Abstract

Recent clinical studies on human skin indicated that in vivo multi-harmonic generation microscopy (HGM) can achieve sub-micron resolution for histopathological analysis with a high penetration depth and leave no energy or photodamages in the interacted tissues. It is thus highly desired to apply HGM for in vivo mucosa histopathological diagnosis. In this paper, the first in vivo optical virtual biopsy of human oral mucosa by using epi-HGM is demonstrated. We modified an upright microscope to rotate the angle of objective for in vivo observation. Our clinical study reveals the capability of HGM to in vivo image cell distributions in human oral mucosa, including epithelium and lamina propria with a high penetration depth greater than 280 μm and a high spatial resolution better than 500 nm. We also found that the third-harmonic-generation (THG) contrast on nucleus depends strongly on its thicknesses, in agreement with a numerical simulation. Besides, 4% acetic acid was found to be able to enhance the THG contrast of nucleus in oral mucosa, while such enhancement was found to decay due to the metabolic clearance of the contrast enhancer by the oral mucosa. Our clinical study indicated that, the combined epi-THG and epi-second-harmonic-generation (SHG) microscopy is a promising imaging tool for in vivo noninvasive optical virtual biopsy and disease diagnosis in human mucosa.

© 2011 OSA

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2010 (4)

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.-F. Chang, C.-H. Yu, and C.-K. Sun, “Multi-photon resonance enhancement of third harmonic generation in human oxyhemoglobin and deoxyhemoglobin,” J Biophotonics 3(10-11), 678–685 (2010).
[CrossRef] [PubMed]

A. H. Hande and M. S. Chaudhary, “Cytomorphometric analysis of buccal mucosa of tobacco chewers,” Rom. J. Morphol. Embryol. 51(3), 527–532 (2010).
[PubMed]

S.-H. Chia, T.-M. Liu, A. A. Ivanov, A. B. Fedotov, A. M. Zheltikov, M.-R. Tsai, M.-C. Chan, C.-H. Yu, and C.-K. Sun, “A sub-100 fs self-starting Cr:forsterite laser generating 1.4 W output power,” Opt. Express 18(23), 24085–24091 (2010).
[CrossRef] [PubMed]

2009 (2)

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]

N. Ozawa, Y. Sumi, K. Shimozato, C. Chong, and T. Kurabayashi, “In vivo imaging of human labial glands using advanced optical coherence tomography,” Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 108(3), 425–429 (2009).
[CrossRef] [PubMed]

2008 (4)

K. C. Maitland, A. M. Gillenwater, M. D. Williams, A. K. El-Naggar, M. R. Descour, and R. R. Richards-Kortum, “In vivo imaging of oral neoplasia using a miniaturized fiber optic confocal reflectance microscope,” Oral Oncol. 44(11), 1059–1066 (2008).
[CrossRef] [PubMed]

G. C. Zografos, F. Zagouri, T. N. Sergentanis, A. Nonni, D. Koulocheri, M. Fotou, E. Panopoulou, N. Pararas, C. Fotiadis, and J. Bramis, “Minimizing underestimation rate of microcalcifications excised via vacuum-assisted breast biopsy: a blind study,” Breast Cancer Res. Treat. 109(2), 397–402 (2008).
[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 embryos nerve systems by using harmonic generation microscopy and morphant technology,” J. Biomed. Opt. 13(6), 064041 (2008).
[CrossRef] [PubMed]

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).
[PubMed]

2007 (4)

C.-K. Sun, C.-H. Yu, S.-P. Tai, C.-T. Kung, I.-J. Wang, H.-C. Yu, H.-J. Huang, W.-J. Lee, Y.-F. Chan, and C.-K. Sun, “In vivo and ex vivo imaging of intra-tissue elastic fibers using third-harmonic-generation microscopy,” Opt. Express 15(18), 11167–11177 (2007).
[CrossRef] [PubMed]

S.-W. Chu, S.-P. Tai, M.-C. Chan, C.-K. Sun, I.-C. Hsiao, C.-H. Lin, Y.-C. Chen, and B.-L. Lin, “Thickness dependence of optical second harmonic generation in collagen fibrils,” Opt. Express 15(19), 12005–12010 (2007).
[CrossRef] [PubMed]

N. Houssami, S. Ciatto, I. Ellis, and D. Ambrogetti, “Underestimation of malignancy of breast core-needle biopsy: concepts and precise overall and category-specific estimates,” Cancer 109(3), 487–495 (2007).
[CrossRef] [PubMed]

W.-J. Lee, C.-H. Yu, S.-P. Tai, H.-Y. Huang, and C.-K. Sun, “Acetic acid as a cell nucleus contrast agent in third-harmonic generation microscopy,” J. Med. Biol. Eng. 27, 161–164 (2007).

2006 (4)

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] [PubMed]

J. M. Ridgway, W. B. Armstrong, S. Guo, U. Mahmood, J. Su, R. P. Jackson, T. Shibuya, R. L. Crumley, M. Gu, Z. Chen, and B. J. Wong, “In vivo optical coherence tomography of the human oral cavity and oropharynx,” Arch. Otolaryngol. Head Neck Surg. 132(10), 1074–1081 (2006).
[CrossRef] [PubMed]

T.-H. Tsai, S.-P. Tai, W.-J. Lee, H.-Y. Huang, Y.-H. Liao, and C.-K. Sun, “Optical signal degradation study in fixed human skin using confocal microscopy and higher-harmonic optical microscopy,” Opt. Express 14(2), 749–758 (2006).
[CrossRef] [PubMed]

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] [PubMed]

2005 (4)

2004 (4)

A. B. MacLean, “Acetowhite epithelium,” Gynecol. Oncol. 95(3), 691–694 (2004).
[CrossRef] [PubMed]

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] [PubMed]

P. Wilder-Smith, K. Osann, N. Hanna, N. E. Abbadi, M. Brenner, D. Messadi, and T. Krasieva, “In vivo multiphoton fluorescence imaging: a novel approach to oral malignancy,” Lasers Surg. Med. 35(2), 96–103 (2004).
[CrossRef] [PubMed]

J. Sun, T. Shilagard, B. Bell, M. Motamedi, and G. Vargas, “In vivo multimodal nonlinear optical imaging of mucosal tissue,” Opt. Express 12(11), 2478–2486 (2004).
[CrossRef] [PubMed]

2003 (1)

2002 (4)

J. M. Schins, T. Schrama, J. Squier, G. J. Brakenhoff, and M. Muller, “Determination of material properties by use of third-harmonic generation microscopy,” J. Opt. Soc. Am. B 19(7), 1627–1634 (2002).
[CrossRef]

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[CrossRef] [PubMed]

A. Myakov, L. Nieman, L. Wicky, U. Utzinger, R. Richards-Kortum, and K. Sokolov, “Fiber optic probe for polarized reflectance spectroscopy in vivo: design and performance,” J. Biomed. Opt. 7(3), 388–397 (2002).
[CrossRef] [PubMed]

K.-B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, and R. Richards-Kortum, “Fiber-optic confocal reflectance microscope with miniature objective for in vivo imaging of human tissues,” IEEE Trans. Biomed. Eng. 49(10), 1168–1172 (2002).
[CrossRef] [PubMed]

2001 (2)

2000 (2)

J. Sato, M. Yanai, T. Hirao, and M. Denda, “Water content and thickness of the stratum corneum contribute to skin surface morphology,” Arch. Dermatol. Res. 292(8), 412–417 (2000).
[CrossRef] [PubMed]

A. C. Millard, D. N. Fittinghoff, P. W. Wiseman, M. Muller, G. J. Brakenhoff, J. A. Squier, and K. R. Wilson, “Three dimensional, third harmonic microscopy of living systems,” Biophys. J. 78, 800 (2000).
[PubMed]

1999 (2)

W. M. White, M. Rajadhyaksha, S. González, R. L. Fabian, and R. R. Anderson, “Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy,” Laryngoscope 109(10), 1709–1717 (1999).
[CrossRef] [PubMed]

C. J. Balas, G. C. Themelis, E. P. Prokopakis, I. Orfanudaki, E. Koumantakis, and E. S. Helidonis, “In vivo detection and staging of epithelial dysplasias and malignancies based on the quantitative assessment of acetic acid-tissue interaction kinetics,” J. Photochem. Photobiol. B 53(1-3), 153–157 (1999).
[CrossRef] [PubMed]

1998 (1)

1996 (1)

1988 (1)

J. G. Cowpe, R. B. Longmore, and M. W. Green, “Quantitative exfoliative cytology of abnormal oral mucosal smears,” J. R. Soc. Med. 81(9), 509–513 (1988).
[PubMed]

1977 (1)

M. A. Landay and H. E. Schroeder, “Quantitative electron microscopic analysis of the stratified epithelium of normal human buccal mucosa,” Cell Tissue Res. 177(3), 383–405 (1977).
[CrossRef] [PubMed]

Abbadi, N. E.

P. Wilder-Smith, K. Osann, N. Hanna, N. E. Abbadi, M. Brenner, D. Messadi, and T. Krasieva, “In vivo multiphoton fluorescence imaging: a novel approach to oral malignancy,” Lasers Surg. Med. 35(2), 96–103 (2004).
[CrossRef] [PubMed]

Ambrogetti, D.

N. Houssami, S. Ciatto, I. Ellis, and D. Ambrogetti, “Underestimation of malignancy of breast core-needle biopsy: concepts and precise overall and category-specific estimates,” Cancer 109(3), 487–495 (2007).
[CrossRef] [PubMed]

Anderson, R. R.

W. M. White, M. Rajadhyaksha, S. González, R. L. Fabian, and R. R. Anderson, “Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy,” Laryngoscope 109(10), 1709–1717 (1999).
[CrossRef] [PubMed]

Armstrong, W. B.

J. M. Ridgway, W. B. Armstrong, S. Guo, U. Mahmood, J. Su, R. P. Jackson, T. Shibuya, R. L. Crumley, M. Gu, Z. Chen, and B. J. Wong, “In vivo optical coherence tomography of the human oral cavity and oropharynx,” Arch. Otolaryngol. Head Neck Surg. 132(10), 1074–1081 (2006).
[CrossRef] [PubMed]

Aus der Au, J.

Balas, C. J.

C. J. Balas, G. C. Themelis, E. P. Prokopakis, I. Orfanudaki, E. Koumantakis, and E. S. Helidonis, “In vivo detection and staging of epithelial dysplasias and malignancies based on the quantitative assessment of acetic acid-tissue interaction kinetics,” J. Photochem. Photobiol. B 53(1-3), 153–157 (1999).
[CrossRef] [PubMed]

Barzda, V.

Bell, B.

Bilinsky, I. P.

Bouma, B. E.

Brakenhoff, G. J.

J. M. Schins, T. Schrama, J. Squier, G. J. Brakenhoff, and M. Muller, “Determination of material properties by use of third-harmonic generation microscopy,” J. Opt. Soc. Am. B 19(7), 1627–1634 (2002).
[CrossRef]

A. C. Millard, D. N. Fittinghoff, P. W. Wiseman, M. Muller, G. J. Brakenhoff, J. A. Squier, and K. R. Wilson, “Three dimensional, third harmonic microscopy of living systems,” Biophys. J. 78, 800 (2000).
[PubMed]

Bramis, J.

G. C. Zografos, F. Zagouri, T. N. Sergentanis, A. Nonni, D. Koulocheri, M. Fotou, E. Panopoulou, N. Pararas, C. Fotiadis, and J. Bramis, “Minimizing underestimation rate of microcalcifications excised via vacuum-assisted breast biopsy: a blind study,” Breast Cancer Res. Treat. 109(2), 397–402 (2008).
[CrossRef] [PubMed]

Brenner, M.

P. Wilder-Smith, K. Osann, N. Hanna, N. E. Abbadi, M. Brenner, D. Messadi, and T. Krasieva, “In vivo multiphoton fluorescence imaging: a novel approach to oral malignancy,” Lasers Surg. Med. 35(2), 96–103 (2004).
[CrossRef] [PubMed]

Chan, M.-C.

Chan, Y.-F.

Chang, C.-F.

C.-F. Chang, C.-H. Yu, and C.-K. Sun, “Multi-photon resonance enhancement of third harmonic generation in human oxyhemoglobin and deoxyhemoglobin,” J Biophotonics 3(10-11), 678–685 (2010).
[CrossRef] [PubMed]

Chaudhary, M. S.

A. H. Hande and M. S. Chaudhary, “Cytomorphometric analysis of buccal mucosa of tobacco chewers,” Rom. J. Morphol. Embryol. 51(3), 527–532 (2010).
[PubMed]

Chen, I.-H.

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[CrossRef] [PubMed]

S.-W. Chu, I.-H. Chen, T.-M. Liu, P. C. Chen, C.-K. Sun, and B.-L. Lin, “Multimodal nonlinear spectral microscopy based on a femtosecond Cr:forsterite laser,” Opt. Lett. 26(23), 1909–1911 (2001).
[CrossRef] [PubMed]

Chen, P. C.

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).
[PubMed]

Chen, S.-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]

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 embryos nerve systems by using harmonic generation microscopy and morphant technology,” J. Biomed. Opt. 13(6), 064041 (2008).
[CrossRef] [PubMed]

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] [PubMed]

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] [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]

Chen, Y.-C.

S.-W. Chu, S.-P. Tai, M.-C. Chan, C.-K. Sun, I.-C. Hsiao, C.-H. Lin, Y.-C. Chen, and B.-L. Lin, “Thickness dependence of optical second harmonic generation in collagen fibrils,” Opt. Express 15(19), 12005–12010 (2007).
[CrossRef] [PubMed]

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] [PubMed]

Chen, Z.

J. M. Ridgway, W. B. Armstrong, S. Guo, U. Mahmood, J. Su, R. P. Jackson, T. Shibuya, R. L. Crumley, M. Gu, Z. Chen, and B. J. Wong, “In vivo optical coherence tomography of the human oral cavity and oropharynx,” Arch. Otolaryngol. Head Neck Surg. 132(10), 1074–1081 (2006).
[CrossRef] [PubMed]

Cheng, P.-C.

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[CrossRef] [PubMed]

Chia, S.-H.

Chong, C.

N. Ozawa, Y. Sumi, K. Shimozato, C. Chong, and T. Kurabayashi, “In vivo imaging of human labial glands using advanced optical coherence tomography,” Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 108(3), 425–429 (2009).
[CrossRef] [PubMed]

Chu, S.-W.

S.-W. Chu, S.-P. Tai, M.-C. Chan, C.-K. Sun, I.-C. Hsiao, C.-H. Lin, Y.-C. Chen, and B.-L. Lin, “Thickness dependence of optical second harmonic generation in collagen fibrils,” Opt. Express 15(19), 12005–12010 (2007).
[CrossRef] [PubMed]

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] [PubMed]

S.-W. Chu, S.-P. Tai, C.-L. Ho, C.-H. Lin, and C.-K. Sun, “High-resolution simultaneous three-photon fluorescence and third-harmonic-generation microscopy,” Microsc. Res. Tech. 66(4), 193–197 (2005).
[CrossRef] [PubMed]

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] [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]

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[CrossRef] [PubMed]

S.-W. Chu, I.-H. Chen, T.-M. Liu, P. C. Chen, C.-K. Sun, and B.-L. Lin, “Multimodal nonlinear spectral microscopy based on a femtosecond Cr:forsterite laser,” Opt. Lett. 26(23), 1909–1911 (2001).
[CrossRef] [PubMed]

Ciatto, S.

N. Houssami, S. Ciatto, I. Ellis, and D. Ambrogetti, “Underestimation of malignancy of breast core-needle biopsy: concepts and precise overall and category-specific estimates,” Cancer 109(3), 487–495 (2007).
[CrossRef] [PubMed]

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K.-B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, and R. Richards-Kortum, “Fiber-optic confocal reflectance microscope with miniature objective for in vivo imaging of human tissues,” IEEE Trans. Biomed. Eng. 49(10), 1168–1172 (2002).
[CrossRef] [PubMed]

Cowpe, J. G.

J. G. Cowpe, R. B. Longmore, and M. W. Green, “Quantitative exfoliative cytology of abnormal oral mucosal smears,” J. R. Soc. Med. 81(9), 509–513 (1988).
[PubMed]

Crumley, R. L.

J. M. Ridgway, W. B. Armstrong, S. Guo, U. Mahmood, J. Su, R. P. Jackson, T. Shibuya, R. L. Crumley, M. Gu, Z. Chen, and B. J. Wong, “In vivo optical coherence tomography of the human oral cavity and oropharynx,” Arch. Otolaryngol. Head Neck Surg. 132(10), 1074–1081 (2006).
[CrossRef] [PubMed]

Denda, M.

J. Sato, M. Yanai, T. Hirao, and M. Denda, “Water content and thickness of the stratum corneum contribute to skin surface morphology,” Arch. Dermatol. Res. 292(8), 412–417 (2000).
[CrossRef] [PubMed]

Descour, M.

K.-B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, and R. Richards-Kortum, “Fiber-optic confocal reflectance microscope with miniature objective for in vivo imaging of human tissues,” IEEE Trans. Biomed. Eng. 49(10), 1168–1172 (2002).
[CrossRef] [PubMed]

Descour, M. R.

K. C. Maitland, A. M. Gillenwater, M. D. Williams, A. K. El-Naggar, M. R. Descour, and R. R. Richards-Kortum, “In vivo imaging of oral neoplasia using a miniaturized fiber optic confocal reflectance microscope,” Oral Oncol. 44(11), 1059–1066 (2008).
[CrossRef] [PubMed]

Ellis, I.

N. Houssami, S. Ciatto, I. Ellis, and D. Ambrogetti, “Underestimation of malignancy of breast core-needle biopsy: concepts and precise overall and category-specific estimates,” Cancer 109(3), 487–495 (2007).
[CrossRef] [PubMed]

Elmore, S.

El-Naggar, A. K.

K. C. Maitland, A. M. Gillenwater, M. D. Williams, A. K. El-Naggar, M. R. Descour, and R. R. Richards-Kortum, “In vivo imaging of oral neoplasia using a miniaturized fiber optic confocal reflectance microscope,” Oral Oncol. 44(11), 1059–1066 (2008).
[CrossRef] [PubMed]

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W. M. White, M. Rajadhyaksha, S. González, R. L. Fabian, and R. R. Anderson, “Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy,” Laryngoscope 109(10), 1709–1717 (1999).
[CrossRef] [PubMed]

Fedotov, A. B.

Feldchtein, F.

Fittinghoff, D. N.

A. C. Millard, D. N. Fittinghoff, P. W. Wiseman, M. Muller, G. J. Brakenhoff, J. A. Squier, and K. R. Wilson, “Three dimensional, third harmonic microscopy of living systems,” Biophys. J. 78, 800 (2000).
[PubMed]

Follen, M.

K.-B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, and R. Richards-Kortum, “Fiber-optic confocal reflectance microscope with miniature objective for in vivo imaging of human tissues,” IEEE Trans. Biomed. Eng. 49(10), 1168–1172 (2002).
[CrossRef] [PubMed]

Fotiadis, C.

G. C. Zografos, F. Zagouri, T. N. Sergentanis, A. Nonni, D. Koulocheri, M. Fotou, E. Panopoulou, N. Pararas, C. Fotiadis, and J. Bramis, “Minimizing underestimation rate of microcalcifications excised via vacuum-assisted breast biopsy: a blind study,” Breast Cancer Res. Treat. 109(2), 397–402 (2008).
[CrossRef] [PubMed]

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G. C. Zografos, F. Zagouri, T. N. Sergentanis, A. Nonni, D. Koulocheri, M. Fotou, E. Panopoulou, N. Pararas, C. Fotiadis, and J. Bramis, “Minimizing underestimation rate of microcalcifications excised via vacuum-assisted breast biopsy: a blind study,” Breast Cancer Res. Treat. 109(2), 397–402 (2008).
[CrossRef] [PubMed]

Fujimoto, J. G.

Gelikonov, G.

Gelikonov, V.

Gillenwater, A. M.

K. C. Maitland, A. M. Gillenwater, M. D. Williams, A. K. El-Naggar, M. R. Descour, and R. R. Richards-Kortum, “In vivo imaging of oral neoplasia using a miniaturized fiber optic confocal reflectance microscope,” Oral Oncol. 44(11), 1059–1066 (2008).
[CrossRef] [PubMed]

Gladkova, N.

Golubovic, B.

González, S.

W. M. White, M. Rajadhyaksha, S. González, R. L. Fabian, and R. R. Anderson, “Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy,” Laryngoscope 109(10), 1709–1717 (1999).
[CrossRef] [PubMed]

Green, M. W.

J. G. Cowpe, R. B. Longmore, and M. W. Green, “Quantitative exfoliative cytology of abnormal oral mucosal smears,” J. R. Soc. Med. 81(9), 509–513 (1988).
[PubMed]

Greenhalgh, C.

Gu, M.

J. M. Ridgway, W. B. Armstrong, S. Guo, U. Mahmood, J. Su, R. P. Jackson, T. Shibuya, R. L. Crumley, M. Gu, Z. Chen, and B. J. Wong, “In vivo optical coherence tomography of the human oral cavity and oropharynx,” Arch. Otolaryngol. Head Neck Surg. 132(10), 1074–1081 (2006).
[CrossRef] [PubMed]

Guo, S.

J. M. Ridgway, W. B. Armstrong, S. Guo, U. Mahmood, J. Su, R. P. Jackson, T. Shibuya, R. L. Crumley, M. Gu, Z. Chen, and B. J. Wong, “In vivo optical coherence tomography of the human oral cavity and oropharynx,” Arch. Otolaryngol. Head Neck Surg. 132(10), 1074–1081 (2006).
[CrossRef] [PubMed]

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A. H. Hande and M. S. Chaudhary, “Cytomorphometric analysis of buccal mucosa of tobacco chewers,” Rom. J. Morphol. Embryol. 51(3), 527–532 (2010).
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P. Wilder-Smith, K. Osann, N. Hanna, N. E. Abbadi, M. Brenner, D. Messadi, and T. Krasieva, “In vivo multiphoton fluorescence imaging: a novel approach to oral malignancy,” Lasers Surg. Med. 35(2), 96–103 (2004).
[CrossRef] [PubMed]

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C. J. Balas, G. C. Themelis, E. P. Prokopakis, I. Orfanudaki, E. Koumantakis, and E. S. Helidonis, “In vivo detection and staging of epithelial dysplasias and malignancies based on the quantitative assessment of acetic acid-tissue interaction kinetics,” J. Photochem. Photobiol. B 53(1-3), 153–157 (1999).
[CrossRef] [PubMed]

Hirao, T.

J. Sato, M. Yanai, T. Hirao, and M. Denda, “Water content and thickness of the stratum corneum contribute to skin surface morphology,” Arch. Dermatol. Res. 292(8), 412–417 (2000).
[CrossRef] [PubMed]

Ho, C.-L.

S.-W. Chu, S.-P. Tai, C.-L. Ho, C.-H. Lin, and C.-K. Sun, “High-resolution simultaneous three-photon fluorescence and third-harmonic-generation microscopy,” Microsc. Res. Tech. 66(4), 193–197 (2005).
[CrossRef] [PubMed]

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A. Hopt and E. Neher, “Highly nonlinear photodamage in two-photon fluorescence microscopy,” Biophys. J. 80(4), 2029–2036 (2001).
[CrossRef] [PubMed]

Houssami, N.

N. Houssami, S. Ciatto, I. Ellis, and D. Ambrogetti, “Underestimation of malignancy of breast core-needle biopsy: concepts and precise overall and category-specific estimates,” Cancer 109(3), 487–495 (2007).
[CrossRef] [PubMed]

Hsiao, I.-C.

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 embryos nerve systems by using harmonic generation microscopy and morphant technology,” J. Biomed. Opt. 13(6), 064041 (2008).
[CrossRef] [PubMed]

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).
[PubMed]

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] [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 embryos nerve systems by using harmonic generation microscopy and morphant technology,” J. Biomed. Opt. 13(6), 064041 (2008).
[CrossRef] [PubMed]

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] [PubMed]

Huang, H.-J.

Huang, H.-Y.

Iksanov, R.

Ivanov, A. A.

Jackson, R. P.

J. M. Ridgway, W. B. Armstrong, S. Guo, U. Mahmood, J. Su, R. P. Jackson, T. Shibuya, R. L. Crumley, M. Gu, Z. Chen, and B. J. Wong, “In vivo optical coherence tomography of the human oral cavity and oropharynx,” Arch. Otolaryngol. Head Neck Surg. 132(10), 1074–1081 (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 embryos nerve systems by using harmonic generation microscopy and morphant technology,” J. Biomed. Opt. 13(6), 064041 (2008).
[CrossRef] [PubMed]

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] [PubMed]

Koulocheri, D.

G. C. Zografos, F. Zagouri, T. N. Sergentanis, A. Nonni, D. Koulocheri, M. Fotou, E. Panopoulou, N. Pararas, C. Fotiadis, and J. Bramis, “Minimizing underestimation rate of microcalcifications excised via vacuum-assisted breast biopsy: a blind study,” Breast Cancer Res. Treat. 109(2), 397–402 (2008).
[CrossRef] [PubMed]

Koumantakis, E.

C. J. Balas, G. C. Themelis, E. P. Prokopakis, I. Orfanudaki, E. Koumantakis, and E. S. Helidonis, “In vivo detection and staging of epithelial dysplasias and malignancies based on the quantitative assessment of acetic acid-tissue interaction kinetics,” J. Photochem. Photobiol. B 53(1-3), 153–157 (1999).
[CrossRef] [PubMed]

Krasieva, T.

P. Wilder-Smith, K. Osann, N. Hanna, N. E. Abbadi, M. Brenner, D. Messadi, and T. Krasieva, “In vivo multiphoton fluorescence imaging: a novel approach to oral malignancy,” Lasers Surg. Med. 35(2), 96–103 (2004).
[CrossRef] [PubMed]

Kung, C.-T.

Kuo, M.-X.

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[CrossRef] [PubMed]

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N. Ozawa, Y. Sumi, K. Shimozato, C. Chong, and T. Kurabayashi, “In vivo imaging of human labial glands using advanced optical coherence tomography,” Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 108(3), 425–429 (2009).
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Kuranov, R.

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M. A. Landay and H. E. Schroeder, “Quantitative electron microscopic analysis of the stratified epithelium of normal human buccal mucosa,” Cell Tissue Res. 177(3), 383–405 (1977).
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Lee, S.-P.

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[CrossRef] [PubMed]

Lee, W.-J.

Lee, Y.-W.

Liang, C.

K.-B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, and R. Richards-Kortum, “Fiber-optic confocal reflectance microscope with miniature objective for in vivo imaging of human tissues,” IEEE Trans. Biomed. Eng. 49(10), 1168–1172 (2002).
[CrossRef] [PubMed]

Liao, Y.-H.

Lin, B.-L.

Lin, C.-H.

S.-W. Chu, S.-P. Tai, M.-C. Chan, C.-K. Sun, I.-C. Hsiao, C.-H. Lin, Y.-C. Chen, and B.-L. Lin, “Thickness dependence of optical second harmonic generation in collagen fibrils,” Opt. Express 15(19), 12005–12010 (2007).
[CrossRef] [PubMed]

S.-W. Chu, S.-P. Tai, C.-L. Ho, C.-H. Lin, and C.-K. Sun, “High-resolution simultaneous three-photon fluorescence and third-harmonic-generation microscopy,” Microsc. Res. Tech. 66(4), 193–197 (2005).
[CrossRef] [PubMed]

Lin, C.-Y.

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] [PubMed]

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] [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]

Lin, D.-J.

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[CrossRef] [PubMed]

Liu, H.-L.

S.-P. Tai, T.-H. Tsai, W.-J. Lee, D.-B. Shieh, Y.-H. Liao, H.-Y. Huang, K. Y.-J. Zhang, H.-L. Liu, and C.-K. Sun, “Optical biopsy of fixed human skin with backward-collected optical harmonics signals,” Opt. Express 13(20), 8231–8242 (2005).
[CrossRef] [PubMed]

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[CrossRef] [PubMed]

Liu, T.-M.

S.-H. Chia, T.-M. Liu, A. A. Ivanov, A. B. Fedotov, A. M. Zheltikov, M.-R. Tsai, M.-C. Chan, C.-H. Yu, and C.-K. Sun, “A sub-100 fs self-starting Cr:forsterite laser generating 1.4 W output power,” Opt. Express 18(23), 24085–24091 (2010).
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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 embryos nerve systems by using harmonic generation microscopy and morphant technology,” J. Biomed. Opt. 13(6), 064041 (2008).
[CrossRef] [PubMed]

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] [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]

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[CrossRef] [PubMed]

S.-W. Chu, I.-H. Chen, T.-M. Liu, P. C. Chen, C.-K. Sun, and B.-L. Lin, “Multimodal nonlinear spectral microscopy based on a femtosecond Cr:forsterite laser,” Opt. Lett. 26(23), 1909–1911 (2001).
[CrossRef] [PubMed]

Longmore, R. B.

J. G. Cowpe, R. B. Longmore, and M. W. Green, “Quantitative exfoliative cytology of abnormal oral mucosal smears,” J. R. Soc. Med. 81(9), 509–513 (1988).
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A. B. MacLean, “Acetowhite epithelium,” Gynecol. Oncol. 95(3), 691–694 (2004).
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J. M. Ridgway, W. B. Armstrong, S. Guo, U. Mahmood, J. Su, R. P. Jackson, T. Shibuya, R. L. Crumley, M. Gu, Z. Chen, and B. J. Wong, “In vivo optical coherence tomography of the human oral cavity and oropharynx,” Arch. Otolaryngol. Head Neck Surg. 132(10), 1074–1081 (2006).
[CrossRef] [PubMed]

Maitland, K. C.

K. C. Maitland, A. M. Gillenwater, M. D. Williams, A. K. El-Naggar, M. R. Descour, and R. R. Richards-Kortum, “In vivo imaging of oral neoplasia using a miniaturized fiber optic confocal reflectance microscope,” Oral Oncol. 44(11), 1059–1066 (2008).
[CrossRef] [PubMed]

Messadi, D.

P. Wilder-Smith, K. Osann, N. Hanna, N. E. Abbadi, M. Brenner, D. Messadi, and T. Krasieva, “In vivo multiphoton fluorescence imaging: a novel approach to oral malignancy,” Lasers Surg. Med. 35(2), 96–103 (2004).
[CrossRef] [PubMed]

Millard, A. C.

A. C. Millard, D. N. Fittinghoff, P. W. Wiseman, M. Muller, G. J. Brakenhoff, J. A. Squier, and K. R. Wilson, “Three dimensional, third harmonic microscopy of living systems,” Biophys. J. 78, 800 (2000).
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Motamedi, M.

Muller, M.

J. M. Schins, T. Schrama, J. Squier, G. J. Brakenhoff, and M. Muller, “Determination of material properties by use of third-harmonic generation microscopy,” J. Opt. Soc. Am. B 19(7), 1627–1634 (2002).
[CrossRef]

A. C. Millard, D. N. Fittinghoff, P. W. Wiseman, M. Muller, G. J. Brakenhoff, J. A. Squier, and K. R. Wilson, “Three dimensional, third harmonic microscopy of living systems,” Biophys. J. 78, 800 (2000).
[PubMed]

Myakov, A.

A. Myakov, L. Nieman, L. Wicky, U. Utzinger, R. Richards-Kortum, and K. Sokolov, “Fiber optic probe for polarized reflectance spectroscopy in vivo: design and performance,” J. Biomed. Opt. 7(3), 388–397 (2002).
[CrossRef] [PubMed]

Neher, E.

A. Hopt and E. Neher, “Highly nonlinear photodamage in two-photon fluorescence microscopy,” Biophys. J. 80(4), 2029–2036 (2001).
[CrossRef] [PubMed]

Nieman, L.

A. Myakov, L. Nieman, L. Wicky, U. Utzinger, R. Richards-Kortum, and K. Sokolov, “Fiber optic probe for polarized reflectance spectroscopy in vivo: design and performance,” J. Biomed. Opt. 7(3), 388–397 (2002).
[CrossRef] [PubMed]

Nonni, A.

G. C. Zografos, F. Zagouri, T. N. Sergentanis, A. Nonni, D. Koulocheri, M. Fotou, E. Panopoulou, N. Pararas, C. Fotiadis, and J. Bramis, “Minimizing underestimation rate of microcalcifications excised via vacuum-assisted breast biopsy: a blind study,” Breast Cancer Res. Treat. 109(2), 397–402 (2008).
[CrossRef] [PubMed]

Orfanudaki, I.

C. J. Balas, G. C. Themelis, E. P. Prokopakis, I. Orfanudaki, E. Koumantakis, and E. S. Helidonis, “In vivo detection and staging of epithelial dysplasias and malignancies based on the quantitative assessment of acetic acid-tissue interaction kinetics,” J. Photochem. Photobiol. B 53(1-3), 153–157 (1999).
[CrossRef] [PubMed]

Osann, K.

P. Wilder-Smith, K. Osann, N. Hanna, N. E. Abbadi, M. Brenner, D. Messadi, and T. Krasieva, “In vivo multiphoton fluorescence imaging: a novel approach to oral malignancy,” Lasers Surg. Med. 35(2), 96–103 (2004).
[CrossRef] [PubMed]

Ourutina, M.

Ozawa, N.

N. Ozawa, Y. Sumi, K. Shimozato, C. Chong, and T. Kurabayashi, “In vivo imaging of human labial glands using advanced optical coherence tomography,” Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 108(3), 425–429 (2009).
[CrossRef] [PubMed]

Panopoulou, E.

G. C. Zografos, F. Zagouri, T. N. Sergentanis, A. Nonni, D. Koulocheri, M. Fotou, E. Panopoulou, N. Pararas, C. Fotiadis, and J. Bramis, “Minimizing underestimation rate of microcalcifications excised via vacuum-assisted breast biopsy: a blind study,” Breast Cancer Res. Treat. 109(2), 397–402 (2008).
[CrossRef] [PubMed]

Pararas, N.

G. C. Zografos, F. Zagouri, T. N. Sergentanis, A. Nonni, D. Koulocheri, M. Fotou, E. Panopoulou, N. Pararas, C. Fotiadis, and J. Bramis, “Minimizing underestimation rate of microcalcifications excised via vacuum-assisted breast biopsy: a blind study,” Breast Cancer Res. Treat. 109(2), 397–402 (2008).
[CrossRef] [PubMed]

Prokopakis, E. P.

C. J. Balas, G. C. Themelis, E. P. Prokopakis, I. Orfanudaki, E. Koumantakis, and E. S. Helidonis, “In vivo detection and staging of epithelial dysplasias and malignancies based on the quantitative assessment of acetic acid-tissue interaction kinetics,” J. Photochem. Photobiol. B 53(1-3), 153–157 (1999).
[CrossRef] [PubMed]

Rajadhyaksha, M.

W. M. White, M. Rajadhyaksha, S. González, R. L. Fabian, and R. R. Anderson, “Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy,” Laryngoscope 109(10), 1709–1717 (1999).
[CrossRef] [PubMed]

Reitze, D.

Richards-Kortum, R.

A. Myakov, L. Nieman, L. Wicky, U. Utzinger, R. Richards-Kortum, and K. Sokolov, “Fiber optic probe for polarized reflectance spectroscopy in vivo: design and performance,” J. Biomed. Opt. 7(3), 388–397 (2002).
[CrossRef] [PubMed]

K.-B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, and R. Richards-Kortum, “Fiber-optic confocal reflectance microscope with miniature objective for in vivo imaging of human tissues,” IEEE Trans. Biomed. Eng. 49(10), 1168–1172 (2002).
[CrossRef] [PubMed]

Richards-Kortum, R. R.

K. C. Maitland, A. M. Gillenwater, M. D. Williams, A. K. El-Naggar, M. R. Descour, and R. R. Richards-Kortum, “In vivo imaging of oral neoplasia using a miniaturized fiber optic confocal reflectance microscope,” Oral Oncol. 44(11), 1059–1066 (2008).
[CrossRef] [PubMed]

Ridgway, J. M.

J. M. Ridgway, W. B. Armstrong, S. Guo, U. Mahmood, J. Su, R. P. Jackson, T. Shibuya, R. L. Crumley, M. Gu, Z. Chen, and B. J. Wong, “In vivo optical coherence tomography of the human oral cavity and oropharynx,” Arch. Otolaryngol. Head Neck Surg. 132(10), 1074–1081 (2006).
[CrossRef] [PubMed]

Sato, J.

J. Sato, M. Yanai, T. Hirao, and M. Denda, “Water content and thickness of the stratum corneum contribute to skin surface morphology,” Arch. Dermatol. Res. 292(8), 412–417 (2000).
[CrossRef] [PubMed]

Schins, J. M.

Schrama, T.

Schroeder, H. E.

M. A. Landay and H. E. Schroeder, “Quantitative electron microscopic analysis of the stratified epithelium of normal human buccal mucosa,” Cell Tissue Res. 177(3), 383–405 (1977).
[CrossRef] [PubMed]

Sergeev, A.

Sergentanis, T. N.

G. C. Zografos, F. Zagouri, T. N. Sergentanis, A. Nonni, D. Koulocheri, M. Fotou, E. Panopoulou, N. Pararas, C. Fotiadis, and J. Bramis, “Minimizing underestimation rate of microcalcifications excised via vacuum-assisted breast biopsy: a blind study,” Breast Cancer Res. Treat. 109(2), 397–402 (2008).
[CrossRef] [PubMed]

Shibuya, T.

J. M. Ridgway, W. B. Armstrong, S. Guo, U. Mahmood, J. Su, R. P. Jackson, T. Shibuya, R. L. Crumley, M. Gu, Z. Chen, and B. J. Wong, “In vivo optical coherence tomography of the human oral cavity and oropharynx,” Arch. Otolaryngol. Head Neck Surg. 132(10), 1074–1081 (2006).
[CrossRef] [PubMed]

Shieh, D.-B.

Shilagard, T.

Shimozato, K.

N. Ozawa, Y. Sumi, K. Shimozato, C. Chong, and T. Kurabayashi, “In vivo imaging of human labial glands using advanced optical coherence tomography,” Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 108(3), 425–429 (2009).
[CrossRef] [PubMed]

Sokolov, K.

A. Myakov, L. Nieman, L. Wicky, U. Utzinger, R. Richards-Kortum, and K. Sokolov, “Fiber optic probe for polarized reflectance spectroscopy in vivo: design and performance,” J. Biomed. Opt. 7(3), 388–397 (2002).
[CrossRef] [PubMed]

Squier, J.

Squier, J. A.

A. C. Millard, D. N. Fittinghoff, P. W. Wiseman, M. Muller, G. J. Brakenhoff, J. A. Squier, and K. R. Wilson, “Three dimensional, third harmonic microscopy of living systems,” Biophys. J. 78, 800 (2000).
[PubMed]

Su, J.

J. M. Ridgway, W. B. Armstrong, S. Guo, U. Mahmood, J. Su, R. P. Jackson, T. Shibuya, R. L. Crumley, M. Gu, Z. Chen, and B. J. Wong, “In vivo optical coherence tomography of the human oral cavity and oropharynx,” Arch. Otolaryngol. Head Neck Surg. 132(10), 1074–1081 (2006).
[CrossRef] [PubMed]

Sumi, Y.

N. Ozawa, Y. Sumi, K. Shimozato, C. Chong, and T. Kurabayashi, “In vivo imaging of human labial glands using advanced optical coherence tomography,” Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 108(3), 425–429 (2009).
[CrossRef] [PubMed]

Sun, C.-K.

C.-F. Chang, C.-H. Yu, and C.-K. Sun, “Multi-photon resonance enhancement of third harmonic generation in human oxyhemoglobin and deoxyhemoglobin,” J Biophotonics 3(10-11), 678–685 (2010).
[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.-H. Chia, T.-M. Liu, A. A. Ivanov, A. B. Fedotov, A. M. Zheltikov, M.-R. Tsai, M.-C. Chan, C.-H. Yu, and C.-K. Sun, “A sub-100 fs self-starting Cr:forsterite laser generating 1.4 W output power,” Opt. Express 18(23), 24085–24091 (2010).
[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]

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 embryos nerve systems by using harmonic generation microscopy and morphant technology,” J. Biomed. Opt. 13(6), 064041 (2008).
[CrossRef] [PubMed]

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).
[PubMed]

C.-K. Sun, C.-H. Yu, S.-P. Tai, C.-T. Kung, I.-J. Wang, H.-C. Yu, H.-J. Huang, W.-J. Lee, Y.-F. Chan, and C.-K. Sun, “In vivo and ex vivo imaging of intra-tissue elastic fibers using third-harmonic-generation microscopy,” Opt. Express 15(18), 11167–11177 (2007).
[CrossRef] [PubMed]

C.-K. Sun, C.-H. Yu, S.-P. Tai, C.-T. Kung, I.-J. Wang, H.-C. Yu, H.-J. Huang, W.-J. Lee, Y.-F. Chan, and C.-K. Sun, “In vivo and ex vivo imaging of intra-tissue elastic fibers using third-harmonic-generation microscopy,” Opt. Express 15(18), 11167–11177 (2007).
[CrossRef] [PubMed]

W.-J. Lee, C.-H. Yu, S.-P. Tai, H.-Y. Huang, and C.-K. Sun, “Acetic acid as a cell nucleus contrast agent in third-harmonic generation microscopy,” J. Med. Biol. Eng. 27, 161–164 (2007).

S.-W. Chu, S.-P. Tai, M.-C. Chan, C.-K. Sun, I.-C. Hsiao, C.-H. Lin, Y.-C. Chen, and B.-L. Lin, “Thickness dependence of optical second harmonic generation in collagen fibrils,” Opt. Express 15(19), 12005–12010 (2007).
[CrossRef] [PubMed]

T.-H. Tsai, S.-P. Tai, W.-J. Lee, H.-Y. Huang, Y.-H. Liao, and C.-K. Sun, “Optical signal degradation study in fixed human skin using confocal microscopy and higher-harmonic optical microscopy,” Opt. Express 14(2), 749–758 (2006).
[CrossRef] [PubMed]

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] [PubMed]

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] [PubMed]

S.-P. Tai, T.-H. Tsai, W.-J. Lee, D.-B. Shieh, Y.-H. Liao, H.-Y. Huang, K. Y.-J. Zhang, H.-L. Liu, and C.-K. Sun, “Optical biopsy of fixed human skin with backward-collected optical harmonics signals,” Opt. Express 13(20), 8231–8242 (2005).
[CrossRef] [PubMed]

C.-K. Sun, “Higher harmonic generation microscopy,” Adv. Biochem. Eng. Biotechnol. 95, 17–56 (2005).
[PubMed]

S.-W. Chu, S.-P. Tai, C.-L. Ho, C.-H. Lin, and C.-K. Sun, “High-resolution simultaneous three-photon fluorescence and third-harmonic-generation microscopy,” Microsc. Res. Tech. 66(4), 193–197 (2005).
[CrossRef] [PubMed]

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] [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]

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[CrossRef] [PubMed]

S.-W. Chu, I.-H. Chen, T.-M. Liu, P. C. Chen, C.-K. Sun, and B.-L. Lin, “Multimodal nonlinear spectral microscopy based on a femtosecond Cr:forsterite laser,” Opt. Lett. 26(23), 1909–1911 (2001).
[CrossRef] [PubMed]

Sun, J.

Sung, K.-B.

K.-B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, and R. Richards-Kortum, “Fiber-optic confocal reflectance microscope with miniature objective for in vivo imaging of human tissues,” IEEE Trans. Biomed. Eng. 49(10), 1168–1172 (2002).
[CrossRef] [PubMed]

Tai, S.-P.

S.-W. Chu, S.-P. Tai, M.-C. Chan, C.-K. Sun, I.-C. Hsiao, C.-H. Lin, Y.-C. Chen, and B.-L. Lin, “Thickness dependence of optical second harmonic generation in collagen fibrils,” Opt. Express 15(19), 12005–12010 (2007).
[CrossRef] [PubMed]

W.-J. Lee, C.-H. Yu, S.-P. Tai, H.-Y. Huang, and C.-K. Sun, “Acetic acid as a cell nucleus contrast agent in third-harmonic generation microscopy,” J. Med. Biol. Eng. 27, 161–164 (2007).

C.-K. Sun, C.-H. Yu, S.-P. Tai, C.-T. Kung, I.-J. Wang, H.-C. Yu, H.-J. Huang, W.-J. Lee, Y.-F. Chan, and C.-K. Sun, “In vivo and ex vivo imaging of intra-tissue elastic fibers using third-harmonic-generation microscopy,” Opt. Express 15(18), 11167–11177 (2007).
[CrossRef] [PubMed]

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] [PubMed]

T.-H. Tsai, S.-P. Tai, W.-J. Lee, H.-Y. Huang, Y.-H. Liao, and C.-K. Sun, “Optical signal degradation study in fixed human skin using confocal microscopy and higher-harmonic optical microscopy,” Opt. Express 14(2), 749–758 (2006).
[CrossRef] [PubMed]

S.-P. Tai, T.-H. Tsai, W.-J. Lee, D.-B. Shieh, Y.-H. Liao, H.-Y. Huang, K. Y.-J. Zhang, H.-L. Liu, and C.-K. Sun, “Optical biopsy of fixed human skin with backward-collected optical harmonics signals,” Opt. Express 13(20), 8231–8242 (2005).
[CrossRef] [PubMed]

S.-W. Chu, S.-P. Tai, C.-L. Ho, C.-H. Lin, and C.-K. Sun, “High-resolution simultaneous three-photon fluorescence and third-harmonic-generation microscopy,” Microsc. Res. Tech. 66(4), 193–197 (2005).
[CrossRef] [PubMed]

Tearney, G. J.

Themelis, G. C.

C. J. Balas, G. C. Themelis, E. P. Prokopakis, I. Orfanudaki, E. Koumantakis, and E. S. Helidonis, “In vivo detection and staging of epithelial dysplasias and malignancies based on the quantitative assessment of acetic acid-tissue interaction kinetics,” J. Photochem. Photobiol. B 53(1-3), 153–157 (1999).
[CrossRef] [PubMed]

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).
[CrossRef] [PubMed]

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] [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]

Tsai, M.-R.

Tsai, T.-H.

Utzinger, U.

A. Myakov, L. Nieman, L. Wicky, U. Utzinger, R. Richards-Kortum, and K. Sokolov, “Fiber optic probe for polarized reflectance spectroscopy in vivo: design and performance,” J. Biomed. Opt. 7(3), 388–397 (2002).
[CrossRef] [PubMed]

van Beek, J.

Vargas, G.

Wang, I.-J.

Warren, J.

White, W. M.

W. M. White, M. Rajadhyaksha, S. González, R. L. Fabian, and R. R. Anderson, “Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy,” Laryngoscope 109(10), 1709–1717 (1999).
[CrossRef] [PubMed]

Wicky, L.

A. Myakov, L. Nieman, L. Wicky, U. Utzinger, R. Richards-Kortum, and K. Sokolov, “Fiber optic probe for polarized reflectance spectroscopy in vivo: design and performance,” J. Biomed. Opt. 7(3), 388–397 (2002).
[CrossRef] [PubMed]

Wilder-Smith, P.

P. Wilder-Smith, K. Osann, N. Hanna, N. E. Abbadi, M. Brenner, D. Messadi, and T. Krasieva, “In vivo multiphoton fluorescence imaging: a novel approach to oral malignancy,” Lasers Surg. Med. 35(2), 96–103 (2004).
[CrossRef] [PubMed]

Williams, M. D.

K. C. Maitland, A. M. Gillenwater, M. D. Williams, A. K. El-Naggar, M. R. Descour, and R. R. Richards-Kortum, “In vivo imaging of oral neoplasia using a miniaturized fiber optic confocal reflectance microscope,” Oral Oncol. 44(11), 1059–1066 (2008).
[CrossRef] [PubMed]

Wilson, K. R.

A. C. Millard, D. N. Fittinghoff, P. W. Wiseman, M. Muller, G. J. Brakenhoff, J. A. Squier, and K. R. Wilson, “Three dimensional, third harmonic microscopy of living systems,” Biophys. J. 78, 800 (2000).
[PubMed]

Wiseman, P. W.

A. C. Millard, D. N. Fittinghoff, P. W. Wiseman, M. Muller, G. J. Brakenhoff, J. A. Squier, and K. R. Wilson, “Three dimensional, third harmonic microscopy of living systems,” Biophys. J. 78, 800 (2000).
[PubMed]

Wong, B. J.

J. M. Ridgway, W. B. Armstrong, S. Guo, U. Mahmood, J. Su, R. P. Jackson, T. Shibuya, R. L. Crumley, M. Gu, Z. Chen, and B. J. Wong, “In vivo optical coherence tomography of the human oral cavity and oropharynx,” Arch. Otolaryngol. Head Neck Surg. 132(10), 1074–1081 (2006).
[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 embryos nerve systems by using harmonic generation microscopy and morphant technology,” J. Biomed. Opt. 13(6), 064041 (2008).
[CrossRef] [PubMed]

Wu, P.-C.

Yanai, M.

J. Sato, M. Yanai, T. Hirao, and M. Denda, “Water content and thickness of the stratum corneum contribute to skin surface morphology,” Arch. Dermatol. Res. 292(8), 412–417 (2000).
[CrossRef] [PubMed]

Yang, Y.-S.

Yu, C.-H.

Yu, H.-C.

Zagouri, F.

G. C. Zografos, F. Zagouri, T. N. Sergentanis, A. Nonni, D. Koulocheri, M. Fotou, E. Panopoulou, N. Pararas, C. Fotiadis, and J. Bramis, “Minimizing underestimation rate of microcalcifications excised via vacuum-assisted breast biopsy: a blind study,” Breast Cancer Res. Treat. 109(2), 397–402 (2008).
[CrossRef] [PubMed]

Zhang, K. Y.-J.

Zheltikov, A. M.

Zografos, G. C.

G. C. Zografos, F. Zagouri, T. N. Sergentanis, A. Nonni, D. Koulocheri, M. Fotou, E. Panopoulou, N. Pararas, C. Fotiadis, and J. Bramis, “Minimizing underestimation rate of microcalcifications excised via vacuum-assisted breast biopsy: a blind study,” Breast Cancer Res. Treat. 109(2), 397–402 (2008).
[CrossRef] [PubMed]

Adv. Biochem. Eng. Biotechnol. (1)

C.-K. Sun, “Higher harmonic generation microscopy,” Adv. Biochem. Eng. Biotechnol. 95, 17–56 (2005).
[PubMed]

Arch. Dermatol. Res. (1)

J. Sato, M. Yanai, T. Hirao, and M. Denda, “Water content and thickness of the stratum corneum contribute to skin surface morphology,” Arch. Dermatol. Res. 292(8), 412–417 (2000).
[CrossRef] [PubMed]

Arch. Otolaryngol. Head Neck Surg. (1)

J. M. Ridgway, W. B. Armstrong, S. Guo, U. Mahmood, J. Su, R. P. Jackson, T. Shibuya, R. L. Crumley, M. Gu, Z. Chen, and B. J. Wong, “In vivo optical coherence tomography of the human oral cavity and oropharynx,” Arch. Otolaryngol. Head Neck Surg. 132(10), 1074–1081 (2006).
[CrossRef] [PubMed]

Biophys. J. (2)

A. Hopt and E. Neher, “Highly nonlinear photodamage in two-photon fluorescence microscopy,” Biophys. J. 80(4), 2029–2036 (2001).
[CrossRef] [PubMed]

A. C. Millard, D. N. Fittinghoff, P. W. Wiseman, M. Muller, G. J. Brakenhoff, J. A. Squier, and K. R. Wilson, “Three dimensional, third harmonic microscopy of living systems,” Biophys. J. 78, 800 (2000).
[PubMed]

Breast Cancer Res. Treat. (1)

G. C. Zografos, F. Zagouri, T. N. Sergentanis, A. Nonni, D. Koulocheri, M. Fotou, E. Panopoulou, N. Pararas, C. Fotiadis, and J. Bramis, “Minimizing underestimation rate of microcalcifications excised via vacuum-assisted breast biopsy: a blind study,” Breast Cancer Res. Treat. 109(2), 397–402 (2008).
[CrossRef] [PubMed]

Cancer (1)

N. Houssami, S. Ciatto, I. Ellis, and D. Ambrogetti, “Underestimation of malignancy of breast core-needle biopsy: concepts and precise overall and category-specific estimates,” Cancer 109(3), 487–495 (2007).
[CrossRef] [PubMed]

Cell Tissue Res. (1)

M. A. Landay and H. E. Schroeder, “Quantitative electron microscopic analysis of the stratified epithelium of normal human buccal mucosa,” Cell Tissue Res. 177(3), 383–405 (1977).
[CrossRef] [PubMed]

Gynecol. Oncol. (1)

A. B. MacLean, “Acetowhite epithelium,” Gynecol. Oncol. 95(3), 691–694 (2004).
[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. Biomed. Eng. (1)

K.-B. Sung, C. Liang, M. Descour, T. Collier, M. Follen, and R. Richards-Kortum, “Fiber-optic confocal reflectance microscope with miniature objective for in vivo imaging of human tissues,” IEEE Trans. Biomed. Eng. 49(10), 1168–1172 (2002).
[CrossRef] [PubMed]

J Biophotonics (1)

C.-F. Chang, C.-H. Yu, and C.-K. Sun, “Multi-photon resonance enhancement of third harmonic generation in human oxyhemoglobin and deoxyhemoglobin,” J Biophotonics 3(10-11), 678–685 (2010).
[CrossRef] [PubMed]

J. Biomed. Opt. (4)

A. Myakov, L. Nieman, L. Wicky, U. Utzinger, R. Richards-Kortum, and K. Sokolov, “Fiber optic probe for polarized reflectance spectroscopy in vivo: design and performance,” J. Biomed. Opt. 7(3), 388–397 (2002).
[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]

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 embryos nerve systems by using harmonic generation microscopy and morphant technology,” J. Biomed. Opt. 13(6), 064041 (2008).
[CrossRef] [PubMed]

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] [PubMed]

J. Med. Biol. Eng. (1)

W.-J. Lee, C.-H. Yu, S.-P. Tai, H.-Y. Huang, and C.-K. Sun, “Acetic acid as a cell nucleus contrast agent in third-harmonic generation microscopy,” J. Med. Biol. Eng. 27, 161–164 (2007).

J. Microsc. (1)

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[CrossRef] [PubMed]

J. Opt. Soc. Am. B (1)

J. Photochem. Photobiol. B (1)

C. J. Balas, G. C. Themelis, E. P. Prokopakis, I. Orfanudaki, E. Koumantakis, and E. S. Helidonis, “In vivo detection and staging of epithelial dysplasias and malignancies based on the quantitative assessment of acetic acid-tissue interaction kinetics,” J. Photochem. Photobiol. B 53(1-3), 153–157 (1999).
[CrossRef] [PubMed]

J. R. Soc. Med. (1)

J. G. Cowpe, R. B. Longmore, and M. W. Green, “Quantitative exfoliative cytology of abnormal oral mucosal smears,” J. R. Soc. Med. 81(9), 509–513 (1988).
[PubMed]

J. Struct. Biol. (1)

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] [PubMed]

Laryngoscope (1)

W. M. White, M. Rajadhyaksha, S. González, R. L. Fabian, and R. R. Anderson, “Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy,” Laryngoscope 109(10), 1709–1717 (1999).
[CrossRef] [PubMed]

Lasers Surg. Med. (1)

P. Wilder-Smith, K. Osann, N. Hanna, N. E. Abbadi, M. Brenner, D. Messadi, and T. Krasieva, “In vivo multiphoton fluorescence imaging: a novel approach to oral malignancy,” Lasers Surg. Med. 35(2), 96–103 (2004).
[CrossRef] [PubMed]

Microsc. Res. Tech. (1)

S.-W. Chu, S.-P. Tai, C.-L. Ho, C.-H. Lin, and C.-K. Sun, “High-resolution simultaneous three-photon fluorescence and third-harmonic-generation microscopy,” Microsc. Res. Tech. 66(4), 193–197 (2005).
[CrossRef] [PubMed]

Opt. Express (11)

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]

J. Sun, T. Shilagard, B. Bell, M. Motamedi, and G. Vargas, “In vivo multimodal nonlinear optical imaging of mucosal tissue,” Opt. Express 12(11), 2478–2486 (2004).
[CrossRef] [PubMed]

S.-P. Tai, T.-H. Tsai, W.-J. Lee, D.-B. Shieh, Y.-H. Liao, H.-Y. Huang, K. Y.-J. Zhang, H.-L. Liu, and C.-K. Sun, “Optical biopsy of fixed human skin with backward-collected optical harmonics signals,” Opt. Express 13(20), 8231–8242 (2005).
[CrossRef] [PubMed]

V. Barzda, C. Greenhalgh, J. Aus der Au, S. Elmore, J. van Beek, and J. Squier, “Visualization of mitochondria in cardiomyocytes by simultaneous harmonic generation and fluorescence microscopy,” Opt. Express 13(20), 8263–8276 (2005).
[CrossRef] [PubMed]

T.-H. Tsai, S.-P. Tai, W.-J. Lee, H.-Y. Huang, Y.-H. Liao, and C.-K. Sun, “Optical signal degradation study in fixed human skin using confocal microscopy and higher-harmonic optical microscopy,” Opt. Express 14(2), 749–758 (2006).
[CrossRef] [PubMed]

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] [PubMed]

C.-K. Sun, C.-H. Yu, S.-P. Tai, C.-T. Kung, I.-J. Wang, H.-C. Yu, H.-J. Huang, W.-J. Lee, Y.-F. Chan, and C.-K. Sun, “In vivo and ex vivo imaging of intra-tissue elastic fibers using third-harmonic-generation microscopy,” Opt. Express 15(18), 11167–11177 (2007).
[CrossRef] [PubMed]

S.-W. Chu, S.-P. Tai, M.-C. Chan, C.-K. Sun, I.-C. Hsiao, C.-H. Lin, Y.-C. Chen, and B.-L. Lin, “Thickness dependence of optical second harmonic generation in collagen fibrils,” Opt. Express 15(19), 12005–12010 (2007).
[CrossRef] [PubMed]

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).
[PubMed]

S.-H. Chia, T.-M. Liu, A. A. Ivanov, A. B. Fedotov, A. M. Zheltikov, M.-R. Tsai, M.-C. Chan, C.-H. Yu, and C.-K. Sun, “A sub-100 fs self-starting Cr:forsterite laser generating 1.4 W output power,” Opt. Express 18(23), 24085–24091 (2010).
[CrossRef] [PubMed]

F. Feldchtein, V. Gelikonov, R. Iksanov, G. Gelikonov, R. Kuranov, A. Sergeev, N. Gladkova, M. Ourutina, D. Reitze, and J. Warren, “In vivo OCT imaging of hard and soft tissue of the oral cavity,” Opt. Express 3(6), 239–250 (1998).
[CrossRef] [PubMed]

Opt. Lett. (2)

Oral Oncol. (1)

K. C. Maitland, A. M. Gillenwater, M. D. Williams, A. K. El-Naggar, M. R. Descour, and R. R. Richards-Kortum, “In vivo imaging of oral neoplasia using a miniaturized fiber optic confocal reflectance microscope,” Oral Oncol. 44(11), 1059–1066 (2008).
[CrossRef] [PubMed]

Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. (1)

N. Ozawa, Y. Sumi, K. Shimozato, C. Chong, and T. Kurabayashi, “In vivo imaging of human labial glands using advanced optical coherence tomography,” Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 108(3), 425–429 (2009).
[CrossRef] [PubMed]

Rom. J. Morphol. Embryol. (1)

A. H. Hande and M. S. Chaudhary, “Cytomorphometric analysis of buccal mucosa of tobacco chewers,” Rom. J. Morphol. Embryol. 51(3), 527–532 (2010).
[PubMed]

Other (3)

D. W. Fawcett, “Oral cavity and associated glands,” in A Textbook of Histology (Saunders, 1986), pp. 579–601.

H. G. Burkitt, B. Young, and J. W. Heath, Wheater's Functional Histology: A Text and Colour Atlas, (Churchill-Livingstone, 1993), pp. 235–246.

A. N. S. I. Standard, Z136.1–2007, American National Standard for the Safe Use of Lasers (2007).

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Figures (7)

Fig. 1
Fig. 1

In vivo harmonic generation biopsy system. (a) Photograph of the optical virtual biopsy system. The illumination source was a Cr:forsterite laser. The collimated laser beam performed a 2D scan by a pair of fast galvanometer mirrors and PMT (photomultiplier tube) recorded the harmonic signals. A z-motor changed the tissue stabilizer (magnetic cup and vacuum cup) position along the light propagation axis so that the relative position between the objective and the tissue surface can be controlled. (b, c) A schematic diagram and a photograph of the rotatable system. SHG and THG signals were divided by a beamsplitter and guided into two PMTs. The objective of the imaging system was fixed on a rotatable arm to adapt the volunteer’s oral cavity.

Fig. 2
Fig. 2

Harmonic generation images of normal oral mucosa tissue in one healthy human subject. The horizontal section images are serial sections beginning at the top surface of the mucosa and progressing deeper into the tissue. The purple color represents THG signals and the green color indicates SHG signals. (a) The superficial epithelial cell layer at a depth of 25 μm; (b) the deeper superficial epithelial cell layer at a depth of 40 μm; (c) the intermediate epithelial cell layer at a depth of 90 μm; (d) the basal cell layer and the adjacent collagen fibers at a depth of 190 μm; (e) the collagen fibers and the erythrocytes (arrowheads) in the lamina propria with blood flow at a depth of 220 μm; (f) collagen fibers in the deeper lamina propria at a depth of 250 μm. (Scale bar: 20 μm).

Fig. 3
Fig. 3

(a) Sample THG image for NC ratio analysis. The areas of cells and nuclei were defined with dashed and solid lines, respectively. (b) The nucleus-cytoplasmic (NC) ratio in the superficial and the basal cell layers from five volunteers. The average values of thus analyzed NC ratios in the superficial and basal cell layers for five volunteers are 0.051 ± 0.006 and 0.392 ± 0.045, respectively.

Fig. 4
Fig. 4

The lateral resolution of HGM images in human oral mucosa. (a) The spatial intensity distribution of SHG or THG was fitted by a Gaussian curve. We analyzed the resolutions of SHG and THG images by using (b) collagen fibers (arrowhead) for SHG and (c) cell membranes (arrowhead) for THG. (d) THG (solid squares) and SHG (solid triangles) lateral resolution versus depth in epithelium and lamina propria are summarized. (Scale bar: 20 μm)

Fig. 5
Fig. 5

(a) A diagram of the laser beam focusing in a cell. The position z = 0 is set in the middle of the cell nucleus and the third-order susceptibility of the nucleus is equal to the susceptibility of the cytoplasm. (b) Numerical simulations of THG intensities versus beam focusing position z with different thickness of the cell nucleus (L). (c) Transverse histological image of human oral mucosa. The thicknesses of cell nuclei in the superficial cell layer (white arrow) and the deeper epithelial cell layer (yellow arrow) are 3.36 ± 0.94 μm and 9.03 ± 0.71 μm, respectively.

Fig. 6
Fig. 6

Numerical simulations of THG intensities as a function of beam focusing position z with different third-order susceptibility conditions, including χ(3) cyto = 0 (red line), χ(3) uncl = 0 (blue line), and χ(3) uncl = χ(3) cyto (black line). THG intensities with the nucleus thicknesses of (a) 9 μm, (b) 5 μm, (c) 3 μm, and (d) 1μm.

Fig. 7
Fig. 7

Comparison of in vivo THG images of human oral epithelium in the same epithelial layer, (a) before, (b) 5 minutes after, and (c) 20 minutes after applying acetic acid. (d) The values of nucleus-to-membrane (NM) ratio were summarized. (Scale bar: 20 μm)

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