel enhancement filtering,” Med. Image Comput. Comput. Assist. Interv. 1496, 130–137 (1998).

Fredenburgh, J.

I. Eltoum, J. Fredenburgh, R. B. Myers, and W. E. Grizzle, “Introduction to the theory and practice of fixation of tissues,” J. Histotechnol. 24(3), 173–190 (2001).
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Fukushima, S.

T. Yasui, M. Yonetsu, R. Tanaka, Y. Tanaka, S. Fukushima, T. Yamashita, Y. Ogura, T. Hirao, H. Murota, and T. Araki, “In vivo observation of age-related structural changes of dermal collagen in human facial skin using collagen-sensitive second harmonic generation microscope equipped with 1250-nm mode-locked Cr:Forsterite laser,” J. Biomed. Opt. 18(3), 031108 (2013).
[Crossref] [PubMed]

Gallinat, S.

S. Puschmann, C. D. Rahn, H. Wenck, S. Gallinat, and F. Fischer, “Approach to quantify human dermal skin aging using multiphoton laser scanning microscopy,” J. Biomed. Opt. 17(3), 036005 (2012).
[Crossref] [PubMed]

Gambichler, T.

K. Sauermann, S. Clemann, S. Jaspers, T. Gambichler, P. Altmeyer, K. Hoffmann, and J. Ennen, “Age related changes of human skin investigated with histometric measurements by confocal laser scanning microscopy in vivo,” Skin Res. Technol. 8(1), 52–56 (2002).
[Crossref] [PubMed]

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] [PubMed]

Giangreco, A.

A. Giangreco, S. J. Goldie, V. Failla, G. Saintigny, and F. M. Watt, “Human skin aging is associated with reduced expression of the stem cell markers beta1 integrin and MCSP,” J. Invest. Dermatol. 130(2), 604–608 (2010).
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Giese, G.

Gilchrest, B. A.

B. A. Gilchrest, “Age-associated changes in the skin,” J. Am. Geriatr. Soc. 30(2), 139–143 (1982).
[PubMed]

B. A. Gilchrest, “Age-associated changes in the skin,” J. Am. Geriatr. Soc. 30(2), 139–143 (1982).
[PubMed]

Gillard, M. O.

B. R. Nelson, R. D. Metz, G. Majmudar, T. A. Hamilton, M. O. Gillard, D. Railan, C. E. Griffiths, and T. M. Johnson, “A comparison of wire brush and diamond fraise superficial dermabrasion for photoaged skin. A clinical, immunohistologic, and biochemical study,” J. Am. Acad. Dermatol. 34(2 Pt 1), 235–243 (1996).
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Gniadecka, M.

M. Gniadecka, “Effects of ageing on dermal echogenicity,” Skin Res. Technol. 7(3), 204–207 (2001).
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M. Gniadecka and G. B. Jemec, “Quantitative evaluation of chronological ageing and photoageing in vivo: studies on skin echogenicity and thickness,” Br. J. Dermatol. 139(5), 815–821 (1998).
[Crossref] [PubMed]

Goldie, S. J.

A. Giangreco, S. J. Goldie, V. Failla, G. Saintigny, and F. M. Watt, “Human skin aging is associated with reduced expression of the stem cell markers beta1 integrin and MCSP,” J. Invest. Dermatol. 130(2), 604–608 (2010).
[Crossref] [PubMed]

Goldman, M. P.

M. P. Goldman, N. Marchell, and R. E. Fitzpatrick, “Laser skin resurfacing of the face with a combined CO2/Er:YAG laser,” Dermatol. Surg. 26(2), 102–104 (2000).
[Crossref] [PubMed]

Griffiths, C. E.

B. R. Nelson, R. D. Metz, G. Majmudar, T. A. Hamilton, M. O. Gillard, D. Railan, C. E. Griffiths, and T. M. Johnson, “A comparison of wire brush and diamond fraise superficial dermabrasion for photoaged skin. A clinical, immunohistologic, and biochemical study,” J. Am. Acad. Dermatol. 34(2 Pt 1), 235–243 (1996).
[Crossref] [PubMed]

C. E. Griffiths, A. N. Russman, G. Majmudar, R. S. Singer, T. A. Hamilton, and J. J. Voorhees, “Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid),” N. Engl. J. Med. 329(8), 530–535 (1993).
[Crossref] [PubMed]

Grizzle, W. E.

I. Eltoum, J. Fredenburgh, R. B. Myers, and W. E. Grizzle, “Introduction to the theory and practice of fixation of tissues,” J. Histotechnol. 24(3), 173–190 (2001).
[Crossref]

Hamilton, T. A.

B. R. Nelson, R. D. Metz, G. Majmudar, T. A. Hamilton, M. O. Gillard, D. Railan, C. E. Griffiths, and T. M. Johnson, “A comparison of wire brush and diamond fraise superficial dermabrasion for photoaged skin. A clinical, immunohistologic, and biochemical study,” J. Am. Acad. Dermatol. 34(2 Pt 1), 235–243 (1996).
[Crossref] [PubMed]

C. E. Griffiths, A. N. Russman, G. Majmudar, R. S. Singer, T. A. Hamilton, and J. J. Voorhees, “Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid),” N. Engl. J. Med. 329(8), 530–535 (1993).
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Han, M.

Harman, D.

D. Harman, “Free radical theory of aging: an update: increasing the functional life span,” Ann. N. Y. Acad. Sci. 1067(1), 10–21 (2006).
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Hirao, T.

T. Yasui, M. Yonetsu, R. Tanaka, Y. Tanaka, S. Fukushima, T. Yamashita, Y. Ogura, T. Hirao, H. Murota, and T. Araki, “In vivo observation of age-related structural changes of dermal collagen in human facial skin using collagen-sensitive second harmonic generation microscope equipped with 1250-nm mode-locked Cr:Forsterite laser,” J. Biomed. Opt. 18(3), 031108 (2013).
[Crossref] [PubMed]

Hoffmann, K.

K. Sauermann, S. Clemann, S. Jaspers, T. Gambichler, P. Altmeyer, K. Hoffmann, and J. Ennen, “Age related changes of human skin investigated with histometric measurements by confocal laser scanning microscopy in vivo,” Skin Res. Technol. 8(1), 52–56 (2002).
[Crossref] [PubMed]

Horváth, A.

F. Timár, G. Soós, B. Szende, and A. Horváth, “Interdigitation index - a parameter for differentiating between young and older skin specimens,” Skin Res. Technol. 6(1), 17–20 (2000).
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Hsieh, C.-S.

C.-S. Hsieh, C.-Y. Ko, S.-Y. Chen, T.-M. Liu, J.-S. Wu, C.-H. Hu, and C.-K. Sun, “In vivo long-term continuous observation of gene expression in zebrafish embryo nerve systems by using harmonic generation microscopy and morphant technology,” J. Biomed. Opt. 13(6), 064041 (2008).
[Crossref] [PubMed]

Hu, C.-H.

C.-S. Hsieh, C.-Y. Ko, S.-Y. Chen, T.-M. Liu, J.-S. Wu, C.-H. Hu, and C.-K. Sun, “In vivo long-term continuous observation of gene expression in zebrafish embryo nerve systems by using harmonic generation microscopy and morphant technology,” J. Biomed. Opt. 13(6), 064041 (2008).
[Crossref] [PubMed]

Huang, H. J.

Jaspers, S.

K. Sauermann, S. Clemann, S. Jaspers, T. Gambichler, P. Altmeyer, K. Hoffmann, and J. Ennen, “Age related changes of human skin investigated with histometric measurements by confocal laser scanning microscopy in vivo,” Skin Res. Technol. 8(1), 52–56 (2002).
[Crossref] [PubMed]

Jemec, G. B.

M. Gniadecka and G. B. Jemec, “Quantitative evaluation of chronological ageing and photoageing in vivo: studies on skin echogenicity and thickness,” Br. J. Dermatol. 139(5), 815–821 (1998).
[Crossref] [PubMed]

Johnson, T. M.

B. R. Nelson, R. D. Metz, G. Majmudar, T. A. Hamilton, M. O. Gillard, D. Railan, C. E. Griffiths, and T. M. Johnson, “A comparison of wire brush and diamond fraise superficial dermabrasion for photoaged skin. A clinical, immunohistologic, and biochemical study,” J. Am. Acad. Dermatol. 34(2 Pt 1), 235–243 (1996).
[Crossref] [PubMed]

Kaatz, M.

M. J. Koehler, S. Zimmermann, S. Springer, P. Elsner, K. König, and M. Kaatz, “Keratinocyte morphology of human skin evaluated by in vivo multiphoton laser tomography,” Skin Res. Technol. 17(4), 479–486 (2011).
[Crossref] [PubMed]

M. J. Koehler, K. König, P. Elsner, R. Bückle, and M. Kaatz, “In vivo assessment of human skin aging by multiphoton laser scanning tomography,” Opt. Lett. 31(19), 2879–2881 (2006).
[Crossref] [PubMed]

Kang, S.

J. Varani, M. K. Dame, L. Rittie, S. E. G. Fligiel, S. Kang, G. J. Fisher, and J. J. Voorhees, “Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation,” Am. J. Pathol. 168(6), 1861–1868 (2006).
[Crossref] [PubMed]

Ko, C.-Y.

C.-S. Hsieh, C.-Y. Ko, S.-Y. Chen, T.-M. Liu, J.-S. Wu, C.-H. Hu, and C.-K. Sun, “In vivo long-term continuous observation of gene expression in zebrafish embryo nerve systems by using harmonic generation microscopy and morphant technology,” J. Biomed. Opt. 13(6), 064041 (2008).
[Crossref] [PubMed]

Koehler, M. J.

M. J. Koehler, S. Zimmermann, S. Springer, P. Elsner, K. König, and M. Kaatz, “Keratinocyte morphology of human skin evaluated by in vivo multiphoton laser tomography,” Skin Res. Technol. 17(4), 479–486 (2011).
[Crossref] [PubMed]

M. J. Koehler, K. König, P. Elsner, R. Bückle, and M. Kaatz, “In vivo assessment of human skin aging by multiphoton laser scanning tomography,” Opt. Lett. 31(19), 2879–2881 (2006).
[Crossref] [PubMed]

König, K.

M. J. Koehler, S. Zimmermann, S. Springer, P. Elsner, K. König, and M. Kaatz, “Keratinocyte morphology of human skin evaluated by in vivo multiphoton laser tomography,” Skin Res. Technol. 17(4), 479–486 (2011).
[Crossref] [PubMed]

M. J. Koehler, K. König, P. Elsner, R. Bückle, and M. Kaatz, “In vivo assessment of human skin aging by multiphoton laser scanning tomography,” Opt. Lett. 31(19), 2879–2881 (2006).
[Crossref] [PubMed]

Kopac, C. A.

J. McGough-Csarny and C. A. Kopac, “Skin tears in institutionalized elderly: an epidemiological study,” Ostomy Wound Manage. 44(3ASuppl), 14S–24S (1998).
[PubMed]

Koudoro, S.

E. Decencière, E. Tancrède-Bohin, P. Dokládal, S. Koudoro, A. M. Pena, and T. Baldeweck, “Automatic 3D segmentation of multiphoton images: a key step for the quantification of human skin,” Skin Res. Technol. 19(2), 115–124 (2013).
[Crossref] [PubMed]

Kung, C. T.

Lademann, J.

R. Archid, A. Patzelt, B. Lange-Asschenfeldt, S. S. Ahmad, M. Ulrich, E. Stockfleth, S. Philipp, W. Sterry, and J. Lademann, “Confocal laser-scanning microscopy of capillaries in normal and psoriatic skin,” J. Biomed. Opt. 17(10), 101511 (2012).
[Crossref] [PubMed]

Lagarde, J. 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).
[Crossref] [PubMed]

Lagarrigue, S. G.

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] [PubMed]

Lange-Asschenfeldt, B.

R. Archid, A. Patzelt, B. Lange-Asschenfeldt, S. S. Ahmad, M. Ulrich, E. Stockfleth, S. Philipp, W. Sterry, and J. Lademann, “Confocal laser-scanning microscopy of capillaries in normal and psoriatic skin,” J. Biomed. Opt. 17(10), 101511 (2012).
[Crossref] [PubMed]

Lauze, C.

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] [PubMed]

Lavker, R. M.

R. M. Lavker, P. S. Zheng, and G. Dong, “Aged skin: a study by light, transmission electron, and scanning electron microscopy,” J. Invest. Dermatol. 88(S3), 44s–51s (1987).
[Crossref] [PubMed]

R. M. Lavker, “Structural alterations in exposed and unexposed aged skin,” J. Invest. Dermatol. 73(1), 59–66 (1979).
[Crossref] [PubMed]

Lee, W. J.

Lee, W.-J.

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]

Lenderink, E.

S. Neerken, G. W. Lucassen, M. A. Bisschop, E. Lenderink, and T. A. Nuijs, “Characterization of age-related effects in human skin: A comparative study that applies confocal laser scanning microscopy and optical coherence tomography,” J. Biomed. Opt. 9(2), 274–281 (2004).
[Crossref] [PubMed]

Liao, Y.-H.

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] [PubMed]

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]

Lin, C.-Y.

Liu, T.-M.

C.-S. Hsieh, C.-Y. Ko, S.-Y. Chen, T.-M. Liu, J.-S. Wu, C.-H. Hu, and C.-K. Sun, “In vivo long-term continuous observation of gene expression in zebrafish embryo nerve systems by using harmonic generation microscopy and morphant technology,” J. Biomed. Opt. 13(6), 064041 (2008).
[Crossref] [PubMed]

S.-W. Chu, S.-Y. Chen, T.-H. Tsai, T.-M. Liu, C.-Y. Lin, H.-J. Tsai, and C.-K. Sun, “In vivo developmental biology study using noninvasive multi-harmonic generation microscopy,” Opt. Express 11(23), 3093–3099 (2003).
[Crossref] [PubMed]

Longo, C.

C. Longo, A. Casari, F. Beretti, A. M. Cesinaro, and G. Pellacani, “Skin aging: in vivo microscopic assessment of epidermal and dermal changes by means of confocal microscopy,” J. Am. Acad. Dermatol. 68(3), e73–e82 (2013).
[Crossref] [PubMed]

E. M. Wurm, C. Longo, C. Curchin, H. P. Soyer, T. W. Prow, and G. Pellacani, “In vivo assessment of chronological ageing and photoageing in forearm skin using reflectance confocal microscopy,” Br. J. Dermatol. 167(2), 270–279 (2012).
[Crossref] [PubMed]

Lucassen, G. W.

S. Neerken, G. W. Lucassen, M. A. Bisschop, E. Lenderink, and T. A. Nuijs, “Characterization of age-related effects in human skin: A comparative study that applies confocal laser scanning microscopy and optical coherence tomography,” J. Biomed. Opt. 9(2), 274–281 (2004).
[Crossref] [PubMed]

Maibach, H. I.

M. A. Farage, K. W. Miller, E. Berardesca, and H. I. Maibach, “Clinical implications of aging skin: cutaneous disorders in the elderly,” Am. J. Clin. Dermatol. 10(2), 73–86 (2009).
[Crossref] [PubMed]

M. A. Farage, K. W. Miller, P. Elsner, and H. I. Maibach, “Intrinsic and extrinsic factors in skin ageing: a review,” Int. J. Cosmet. Sci. 30(2), 87–95 (2008).
[Crossref] [PubMed]

Majmudar, G.

B. R. Nelson, R. D. Metz, G. Majmudar, T. A. Hamilton, M. O. Gillard, D. Railan, C. E. Griffiths, and T. M. Johnson, “A comparison of wire brush and diamond fraise superficial dermabrasion for photoaged skin. A clinical, immunohistologic, and biochemical study,” J. Am. Acad. Dermatol. 34(2 Pt 1), 235–243 (1996).
[Crossref] [PubMed]

C. E. Griffiths, A. N. Russman, G. Majmudar, R. S. Singer, T. A. Hamilton, and J. J. Voorhees, “Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid),” N. Engl. J. Med. 329(8), 530–535 (1993).
[Crossref] [PubMed]

Marchell, N.

M. P. Goldman, N. Marchell, and R. E. Fitzpatrick, “Laser skin resurfacing of the face with a combined CO2/Er:YAG laser,” Dermatol. Surg. 26(2), 102–104 (2000).
[Crossref] [PubMed]

McGough-Csarny, J.

J. McGough-Csarny and C. A. Kopac, “Skin tears in institutionalized elderly: an epidemiological study,” Ostomy Wound Manage. 44(3ASuppl), 14S–24S (1998).
[PubMed]

McVitie, E.

S. A. M. Shuster, M. M. Black, and E. McVitie, “The influence of age and sex on skin thickness, skin collagen and density,” Br. J. Dermatol. 93(6), 639–643 (1975).
[Crossref] [PubMed]

Meek, K. M.

C. Boote, S. Dennis, R. H. Newton, H. Puri, and K. M. Meek, “Collagen fibrils appear more closely packed in the prepupillary cornea: optical and biomechanical implications,” Invest. Ophthalmol. Vis. Sci. 44(7), 2941–2948 (2003).
[Crossref] [PubMed]

Metz, R. D.

B. R. Nelson, R. D. Metz, G. Majmudar, T. A. Hamilton, M. O. Gillard, D. Railan, C. E. Griffiths, and T. M. Johnson, “A comparison of wire brush and diamond fraise superficial dermabrasion for photoaged skin. A clinical, immunohistologic, and biochemical study,” J. Am. Acad. Dermatol. 34(2 Pt 1), 235–243 (1996).
[Crossref] [PubMed]

Meyer, N.

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] [PubMed]

Miller, K. W.

M. A. Farage, K. W. Miller, E. Berardesca, and H. I. Maibach, “Clinical implications of aging skin: cutaneous disorders in the elderly,” Am. J. Clin. Dermatol. 10(2), 73–86 (2009).
[Crossref] [PubMed]

M. A. Farage, K. W. Miller, P. Elsner, and H. I. Maibach, “Intrinsic and extrinsic factors in skin ageing: a review,” Int. J. Cosmet. Sci. 30(2), 87–95 (2008).
[Crossref] [PubMed]

Montagna, W.

W. Montagna and K. Carlisle, “Structural changes in aging human skin,” J. Invest. Dermatol. 73(1), 47–53 (1979).
[Crossref] [PubMed]

Murota, H.

T. Yasui, M. Yonetsu, R. Tanaka, Y. Tanaka, S. Fukushima, T. Yamashita, Y. Ogura, T. Hirao, H. Murota, and T. Araki, “In vivo observation of age-related structural changes of dermal collagen in human facial skin using collagen-sensitive second harmonic generation microscope equipped with 1250-nm mode-locked Cr:Forsterite laser,” J. Biomed. Opt. 18(3), 031108 (2013).
[Crossref] [PubMed]

Myers, R. B.

I. Eltoum, J. Fredenburgh, R. B. Myers, and W. E. Grizzle, “Introduction to the theory and practice of fixation of tissues,” J. Histotechnol. 24(3), 173–190 (2001).
[Crossref]

Neerken, S.

S. Neerken, G. W. Lucassen, M. A. Bisschop, E. Lenderink, and T. A. Nuijs, “Characterization of age-related effects in human skin: A comparative study that applies confocal laser scanning microscopy and optical coherence tomography,” J. Biomed. Opt. 9(2), 274–281 (2004).
[Crossref] [PubMed]

Nelson, B. R.

B. R. Nelson, R. D. Metz, G. Majmudar, T. A. Hamilton, M. O. Gillard, D. Railan, C. E. Griffiths, and T. M. Johnson, “A comparison of wire brush and diamond fraise superficial dermabrasion for photoaged skin. A clinical, immunohistologic, and biochemical study,” J. Am. Acad. Dermatol. 34(2 Pt 1), 235–243 (1996).
[Crossref] [PubMed]

Newton, R. H.

C. Boote, S. Dennis, R. H. Newton, H. Puri, and K. M. Meek, “Collagen fibrils appear more closely packed in the prepupillary cornea: optical and biomechanical implications,” Invest. Ophthalmol. Vis. Sci. 44(7), 2941–2948 (2003).
[Crossref] [PubMed]

Niessen, W. J.

A. F. Frangi, W. J. Niessen, and K. L. Vincken, “Multiscale vessel enhancement filtering,” Med. Image Comput. Comput. Assist. Interv. 1496, 130–137 (1998).

Nuijs, T. A.

S. Neerken, G. W. Lucassen, M. A. Bisschop, E. Lenderink, and T. A. Nuijs, “Characterization of age-related effects in human skin: A comparative study that applies confocal laser scanning microscopy and optical coherence tomography,” J. Biomed. Opt. 9(2), 274–281 (2004).
[Crossref] [PubMed]

Ogura, Y.

T. Yasui, M. Yonetsu, R. Tanaka, Y. Tanaka, S. Fukushima, T. Yamashita, Y. Ogura, T. Hirao, H. Murota, and T. Araki, “In vivo observation of age-related structural changes of dermal collagen in human facial skin using collagen-sensitive second harmonic generation microscope equipped with 1250-nm mode-locked Cr:Forsterite laser,” J. Biomed. Opt. 18(3), 031108 (2013).
[Crossref] [PubMed]

Otsu, N.

N. Otsu, “A threshold selection method from gray-level histograms,” IEEE Trans. Syst., Man. Cybernet. SMC-9(1), 62–66 (1979).

Patzelt, A.

R. Archid, A. Patzelt, B. Lange-Asschenfeldt, S. S. Ahmad, M. Ulrich, E. Stockfleth, S. Philipp, W. Sterry, and J. Lademann, “Confocal laser-scanning microscopy of capillaries in normal and psoriatic skin,” J. Biomed. Opt. 17(10), 101511 (2012).
[Crossref] [PubMed]

Paul, C.

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] [PubMed]

Pellacani, G.

C. Longo, A. Casari, F. Beretti, A. M. Cesinaro, and G. Pellacani, “Skin aging: in vivo microscopic assessment of epidermal and dermal changes by means of confocal microscopy,” J. Am. Acad. Dermatol. 68(3), e73–e82 (2013).
[Crossref] [PubMed]

E. M. Wurm, C. Longo, C. Curchin, H. P. Soyer, T. W. Prow, and G. Pellacani, “In vivo assessment of chronological ageing and photoageing in forearm skin using reflectance confocal microscopy,” Br. J. Dermatol. 167(2), 270–279 (2012).
[Crossref] [PubMed]

Pena, A. M.

E. Decencière, E. Tancrède-Bohin, P. Dokládal, S. Koudoro, A. M. Pena, and T. Baldeweck, “Automatic 3D segmentation of multiphoton images: a key step for the quantification of human skin,” Skin Res. Technol. 19(2), 115–124 (2013).
[Crossref] [PubMed]

Philipp, S.

R. Archid, A. Patzelt, B. Lange-Asschenfeldt, S. S. Ahmad, M. Ulrich, E. Stockfleth, S. Philipp, W. Sterry, and J. Lademann, “Confocal laser-scanning microscopy of capillaries in normal and psoriatic skin,” J. Biomed. Opt. 17(10), 101511 (2012).
[Crossref] [PubMed]

Prow, T. W.

E. M. Wurm, C. Longo, C. Curchin, H. P. Soyer, T. W. Prow, and G. Pellacani, “In vivo assessment of chronological ageing and photoageing in forearm skin using reflectance confocal microscopy,” Br. J. Dermatol. 167(2), 270–279 (2012).
[Crossref] [PubMed]

Puri, H.

C. Boote, S. Dennis, R. H. Newton, H. Puri, and K. M. Meek, “Collagen fibrils appear more closely packed in the prepupillary cornea: optical and biomechanical implications,” Invest. Ophthalmol. Vis. Sci. 44(7), 2941–2948 (2003).
[Crossref] [PubMed]

Puschmann, S.

S. Puschmann, C. D. Rahn, H. Wenck, S. Gallinat, and F. Fischer, “Approach to quantify human dermal skin aging using multiphoton laser scanning microscopy,” J. Biomed. Opt. 17(3), 036005 (2012).
[Crossref] [PubMed]

Questel, E.

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] [PubMed]

Rahn, C. D.

S. Puschmann, C. D. Rahn, H. Wenck, S. Gallinat, and F. Fischer, “Approach to quantify human dermal skin aging using multiphoton laser scanning microscopy,” J. Biomed. Opt. 17(3), 036005 (2012).
[Crossref] [PubMed]

Railan, D.

B. R. Nelson, R. D. Metz, G. Majmudar, T. A. Hamilton, M. O. Gillard, D. Railan, C. E. Griffiths, and T. M. Johnson, “A comparison of wire brush and diamond fraise superficial dermabrasion for photoaged skin. A clinical, immunohistologic, and biochemical study,” J. Am. Acad. Dermatol. 34(2 Pt 1), 235–243 (1996).
[Crossref] [PubMed]

Rittie, L.

J. Varani, M. K. Dame, L. Rittie, S. E. G. Fligiel, S. Kang, G. J. Fisher, and J. J. Voorhees, “Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation,” Am. J. Pathol. 168(6), 1861–1868 (2006).
[Crossref] [PubMed]

Russman, A. N.

C. E. Griffiths, A. N. Russman, G. Majmudar, R. S. Singer, T. A. Hamilton, and J. J. Voorhees, “Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid),” N. Engl. J. Med. 329(8), 530–535 (1993).
[Crossref] [PubMed]

Saintigny, G.

A. Giangreco, S. J. Goldie, V. Failla, G. Saintigny, and F. M. Watt, “Human skin aging is associated with reduced expression of the stem cell markers beta1 integrin and MCSP,” J. Invest. Dermatol. 130(2), 604–608 (2010).
[Crossref] [PubMed]

Sauermann, K.

K. Sauermann, S. Clemann, S. Jaspers, T. Gambichler, P. Altmeyer, K. Hoffmann, and J. Ennen, “Age related changes of human skin investigated with histometric measurements by confocal laser scanning microscopy in vivo,” Skin Res. Technol. 8(1), 52–56 (2002).
[Crossref] [PubMed]

Schmitt, A. 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).
[Crossref] [PubMed]

Serre, G.

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] [PubMed]

Shuster, S. A. M.

S. A. M. Shuster, M. M. Black, and E. McVitie, “The influence of age and sex on skin thickness, skin collagen and density,” Br. J. Dermatol. 93(6), 639–643 (1975).
[Crossref] [PubMed]

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).
[Crossref] [PubMed]

Singer, R. S.

C. E. Griffiths, A. N. Russman, G. Majmudar, R. S. Singer, T. A. Hamilton, and J. J. Voorhees, “Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid),” N. Engl. J. Med. 329(8), 530–535 (1993).
[Crossref] [PubMed]

Soós, G.

F. Timár, G. Soós, B. Szende, and A. Horváth, “Interdigitation index - a parameter for differentiating between young and older skin specimens,” Skin Res. Technol. 6(1), 17–20 (2000).
[Crossref] [PubMed]

Soyer, H. P.

E. M. Wurm, C. Longo, C. Curchin, H. P. Soyer, T. W. Prow, and G. Pellacani, “In vivo assessment of chronological ageing and photoageing in forearm skin using reflectance confocal microscopy,” Br. J. Dermatol. 167(2), 270–279 (2012).
[Crossref] [PubMed]

Springer, S.

M. J. Koehler, S. Zimmermann, S. Springer, P. Elsner, K. König, and M. Kaatz, “Keratinocyte morphology of human skin evaluated by in vivo multiphoton laser tomography,” Skin Res. Technol. 17(4), 479–486 (2011).
[Crossref] [PubMed]

Sterry, W.

R. Archid, A. Patzelt, B. Lange-Asschenfeldt, S. S. Ahmad, M. Ulrich, E. Stockfleth, S. Philipp, W. Sterry, and J. Lademann, “Confocal laser-scanning microscopy of capillaries in normal and psoriatic skin,” J. Biomed. Opt. 17(10), 101511 (2012).
[Crossref] [PubMed]

Stockfleth, E.

R. Archid, A. Patzelt, B. Lange-Asschenfeldt, S. S. Ahmad, M. Ulrich, E. Stockfleth, S. Philipp, W. Sterry, and J. Lademann, “Confocal laser-scanning microscopy of capillaries in normal and psoriatic skin,” J. Biomed. Opt. 17(10), 101511 (2012).
[Crossref] [PubMed]

Sun, C. K.

Sun, C.-K.

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] [PubMed]

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] [PubMed]

C.-S. Hsieh, C.-Y. Ko, S.-Y. Chen, T.-M. Liu, J.-S. Wu, C.-H. Hu, and C.-K. Sun, “In vivo long-term continuous observation of gene expression in zebrafish embryo nerve systems by using harmonic generation microscopy and morphant technology,” J. Biomed. Opt. 13(6), 064041 (2008).
[Crossref] [PubMed]

S.-W. Chu, S.-Y. Chen, T.-H. Tsai, T.-M. Liu, C.-Y. Lin, H.-J. Tsai, and C.-K. Sun, “In vivo developmental biology study using noninvasive multi-harmonic generation microscopy,” Opt. Express 11(23), 3093–3099 (2003).
[Crossref] [PubMed]

Szende, B.

F. Timár, G. Soós, B. Szende, and A. Horváth, “Interdigitation index - a parameter for differentiating between young and older skin specimens,” Skin Res. Technol. 6(1), 17–20 (2000).
[Crossref] [PubMed]

Tai, S. P.

Tanaka, R.

T. Yasui, M. Yonetsu, R. Tanaka, Y. Tanaka, S. Fukushima, T. Yamashita, Y. Ogura, T. Hirao, H. Murota, and T. Araki, “In vivo observation of age-related structural changes of dermal collagen in human facial skin using collagen-sensitive second harmonic generation microscope equipped with 1250-nm mode-locked Cr:Forsterite laser,” J. Biomed. Opt. 18(3), 031108 (2013).
[Crossref] [PubMed]

Tanaka, Y.

T. Yasui, M. Yonetsu, R. Tanaka, Y. Tanaka, S. Fukushima, T. Yamashita, Y. Ogura, T. Hirao, H. Murota, and T. Araki, “In vivo observation of age-related structural changes of dermal collagen in human facial skin using collagen-sensitive second harmonic generation microscope equipped with 1250-nm mode-locked Cr:Forsterite laser,” J. Biomed. Opt. 18(3), 031108 (2013).
[Crossref] [PubMed]

Tancrède-Bohin, E.

E. Decencière, E. Tancrède-Bohin, P. Dokládal, S. Koudoro, A. M. Pena, and T. Baldeweck, “Automatic 3D segmentation of multiphoton images: a key step for the quantification of human skin,” Skin Res. Technol. 19(2), 115–124 (2013).
[Crossref] [PubMed]

Timár, F.

F. Timár, G. Soós, B. Szende, and A. Horváth, “Interdigitation index - a parameter for differentiating between young and older skin specimens,” Skin Res. Technol. 6(1), 17–20 (2000).
[Crossref] [PubMed]

Tsai, H.-J.

Tsai, M.-R.

Tsai, T.-H.

Ulrich, M.

R. Archid, A. Patzelt, B. Lange-Asschenfeldt, S. S. Ahmad, M. Ulrich, E. Stockfleth, S. Philipp, W. Sterry, and J. Lademann, “Confocal laser-scanning microscopy of capillaries in normal and psoriatic skin,” J. Biomed. Opt. 17(10), 101511 (2012).
[Crossref] [PubMed]

Varani, J.

J. Varani, M. K. Dame, L. Rittie, S. E. G. Fligiel, S. Kang, G. J. Fisher, and J. J. Voorhees, “Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation,” Am. J. Pathol. 168(6), 1861–1868 (2006).
[Crossref] [PubMed]

Vincken, K. L.

A. F. Frangi, W. J. Niessen, and K. L. Vincken, “Multiscale vessel enhancement filtering,” Med. Image Comput. Comput. Assist. Interv. 1496, 130–137 (1998).

Voorhees, J. J.

J. Varani, M. K. Dame, L. Rittie, S. E. G. Fligiel, S. Kang, G. J. Fisher, and J. J. Voorhees, “Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation,” Am. J. Pathol. 168(6), 1861–1868 (2006).
[Crossref] [PubMed]

C. E. Griffiths, A. N. Russman, G. Majmudar, R. S. Singer, T. A. Hamilton, and J. J. Voorhees, “Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid),” N. Engl. J. Med. 329(8), 530–535 (1993).
[Crossref] [PubMed]

Wang, I. J.

Wang, P.-H.

Watt, F. M.

A. Giangreco, S. J. Goldie, V. Failla, G. Saintigny, and F. M. Watt, “Human skin aging is associated with reduced expression of the stem cell markers beta1 integrin and MCSP,” J. Invest. Dermatol. 130(2), 604–608 (2010).
[Crossref] [PubMed]

Wenck, H.

S. Puschmann, C. D. Rahn, H. Wenck, S. Gallinat, and F. Fischer, “Approach to quantify human dermal skin aging using multiphoton laser scanning microscopy,” J. Biomed. Opt. 17(3), 036005 (2012).
[Crossref] [PubMed]

Wu, H.-Y.

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] [PubMed]

Wu, J.-S.

C.-S. Hsieh, C.-Y. Ko, S.-Y. Chen, T.-M. Liu, J.-S. Wu, C.-H. Hu, and C.-K. Sun, “In vivo long-term continuous observation of gene expression in zebrafish embryo nerve systems by using harmonic generation microscopy and morphant technology,” J. Biomed. Opt. 13(6), 064041 (2008).
[Crossref] [PubMed]

Wurm, E. M.

E. M. Wurm, C. Longo, C. Curchin, H. P. Soyer, T. W. Prow, and G. Pellacani, “In vivo assessment of chronological ageing and photoageing in forearm skin using reflectance confocal microscopy,” Br. J. Dermatol. 167(2), 270–279 (2012).
[Crossref] [PubMed]

Yamashita, T.

T. Yasui, M. Yonetsu, R. Tanaka, Y. Tanaka, S. Fukushima, T. Yamashita, Y. Ogura, T. Hirao, H. Murota, and T. Araki, “In vivo observation of age-related structural changes of dermal collagen in human facial skin using collagen-sensitive second harmonic generation microscope equipped with 1250-nm mode-locked Cr:Forsterite laser,” J. Biomed. Opt. 18(3), 031108 (2013).
[Crossref] [PubMed]

Yasui, T.

T. Yasui, M. Yonetsu, R. Tanaka, Y. Tanaka, S. Fukushima, T. Yamashita, Y. Ogura, T. Hirao, H. Murota, and T. Araki, “In vivo observation of age-related structural changes of dermal collagen in human facial skin using collagen-sensitive second harmonic generation microscope equipped with 1250-nm mode-locked Cr:Forsterite laser,” J. Biomed. Opt. 18(3), 031108 (2013).
[Crossref] [PubMed]

Yonetsu, M.

T. Yasui, M. Yonetsu, R. Tanaka, Y. Tanaka, S. Fukushima, T. Yamashita, Y. Ogura, T. Hirao, H. Murota, and T. Araki, “In vivo observation of age-related structural changes of dermal collagen in human facial skin using collagen-sensitive second harmonic generation microscope equipped with 1250-nm mode-locked Cr:Forsterite laser,” J. Biomed. Opt. 18(3), 031108 (2013).
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Yu, C. H.

Yu, H. C.

Zheng, P. S.

R. M. Lavker, P. S. Zheng, and G. Dong, “Aged skin: a study by light, transmission electron, and scanning electron microscopy,” J. Invest. Dermatol. 88(S3), 44s–51s (1987).
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Zimmermann, S.

M. J. Koehler, S. Zimmermann, S. Springer, P. Elsner, K. König, and M. Kaatz, “Keratinocyte morphology of human skin evaluated by in vivo multiphoton laser tomography,” Skin Res. Technol. 17(4), 479–486 (2011).
[Crossref] [PubMed]

Am. J. Clin. Dermatol. (1)

M. A. Farage, K. W. Miller, E. Berardesca, and H. I. Maibach, “Clinical implications of aging skin: cutaneous disorders in the elderly,” Am. J. Clin. Dermatol. 10(2), 73–86 (2009).
[Crossref] [PubMed]

Am. J. Pathol. (1)

J. Varani, M. K. Dame, L. Rittie, S. E. G. Fligiel, S. Kang, G. J. Fisher, and J. J. Voorhees, “Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation,” Am. J. Pathol. 168(6), 1861–1868 (2006).
[Crossref] [PubMed]

Ann. N. Y. Acad. Sci. (1)

D. Harman, “Free radical theory of aging: an update: increasing the functional life span,” Ann. N. Y. Acad. Sci. 1067(1), 10–21 (2006).
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Biomed. Opt. Express (1)

Br. J. Dermatol. (3)

S. A. M. Shuster, M. M. Black, and E. McVitie, “The influence of age and sex on skin thickness, skin collagen and density,” Br. J. Dermatol. 93(6), 639–643 (1975).
[Crossref] [PubMed]

M. Gniadecka and G. B. Jemec, “Quantitative evaluation of chronological ageing and photoageing in vivo: studies on skin echogenicity and thickness,” Br. J. Dermatol. 139(5), 815–821 (1998).
[Crossref] [PubMed]

E. M. Wurm, C. Longo, C. Curchin, H. P. Soyer, T. W. Prow, and G. Pellacani, “In vivo assessment of chronological ageing and photoageing in forearm skin using reflectance confocal microscopy,” Br. J. Dermatol. 167(2), 270–279 (2012).
[Crossref] [PubMed]

Dermatol. Surg. (1)

M. P. Goldman, N. Marchell, and R. E. Fitzpatrick, “Laser skin resurfacing of the face with a combined CO2/Er:YAG laser,” Dermatol. Surg. 26(2), 102–104 (2000).
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Exp. Dermatol. (1)

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] [PubMed]

IEEE J. Sel. Top. Quantum Electron. (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]

IEEE Trans. Syst., Man. Cybernet. (1)

N. Otsu, “A threshold selection method from gray-level histograms,” IEEE Trans. Syst., Man. Cybernet. SMC-9(1), 62–66 (1979).

Int. J. Cosmet. Sci. (1)

M. A. Farage, K. W. Miller, P. Elsner, and H. I. Maibach, “Intrinsic and extrinsic factors in skin ageing: a review,” Int. J. Cosmet. Sci. 30(2), 87–95 (2008).
[Crossref] [PubMed]

Invest. Ophthalmol. Vis. Sci. (1)

C. Boote, S. Dennis, R. H. Newton, H. Puri, and K. M. Meek, “Collagen fibrils appear more closely packed in the prepupillary cornea: optical and biomechanical implications,” Invest. Ophthalmol. Vis. Sci. 44(7), 2941–2948 (2003).
[Crossref] [PubMed]

J. Am. Acad. Dermatol. (2)

B. R. Nelson, R. D. Metz, G. Majmudar, T. A. Hamilton, M. O. Gillard, D. Railan, C. E. Griffiths, and T. M. Johnson, “A comparison of wire brush and diamond fraise superficial dermabrasion for photoaged skin. A clinical, immunohistologic, and biochemical study,” J. Am. Acad. Dermatol. 34(2 Pt 1), 235–243 (1996).
[Crossref] [PubMed]

C. Longo, A. Casari, F. Beretti, A. M. Cesinaro, and G. Pellacani, “Skin aging: in vivo microscopic assessment of epidermal and dermal changes by means of confocal microscopy,” J. Am. Acad. Dermatol. 68(3), e73–e82 (2013).
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Figures (9)

Fig. 1
Fig. 1 A representative in vivo XYZ image stack obtained by HGM from the volar forearm of a 28-year-old male. (a-i) The image stack labeled at different depths included stratum corneum (SC), stratum granulosum (SG), stratum spinosum (SS), stratum basale (SB), the dermal papilla (DP) area, and the upper reticular dermis (RD). The SHG/THG signals were represented by green/purple pseudo-colors. (d-k) As the plane of observation moved down from the dermal-epidermal junction, the region of isolated dermal papilla (DP) expanded (arrows in (d)-(h)), and connected with their neighboring isolated DP in the successive frames (arrowheads in (f)-(h)). The lower boundary of DPZ was defined at the level where SB disappeared. The large circular cavities inside collagen network were the superficial capillary plexuses. (l) The reticular dermis (RD) was characterized by thick bundles of collagen fibers parallel to the skin surface. Scale bar = 50 μm.
Fig. 2
Fig. 2 The parameters of dermal papilla zone (DPZ) for image analysis. (a) Definition of dermal papilla (DP) parameters in our study. (b) Formulation of these parameters. OAmax, the maximum occupied section area; Ntotal, the total number of DP; Vtotal, the total DP volume; Ctotal, the total collagen volume; IAtotal, the total interface area of DEJ.
Fig. 3
Fig. 3 Algorithmic framework. We segmented the region of DPZ as our region of interest (ROI) in the top route, and the collagen structure in the bottom route. Then we defined the 2D collagen density as the ratio of the area of collagen fibers to the ROI area. CC, connected components; LPF, low pass filter.
Fig. 4
Fig. 4 ROI segmentation. (a) Original image. (b) Dilated image. (c) Smoothed dilated image. (d) Three-class global Otsu image. The top two classes, the gray and white regions, were considered as the collagen fiber areas. The capillary cavity is the big round dark region at the lower right corner of images (b-d). Note that collagen region with weak intensity was well preserved in the ROI segmentation.
Fig. 5
Fig. 5 Collagen segmentation. (a) Original image enhanced by CLAHE. (b) Frangi-filtered image. (c) 3-class local Otsu image in 4x4 tiles. (d) Collagen segmentation overlaid on original image. The cylindrical structure of collagen was well-preserved.
Fig. 6
Fig. 6 Plot of P-value against tunable threshold parameter X. Note the strong correlation between threshold parameter and P-value, suggesting that hand-tuned thresholds are not suitable for SHG collagen statistical study.
Fig. 7
Fig. 7 The depth of dermal papilla zone and the 3D interdigitation index were negatively correlated with age. The results of linear regression (a, c, e, g) and ANOVA analysis (b, d, f, h) for number density of dermal papillae (N), depth of dermal papilla zone (T), DP volume per unit area (V), and the 3D interdigitation index (I). (a, b) No significant correlation was found between N and age. (c, d) T significantly decreased with age. (e, f) V showed no correlation with age. (g, h) Parameter I was negatively correlated with age. NS, not significant. **, P < 0.01. The data were presented as mean ± standard deviation.
Fig. 8
Fig. 8 The average height of isolated dermal papilla significantly decreased with age. (a) Linear regression analysis; **, P < 0.01. (b) ANOVA analysis in three age groups; **, P < 0.01. Representative 3D reconstructions of the dermal papilla zone (DPZ) obtained from the volar forearm of (c) 28-, (d) 47-, (e) 69-year-old subjects. Only SHG signals from XYZ image stacks within the DPZ were used in the reconstruction, which revealed the structure of isolated dermal papillae. The coordinate axes were added beside the reconstructions with the z-axis pointed to the lower dermis. It was shown that the average height of isolated dermal papilla (H), the depth of DPZ (T), and the 3D interdigitation index (I) decreased with age.
Fig. 9
Fig. 9 The collagen density of the dermal papilla zone over volar forearms was not significantly altered with age. (a, c) The CLAHE-enhanced images. (b, d) The results of binary collagen segmentation overlaid on original images. The match between collagen segmentation and the original image is great. (a, b) The collagen density in a 20-year-old male was calculated to be 0.379, meaning that collagen occupies 37.9% of the DPZ. (c, d) The collagen density in a 63-year-old male was calculated to be 0.372. The density values matched our intuition that subfigures a and c had similar collagen density. (e, f) Statistical analyses of the outputs of density analysis algorithm with age by linear regression (e) and one-way ANOVA (f). No significant correlation could be found. The data were presented as mean ± standard deviation.

Tables (1)

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Table 1 Correlation between age and DPZ parameters

Equations (4)

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A<C D l ,
C D l <A<C D u P< P thr .
P Perimete r 2 A ,
v(s)=exp( R 2 2 B 2 )(1exp( S 2 2 C 2 ))

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