Abstract

Abstract: Real-time histology or virtual biopsy for the diagnosis of colonic cancer is of great medical significance. In this work, we show that label-free multiphoton imaging is feasible and effective in monitoring colonic cancer progression by providing cellular and subcellular details in fresh, unfixed, unstained colonic specimens. Our results also demonstrate the capability of using tissue quantitative analysis of the redox ratio for quantifying colonic cancer progression. These results suggest that multiphoton microscopy has potential to become an in situ histological tool, which is free from the labeling requirement of conventional methods, for the early diagnosis and detection of malignant lesions in the colon.

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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]

2010 (5)

M. Goetz and R. Kiesslich, “Advances of endomicroscopy for gastrointestinal physiology and diseases,” Am. J. Physiol. Gastrointest. Liver Physiol. 298(6), G797–G806 (2010).
[CrossRef] [PubMed]

S. M. Zhuo, L. Q. Zheng, J. X. Chen, S. S. Xie, X. Q. Zhu, and X. S. Jiang, “Depth-cumulated epithelial redox ratio and stromal collagen quantity as quantitative intrinsic indicators for differentiating normal, inflammatory, and dysplastic epithelial tissues,” Appl. Phys. Lett. 97(17), 173701 (2010).
[CrossRef]

S. M. Zhuo, J. X. Chen, G. Z. Wu, S. S. Xie, L. Q. Zheng, X. S. Jiang, and X. Q. Zhu, “Quantitatively linking collagen alteration and epithelial tumor progression by second harmonic generation microscopy,” Appl. Phys. Lett. 96(21), 213704 (2010).
[CrossRef]

R. Cicchi, A. Crisci, A. Cosci, G. Nesi, D. Kapsokalyvas, S. Giancane, M. Carini, and F. S. Pavone, “Time- and Spectral-resolved two-photon imaging of healthy bladder mucosa and carcinoma in situ,” Opt. Express 18(4), 3840–3849 (2010).
[CrossRef] [PubMed]

M. Gu, H. C. Bao, and J. L. Li, “Cancer-cell microsurgery using nonlinear optical endomicroscopy,” J. Biomed. Opt. 15(5), 050502 (2010).
[CrossRef] [PubMed]

2009 (3)

S. M. Zhuo, J. X. Chen, S. S. Xie, Z. B. Hong, and X. S. Jiang, “Extracting diagnostic stromal organization features based on intrinsic two-photon excited fluorescence and second-harmonic generation signals,” J. Biomed. Opt. 14(2), 020503 (2009).
[CrossRef] [PubMed]

A. Jemal, R. Siegel, E. Ward, Y. Hao, J. Xu, and M. J. Thun, “Cancer statistics, 2009,” CA Cancer J. Clin. 59(4), 225–249 (2009).
[CrossRef] [PubMed]

V. A. Hovhannisyan, P.-J. Su, S.-J. Lin, and C. Y. Dong, “Quantifying thermodynamics of collagen thermal denaturation by second harmonic generation imaging,” Appl. Phys. Lett. 94(23), 233902 (2009).
[CrossRef]

2008 (1)

J. N. Rogart, J. Nagata, C. S. Loeser, R. D. Roorda, H. Aslanian, M. E. Robert, W. R. Zipfel, and M. H. Nathanson, “Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo,” Clin. Gastroenterol. Hepatol. 6(1), 95–101 (2008).
[CrossRef] [PubMed]

2007 (2)

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

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

2006 (1)

2005 (1)

M. C. Skala, J. M. Squirrell, K. M. Vrotsos, J. C. Eickhoff, A. Gendron-Fitzpatrick, K. W. Eliceiri, and N. Ramanujam, “Multiphoton microscopy of endogenous fluorescence differentiates normal, precancerous, and cancerous squamous epithelial tissues,” Cancer Res. 65(4), 1180–1186 (2005).
[CrossRef] [PubMed]

2004 (1)

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology 127(3), 706–713 (2004).
[CrossRef] [PubMed]

2003 (2)

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

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

2002 (3)

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

J. R. Jass, V. L. Whitehall, J. Young, and B. A. Leggett, “Emerging concepts in colorectal neoplasia,” Gastroenterology 123(3), 862–876 (2002).
[CrossRef] [PubMed]

A. Leslie, F. A. Carey, N. R. Pratt, and R. J. Steele, “The colorectal adenoma-carcinoma sequence,” Br. J. Surg. 89(7), 845–860 (2002).
[CrossRef] [PubMed]

2000 (1)

P. T. C. So, C. Y. Dong, B. R. Masters, and K. M. Berland, “Two-photon excitation fluorescence microscopy,” Annu. Rev. Biomed. Eng. 2(1), 399–429 (2000).
[CrossRef] [PubMed]

1997 (1)

C. Y. Dong, P. T. C. So, C. Buehler, and E. Gratton, “Spatial resolution in pump-probe microscopy,” Optik (Stuttg.) 106, 7–14 (1997).

Aslanian, H.

J. N. Rogart, J. Nagata, C. S. Loeser, R. D. Roorda, H. Aslanian, M. E. Robert, W. R. Zipfel, and M. H. Nathanson, “Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo,” Clin. Gastroenterol. Hepatol. 6(1), 95–101 (2008).
[CrossRef] [PubMed]

Bao, H. C.

M. Gu, H. C. Bao, and J. L. Li, “Cancer-cell microsurgery using nonlinear optical endomicroscopy,” J. Biomed. Opt. 15(5), 050502 (2010).
[CrossRef] [PubMed]

Berland, K. M.

P. T. C. So, C. Y. Dong, B. R. Masters, and K. M. Berland, “Two-photon excitation fluorescence microscopy,” Annu. Rev. Biomed. Eng. 2(1), 399–429 (2000).
[CrossRef] [PubMed]

Bückle, R.

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

Buehler, C.

C. Y. Dong, P. T. C. So, C. Buehler, and E. Gratton, “Spatial resolution in pump-probe microscopy,” Optik (Stuttg.) 106, 7–14 (1997).

Burg, J.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology 127(3), 706–713 (2004).
[CrossRef] [PubMed]

Campagnola, P. J.

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

Carey, F. A.

A. Leslie, F. A. Carey, N. R. Pratt, and R. J. Steele, “The colorectal adenoma-carcinoma sequence,” Br. J. Surg. 89(7), 845–860 (2002).
[CrossRef] [PubMed]

Carini, M.

Chen, J.

Chen, J. X.

S. M. Zhuo, L. Q. Zheng, J. X. Chen, S. S. Xie, X. Q. Zhu, and X. S. Jiang, “Depth-cumulated epithelial redox ratio and stromal collagen quantity as quantitative intrinsic indicators for differentiating normal, inflammatory, and dysplastic epithelial tissues,” Appl. Phys. Lett. 97(17), 173701 (2010).
[CrossRef]

S. M. Zhuo, J. X. Chen, G. Z. Wu, S. S. Xie, L. Q. Zheng, X. S. Jiang, and X. Q. Zhu, “Quantitatively linking collagen alteration and epithelial tumor progression by second harmonic generation microscopy,” Appl. Phys. Lett. 96(21), 213704 (2010).
[CrossRef]

S. M. Zhuo, J. X. Chen, S. S. Xie, Z. B. Hong, and X. S. Jiang, “Extracting diagnostic stromal organization features based on intrinsic two-photon excited fluorescence and second-harmonic generation signals,” J. Biomed. Opt. 14(2), 020503 (2009).
[CrossRef] [PubMed]

Christie, R.

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

Cicchi, R.

Cosci, A.

Crisci, A.

Delaney, P.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology 127(3), 706–713 (2004).
[CrossRef] [PubMed]

Dong, C. Y.

V. A. Hovhannisyan, P.-J. Su, S.-J. Lin, and C. Y. Dong, “Quantifying thermodynamics of collagen thermal denaturation by second harmonic generation imaging,” Appl. Phys. Lett. 94(23), 233902 (2009).
[CrossRef]

P. T. C. So, C. Y. Dong, B. R. Masters, and K. M. Berland, “Two-photon excitation fluorescence microscopy,” Annu. Rev. Biomed. Eng. 2(1), 399–429 (2000).
[CrossRef] [PubMed]

C. Y. Dong, P. T. C. So, C. Buehler, and E. Gratton, “Spatial resolution in pump-probe microscopy,” Optik (Stuttg.) 106, 7–14 (1997).

Ehlers, A.

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

Eickhoff, J.

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

Eickhoff, J. C.

M. C. Skala, J. M. Squirrell, K. M. Vrotsos, J. C. Eickhoff, A. Gendron-Fitzpatrick, K. W. Eliceiri, and N. Ramanujam, “Multiphoton microscopy of endogenous fluorescence differentiates normal, precancerous, and cancerous squamous epithelial tissues,” Cancer Res. 65(4), 1180–1186 (2005).
[CrossRef] [PubMed]

Eliceiri, K. W.

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

M. C. Skala, J. M. Squirrell, K. M. Vrotsos, J. C. Eickhoff, A. Gendron-Fitzpatrick, K. W. Eliceiri, and N. Ramanujam, “Multiphoton microscopy of endogenous fluorescence differentiates normal, precancerous, and cancerous squamous epithelial tissues,” Cancer Res. 65(4), 1180–1186 (2005).
[CrossRef] [PubMed]

Enders, M.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology 127(3), 706–713 (2004).
[CrossRef] [PubMed]

Galle, P. R.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology 127(3), 706–713 (2004).
[CrossRef] [PubMed]

Gendron-Fitzpatrick, A.

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

M. C. Skala, J. M. Squirrell, K. M. Vrotsos, J. C. Eickhoff, A. Gendron-Fitzpatrick, K. W. Eliceiri, and N. Ramanujam, “Multiphoton microscopy of endogenous fluorescence differentiates normal, precancerous, and cancerous squamous epithelial tissues,” Cancer Res. 65(4), 1180–1186 (2005).
[CrossRef] [PubMed]

Giancane, S.

Gnaendiger, J.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology 127(3), 706–713 (2004).
[CrossRef] [PubMed]

Goetz, M.

M. Goetz and R. Kiesslich, “Advances of endomicroscopy for gastrointestinal physiology and diseases,” Am. J. Physiol. Gastrointest. Liver Physiol. 298(6), G797–G806 (2010).
[CrossRef] [PubMed]

Gratton, E.

C. Y. Dong, P. T. C. So, C. Buehler, and E. Gratton, “Spatial resolution in pump-probe microscopy,” Optik (Stuttg.) 106, 7–14 (1997).

Gu, M.

M. Gu, H. C. Bao, and J. L. Li, “Cancer-cell microsurgery using nonlinear optical endomicroscopy,” J. Biomed. Opt. 15(5), 050502 (2010).
[CrossRef] [PubMed]

Hao, Y.

A. Jemal, R. Siegel, E. Ward, Y. Hao, J. Xu, and M. J. Thun, “Cancer statistics, 2009,” CA Cancer J. Clin. 59(4), 225–249 (2009).
[CrossRef] [PubMed]

Heikal, A. A.

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

Hong, Z. B.

S. M. Zhuo, J. X. Chen, S. S. Xie, Z. B. Hong, and X. S. Jiang, “Extracting diagnostic stromal organization features based on intrinsic two-photon excited fluorescence and second-harmonic generation signals,” J. Biomed. Opt. 14(2), 020503 (2009).
[CrossRef] [PubMed]

Hovhannisyan, V. A.

V. A. Hovhannisyan, P.-J. Su, S.-J. Lin, and C. Y. Dong, “Quantifying thermodynamics of collagen thermal denaturation by second harmonic generation imaging,” Appl. Phys. Lett. 94(23), 233902 (2009).
[CrossRef]

Huang, S.

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

Hyman, B. T.

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

Janell, D.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology 127(3), 706–713 (2004).
[CrossRef] [PubMed]

Jass, J. R.

J. R. Jass, V. L. Whitehall, J. Young, and B. A. Leggett, “Emerging concepts in colorectal neoplasia,” Gastroenterology 123(3), 862–876 (2002).
[CrossRef] [PubMed]

Jemal, A.

A. Jemal, R. Siegel, E. Ward, Y. Hao, J. Xu, and M. J. Thun, “Cancer statistics, 2009,” CA Cancer J. Clin. 59(4), 225–249 (2009).
[CrossRef] [PubMed]

Jiang, X. S.

S. M. Zhuo, J. X. Chen, G. Z. Wu, S. S. Xie, L. Q. Zheng, X. S. Jiang, and X. Q. Zhu, “Quantitatively linking collagen alteration and epithelial tumor progression by second harmonic generation microscopy,” Appl. Phys. Lett. 96(21), 213704 (2010).
[CrossRef]

S. M. Zhuo, L. Q. Zheng, J. X. Chen, S. S. Xie, X. Q. Zhu, and X. S. Jiang, “Depth-cumulated epithelial redox ratio and stromal collagen quantity as quantitative intrinsic indicators for differentiating normal, inflammatory, and dysplastic epithelial tissues,” Appl. Phys. Lett. 97(17), 173701 (2010).
[CrossRef]

S. M. Zhuo, J. X. Chen, S. S. Xie, Z. B. Hong, and X. S. Jiang, “Extracting diagnostic stromal organization features based on intrinsic two-photon excited fluorescence and second-harmonic generation signals,” J. Biomed. Opt. 14(2), 020503 (2009).
[CrossRef] [PubMed]

Kaatz, M.

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

Kapsokalyvas, D.

Kiesslich, R.

M. Goetz and R. Kiesslich, “Advances of endomicroscopy for gastrointestinal physiology and diseases,” Am. J. Physiol. Gastrointest. Liver Physiol. 298(6), G797–G806 (2010).
[CrossRef] [PubMed]

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology 127(3), 706–713 (2004).
[CrossRef] [PubMed]

König, K.

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

Leggett, B. A.

J. R. Jass, V. L. Whitehall, J. Young, and B. A. Leggett, “Emerging concepts in colorectal neoplasia,” Gastroenterology 123(3), 862–876 (2002).
[CrossRef] [PubMed]

Leslie, A.

A. Leslie, F. A. Carey, N. R. Pratt, and R. J. Steele, “The colorectal adenoma-carcinoma sequence,” Br. J. Surg. 89(7), 845–860 (2002).
[CrossRef] [PubMed]

Li, J. L.

M. Gu, H. C. Bao, and J. L. Li, “Cancer-cell microsurgery using nonlinear optical endomicroscopy,” J. Biomed. Opt. 15(5), 050502 (2010).
[CrossRef] [PubMed]

Lin, S.-J.

V. A. Hovhannisyan, P.-J. Su, S.-J. Lin, and C. Y. Dong, “Quantifying thermodynamics of collagen thermal denaturation by second harmonic generation imaging,” Appl. Phys. Lett. 94(23), 233902 (2009).
[CrossRef]

Loeser, C. S.

J. N. Rogart, J. Nagata, C. S. Loeser, R. D. Roorda, H. Aslanian, M. E. Robert, W. R. Zipfel, and M. H. Nathanson, “Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo,” Clin. Gastroenterol. Hepatol. 6(1), 95–101 (2008).
[CrossRef] [PubMed]

Loew, L. M.

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

Luo, T.

Masters, B. R.

P. T. C. So, C. Y. Dong, B. R. Masters, and K. M. Berland, “Two-photon excitation fluorescence microscopy,” Annu. Rev. Biomed. Eng. 2(1), 399–429 (2000).
[CrossRef] [PubMed]

McLaren, W.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology 127(3), 706–713 (2004).
[CrossRef] [PubMed]

Nafe, B.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology 127(3), 706–713 (2004).
[CrossRef] [PubMed]

Nagata, J.

J. N. Rogart, J. Nagata, C. S. Loeser, R. D. Roorda, H. Aslanian, M. E. Robert, W. R. Zipfel, and M. H. Nathanson, “Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo,” Clin. Gastroenterol. Hepatol. 6(1), 95–101 (2008).
[CrossRef] [PubMed]

Nathanson, M. H.

J. N. Rogart, J. Nagata, C. S. Loeser, R. D. Roorda, H. Aslanian, M. E. Robert, W. R. Zipfel, and M. H. Nathanson, “Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo,” Clin. Gastroenterol. Hepatol. 6(1), 95–101 (2008).
[CrossRef] [PubMed]

Nesi, G.

Neurath, M. F.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology 127(3), 706–713 (2004).
[CrossRef] [PubMed]

Nikitin, A. Y.

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

Pavone, F. S.

Polglase, A.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology 127(3), 706–713 (2004).
[CrossRef] [PubMed]

Pratt, N. R.

A. Leslie, F. A. Carey, N. R. Pratt, and R. J. Steele, “The colorectal adenoma-carcinoma sequence,” Br. J. Surg. 89(7), 845–860 (2002).
[CrossRef] [PubMed]

Ramanujam, N.

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

M. C. Skala, J. M. Squirrell, K. M. Vrotsos, J. C. Eickhoff, A. Gendron-Fitzpatrick, K. W. Eliceiri, and N. Ramanujam, “Multiphoton microscopy of endogenous fluorescence differentiates normal, precancerous, and cancerous squamous epithelial tissues,” Cancer Res. 65(4), 1180–1186 (2005).
[CrossRef] [PubMed]

Riching, K. M.

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

Riemann, I.

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

Robert, M. E.

J. N. Rogart, J. Nagata, C. S. Loeser, R. D. Roorda, H. Aslanian, M. E. Robert, W. R. Zipfel, and M. H. Nathanson, “Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo,” Clin. Gastroenterol. Hepatol. 6(1), 95–101 (2008).
[CrossRef] [PubMed]

Rogart, J. N.

J. N. Rogart, J. Nagata, C. S. Loeser, R. D. Roorda, H. Aslanian, M. E. Robert, W. R. Zipfel, and M. H. Nathanson, “Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo,” Clin. Gastroenterol. Hepatol. 6(1), 95–101 (2008).
[CrossRef] [PubMed]

Roorda, R. D.

J. N. Rogart, J. Nagata, C. S. Loeser, R. D. Roorda, H. Aslanian, M. E. Robert, W. R. Zipfel, and M. H. Nathanson, “Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo,” Clin. Gastroenterol. Hepatol. 6(1), 95–101 (2008).
[CrossRef] [PubMed]

Schenkl, S.

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

Siegel, R.

A. Jemal, R. Siegel, E. Ward, Y. Hao, J. Xu, and M. J. Thun, “Cancer statistics, 2009,” CA Cancer J. Clin. 59(4), 225–249 (2009).
[CrossRef] [PubMed]

Skala, M. C.

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

M. C. Skala, J. M. Squirrell, K. M. Vrotsos, J. C. Eickhoff, A. Gendron-Fitzpatrick, K. W. Eliceiri, and N. Ramanujam, “Multiphoton microscopy of endogenous fluorescence differentiates normal, precancerous, and cancerous squamous epithelial tissues,” Cancer Res. 65(4), 1180–1186 (2005).
[CrossRef] [PubMed]

So, P. T. C.

P. T. C. So, C. Y. Dong, B. R. Masters, and K. M. Berland, “Two-photon excitation fluorescence microscopy,” Annu. Rev. Biomed. Eng. 2(1), 399–429 (2000).
[CrossRef] [PubMed]

C. Y. Dong, P. T. C. So, C. Buehler, and E. Gratton, “Spatial resolution in pump-probe microscopy,” Optik (Stuttg.) 106, 7–14 (1997).

Squirrell, J. M.

M. C. Skala, J. M. Squirrell, K. M. Vrotsos, J. C. Eickhoff, A. Gendron-Fitzpatrick, K. W. Eliceiri, and N. Ramanujam, “Multiphoton microscopy of endogenous fluorescence differentiates normal, precancerous, and cancerous squamous epithelial tissues,” Cancer Res. 65(4), 1180–1186 (2005).
[CrossRef] [PubMed]

Steele, R. J.

A. Leslie, F. A. Carey, N. R. Pratt, and R. J. Steele, “The colorectal adenoma-carcinoma sequence,” Br. J. Surg. 89(7), 845–860 (2002).
[CrossRef] [PubMed]

Su, P.-J.

V. A. Hovhannisyan, P.-J. Su, S.-J. Lin, and C. Y. Dong, “Quantifying thermodynamics of collagen thermal denaturation by second harmonic generation imaging,” Appl. Phys. Lett. 94(23), 233902 (2009).
[CrossRef]

Thomas, S.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology 127(3), 706–713 (2004).
[CrossRef] [PubMed]

Thun, M. J.

A. Jemal, R. Siegel, E. Ward, Y. Hao, J. Xu, and M. J. Thun, “Cancer statistics, 2009,” CA Cancer J. Clin. 59(4), 225–249 (2009).
[CrossRef] [PubMed]

Vieth, M.

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology 127(3), 706–713 (2004).
[CrossRef] [PubMed]

Vrotsos, K. M.

M. C. Skala, J. M. Squirrell, K. M. Vrotsos, J. C. Eickhoff, A. Gendron-Fitzpatrick, K. W. Eliceiri, and N. Ramanujam, “Multiphoton microscopy of endogenous fluorescence differentiates normal, precancerous, and cancerous squamous epithelial tissues,” Cancer Res. 65(4), 1180–1186 (2005).
[CrossRef] [PubMed]

Ward, E.

A. Jemal, R. Siegel, E. Ward, Y. Hao, J. Xu, and M. J. Thun, “Cancer statistics, 2009,” CA Cancer J. Clin. 59(4), 225–249 (2009).
[CrossRef] [PubMed]

Webb, W. W.

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

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

White, J. G.

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

Whitehall, V. L.

J. R. Jass, V. L. Whitehall, J. Young, and B. A. Leggett, “Emerging concepts in colorectal neoplasia,” Gastroenterology 123(3), 862–876 (2002).
[CrossRef] [PubMed]

Williams, R. M.

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

Wu, G. Z.

S. M. Zhuo, J. X. Chen, G. Z. Wu, S. S. Xie, L. Q. Zheng, X. S. Jiang, and X. Q. Zhu, “Quantitatively linking collagen alteration and epithelial tumor progression by second harmonic generation microscopy,” Appl. Phys. Lett. 96(21), 213704 (2010).
[CrossRef]

Xie, S. S.

S. M. Zhuo, J. X. Chen, G. Z. Wu, S. S. Xie, L. Q. Zheng, X. S. Jiang, and X. Q. Zhu, “Quantitatively linking collagen alteration and epithelial tumor progression by second harmonic generation microscopy,” Appl. Phys. Lett. 96(21), 213704 (2010).
[CrossRef]

S. M. Zhuo, L. Q. Zheng, J. X. Chen, S. S. Xie, X. Q. Zhu, and X. S. Jiang, “Depth-cumulated epithelial redox ratio and stromal collagen quantity as quantitative intrinsic indicators for differentiating normal, inflammatory, and dysplastic epithelial tissues,” Appl. Phys. Lett. 97(17), 173701 (2010).
[CrossRef]

S. M. Zhuo, J. X. Chen, S. S. Xie, Z. B. Hong, and X. S. Jiang, “Extracting diagnostic stromal organization features based on intrinsic two-photon excited fluorescence and second-harmonic generation signals,” J. Biomed. Opt. 14(2), 020503 (2009).
[CrossRef] [PubMed]

Xu, J.

A. Jemal, R. Siegel, E. Ward, Y. Hao, J. Xu, and M. J. Thun, “Cancer statistics, 2009,” CA Cancer J. Clin. 59(4), 225–249 (2009).
[CrossRef] [PubMed]

Young, J.

J. R. Jass, V. L. Whitehall, J. Young, and B. A. Leggett, “Emerging concepts in colorectal neoplasia,” Gastroenterology 123(3), 862–876 (2002).
[CrossRef] [PubMed]

Zhao, J.

Zheng, L. Q.

S. M. Zhuo, L. Q. Zheng, J. X. Chen, S. S. Xie, X. Q. Zhu, and X. S. Jiang, “Depth-cumulated epithelial redox ratio and stromal collagen quantity as quantitative intrinsic indicators for differentiating normal, inflammatory, and dysplastic epithelial tissues,” Appl. Phys. Lett. 97(17), 173701 (2010).
[CrossRef]

S. M. Zhuo, J. X. Chen, G. Z. Wu, S. S. Xie, L. Q. Zheng, X. S. Jiang, and X. Q. Zhu, “Quantitatively linking collagen alteration and epithelial tumor progression by second harmonic generation microscopy,” Appl. Phys. Lett. 96(21), 213704 (2010).
[CrossRef]

Zhu, X. Q.

S. M. Zhuo, L. Q. Zheng, J. X. Chen, S. S. Xie, X. Q. Zhu, and X. S. Jiang, “Depth-cumulated epithelial redox ratio and stromal collagen quantity as quantitative intrinsic indicators for differentiating normal, inflammatory, and dysplastic epithelial tissues,” Appl. Phys. Lett. 97(17), 173701 (2010).
[CrossRef]

S. M. Zhuo, J. X. Chen, G. Z. Wu, S. S. Xie, L. Q. Zheng, X. S. Jiang, and X. Q. Zhu, “Quantitatively linking collagen alteration and epithelial tumor progression by second harmonic generation microscopy,” Appl. Phys. Lett. 96(21), 213704 (2010).
[CrossRef]

Zhuo, S.

Zhuo, S. M.

S. M. Zhuo, J. X. Chen, G. Z. Wu, S. S. Xie, L. Q. Zheng, X. S. Jiang, and X. Q. Zhu, “Quantitatively linking collagen alteration and epithelial tumor progression by second harmonic generation microscopy,” Appl. Phys. Lett. 96(21), 213704 (2010).
[CrossRef]

S. M. Zhuo, L. Q. Zheng, J. X. Chen, S. S. Xie, X. Q. Zhu, and X. S. Jiang, “Depth-cumulated epithelial redox ratio and stromal collagen quantity as quantitative intrinsic indicators for differentiating normal, inflammatory, and dysplastic epithelial tissues,” Appl. Phys. Lett. 97(17), 173701 (2010).
[CrossRef]

S. M. Zhuo, J. X. Chen, S. S. Xie, Z. B. Hong, and X. S. Jiang, “Extracting diagnostic stromal organization features based on intrinsic two-photon excited fluorescence and second-harmonic generation signals,” J. Biomed. Opt. 14(2), 020503 (2009).
[CrossRef] [PubMed]

Zipfel, W. R.

J. N. Rogart, J. Nagata, C. S. Loeser, R. D. Roorda, H. Aslanian, M. E. Robert, W. R. Zipfel, and M. H. Nathanson, “Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo,” Clin. Gastroenterol. Hepatol. 6(1), 95–101 (2008).
[CrossRef] [PubMed]

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

Zou, D.

Am. J. Physiol. Gastrointest. Liver Physiol. (1)

M. Goetz and R. Kiesslich, “Advances of endomicroscopy for gastrointestinal physiology and diseases,” Am. J. Physiol. Gastrointest. Liver Physiol. 298(6), G797–G806 (2010).
[CrossRef] [PubMed]

Annu. Rev. Biomed. Eng. (1)

P. T. C. So, C. Y. Dong, B. R. Masters, and K. M. Berland, “Two-photon excitation fluorescence microscopy,” Annu. Rev. Biomed. Eng. 2(1), 399–429 (2000).
[CrossRef] [PubMed]

Appl. Phys. Lett. (3)

S. M. Zhuo, L. Q. Zheng, J. X. Chen, S. S. Xie, X. Q. Zhu, and X. S. Jiang, “Depth-cumulated epithelial redox ratio and stromal collagen quantity as quantitative intrinsic indicators for differentiating normal, inflammatory, and dysplastic epithelial tissues,” Appl. Phys. Lett. 97(17), 173701 (2010).
[CrossRef]

V. A. Hovhannisyan, P.-J. Su, S.-J. Lin, and C. Y. Dong, “Quantifying thermodynamics of collagen thermal denaturation by second harmonic generation imaging,” Appl. Phys. Lett. 94(23), 233902 (2009).
[CrossRef]

S. M. Zhuo, J. X. Chen, G. Z. Wu, S. S. Xie, L. Q. Zheng, X. S. Jiang, and X. Q. Zhu, “Quantitatively linking collagen alteration and epithelial tumor progression by second harmonic generation microscopy,” Appl. Phys. Lett. 96(21), 213704 (2010).
[CrossRef]

Biophys. J. (1)

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

Br. J. Surg. (1)

A. Leslie, F. A. Carey, N. R. Pratt, and R. J. Steele, “The colorectal adenoma-carcinoma sequence,” Br. J. Surg. 89(7), 845–860 (2002).
[CrossRef] [PubMed]

CA Cancer J. Clin. (1)

A. Jemal, R. Siegel, E. Ward, Y. Hao, J. Xu, and M. J. Thun, “Cancer statistics, 2009,” CA Cancer J. Clin. 59(4), 225–249 (2009).
[CrossRef] [PubMed]

Cancer Res. (1)

M. C. Skala, J. M. Squirrell, K. M. Vrotsos, J. C. Eickhoff, A. Gendron-Fitzpatrick, K. W. Eliceiri, and N. Ramanujam, “Multiphoton microscopy of endogenous fluorescence differentiates normal, precancerous, and cancerous squamous epithelial tissues,” Cancer Res. 65(4), 1180–1186 (2005).
[CrossRef] [PubMed]

Clin. Gastroenterol. Hepatol. (1)

J. N. Rogart, J. Nagata, C. S. Loeser, R. D. Roorda, H. Aslanian, M. E. Robert, W. R. Zipfel, and M. H. Nathanson, “Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo,” Clin. Gastroenterol. Hepatol. 6(1), 95–101 (2008).
[CrossRef] [PubMed]

Gastroenterology (2)

J. R. Jass, V. L. Whitehall, J. Young, and B. A. Leggett, “Emerging concepts in colorectal neoplasia,” Gastroenterology 123(3), 862–876 (2002).
[CrossRef] [PubMed]

R. Kiesslich, J. Burg, M. Vieth, J. Gnaendiger, M. Enders, P. Delaney, A. Polglase, W. McLaren, D. Janell, S. Thomas, B. Nafe, P. R. Galle, and M. F. Neurath, “Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo,” Gastroenterology 127(3), 706–713 (2004).
[CrossRef] [PubMed]

J. Biomed. Opt. (2)

M. Gu, H. C. Bao, and J. L. Li, “Cancer-cell microsurgery using nonlinear optical endomicroscopy,” J. Biomed. Opt. 15(5), 050502 (2010).
[CrossRef] [PubMed]

S. M. Zhuo, J. X. Chen, S. S. Xie, Z. B. Hong, and X. S. Jiang, “Extracting diagnostic stromal organization features based on intrinsic two-photon excited fluorescence and second-harmonic generation signals,” J. Biomed. Opt. 14(2), 020503 (2009).
[CrossRef] [PubMed]

Microsc. Res. Tech. (1)

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

Nat. Biotechnol. (1)

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

Opt. Express (2)

Optik (Stuttg.) (1)

C. Y. Dong, P. T. C. So, C. Buehler, and E. Gratton, “Spatial resolution in pump-probe microscopy,” Optik (Stuttg.) 106, 7–14 (1997).

Proc. Natl. Acad. Sci. U.S.A. (2)

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

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

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Figures (2)

Fig. 1
Fig. 1

Representative multiphoton images from the normal (a), precancerous (b), and cancerous (c) colonic tissues at depth of 0 μm. The excitation wavelength λex was 800 nm. Scale bar = 50 μm.

Fig. 2
Fig. 2

Redox ratio obtained from the normal, precancerous, and cancerous colonic tissues. Error bars indicate calculated standard deviations.

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