Abstract

We compare second harmonic generation (SHG) to histological and immunohistochemical techniques for the visualization and scoring of collagen in biological tissues. We show that SHG microscopy is highly specific for fibrillar collagens and that combined SHG and two-photon excited fluorescence (2PEF) imaging can provide simultaneous three-dimensional visualization of collagen synthesis and assembly sites in transgenic animal models expressing GFP constructs. Finally, we propose several scores for characterizing collagen accumulation based on SHG images and appropriate for different types of collagen distributions. We illustrate the sensitivity of these scores in a murine model of renal fibrosis using a morphological segmentation of the tissue based on endogenous 2PEF signals.

© 2007 Optical Society of America

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  1. P. J. Campagnola, A. C. Millard, M. Terasaki, P. E. Hoppe, C. J. Malone, and W. A. Mohler, “Three-dimensional high-resolution Second-Harmonic Generation imaging of endogenous structural proteins in biological tissues,” Biophys. J. 82,493–508 (2002).
    [CrossRef]
  2. A. Zoumi, A. Yeh, and B. J. Tromberg, “Imaging cells and extracellular matrix in vivo by using second-harmonic generation and two-photon excited fluorescence,” Proc. Natl. Acad. Sci. USA 99,11014–11019 (2002).
    [CrossRef] [PubMed]
  3. G. Cox, E. Kable, A. Jones, I. Fraser, K. Marconi, and M. D. Gorrell, “3-dimensional imaging of collagen using second harmonic generation,” J. Struct. Biol. 141,53–62 (2003).
    [CrossRef] [PubMed]
  4. E. Brown, T. Mckee, E. Ditomaso, A. Pluen, B. Seed, Y. Boucher, and R. K. Jain, “Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation,” Nat. Med. 9,796–800 (2003).
    [CrossRef] [PubMed]
  5. P. Stoller, P. M. Celliers, K. M. Reiser, and A. M. Rubenchik, “Quantitative second-harmonic generation microscopy in collagen,” Appl. Opt. 42,5209–5219 (2003).
    [CrossRef] [PubMed]
  6. 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. USA 100,7075–7080 (2003).
    [CrossRef] [PubMed]
  7. K. König and I. Riemann, “High-resolution multiphoton tomography of human skin with subcellular spatial resolution and picosecond time resolution,” J. Biomed. Opt. 8,432–439 (2003).
    [CrossRef] [PubMed]
  8. A.-M. Pena, M. Strupler, T. Boulesteix, G. Godeau, and M.-C. Schanne-Klein, “Spectroscopic analysis of keratin endogenous signal for skin multiphoton microscopy,” Opt. Express 13,6268–6274; erratum: 13(17), 6667 (2005).
    [CrossRef] [PubMed]
  9. J. A. Palero, H. S. D. Bruijn, A. V. D. P.-V. D. Heuvel, H. J. C. M. Sterenborg, and H. C. Gerritsen, “In vivo nonlinear spectral imaging in mouse skin,” Opt. Express 14,4395–4402 (2006).
    [CrossRef] [PubMed]
  10. T. Boulesteix, A. M. Pena, N. Pagès, G. Godeau, M.-P. Sauviat, E. Beaurepaire, and M. C. Schanne-Klein, “Micrometer scale ex vivo multiphoton imaging of unstained arterial wall structure,” Cytometry 69A,20–26 (2006).
    [CrossRef]
  11. A.-M. Pena, T. Boulesteix, T. Dartigalongue, and M.-C. Schanne-Klein, “Chiroptical effects in the second harmonic signal of collagens I and IV,” J. Am. Chem. Soc. 127,10314–10322 (2005).
    [CrossRef] [PubMed]
  12. S.-J. Lin, R.-Jr Wu, H.-Y. Tan, W. Lo, W.-C. Lin, T.-H. Young, C.-J. Hsu, J.-S. Chen, S.-H. Jee, and C.-Y. Dong, “Evaluating cutaneous photoaging by use of multiphoton fluorescence and second-harmonic generation microscopy,” Opt. Lett. 30,2275–2277 (2005).
    [CrossRef] [PubMed]
  13. M. J. Koehler, K König, P. Elsner, R. Bückle, and M. Kaatz, “In vivo assessment of human skin aging by multiphoton laser scanning tomography,” Opt. Lett. 31,2879–2881 (2006).
    [CrossRef] [PubMed]
  14. A.-M. Pena, A. Fabre, D. Débarre, J. Marchal-Somme, B. Crestani, J.-L. Martin, E. Beaurepaire, and M.-C. Schanne-Klein, “Three-dimensional investigation and scoring of extracellular matrix remodeling during lung fibrosis using multiphoton microscopy,” Microsc. Res. Tech. in press (2007).
    [CrossRef]
  15. A. Zoumi, X. Lu, G. S. Kassab, and B. J. Tromberg, “Imaging coronary artery microstructure using second-harmonic and two-photon fluorescence microscopy,” Biophys. J. 87,2778–2786 (2004).
    [CrossRef] [PubMed]
  16. K. Schenke-Layland, I. Riemann, U. A. Stock, and K. König, “Imaging of cardiovascular structures using near-infrared femtosecond multiphoton laser scanning microscopy,” J. Biomed. Opt. 10,024017 (2005).
    [CrossRef] [PubMed]
  17. N. Buyukbabani and D. Droz, “Distribution of the extracellular matrix components in human glomerular lesions,” J. Pathol. 172,199–207 (1994).
    [CrossRef] [PubMed]
  18. M. S. Razzaque, M. Cheng, Y. Horita, M. Nishihara, T. Harada, and T. Taguchi, “Immunohistochemical analysis of type III and IV collagens in tubulointerstitial damage in human benign nephrosclerosis,” J. Int. Med. Res. 23,480–486 (1995).
    [PubMed]
  19. L. C. U. Junqueira, G. Bignolas, and R. R. Brentani, “Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections,” Histochem. J. 11,447–155 (1979).
    [CrossRef] [PubMed]
  20. P. Whittaker, R. A. Kloner, D. R. Boughner, and J. G. Pickering, “Quantitative assessment of myocardial collagen with picrosirius red staining and circularly polarized light,” Basic Res. Cardiol. 89,397–410 (1994).
    [CrossRef] [PubMed]
  21. M. Oheim, E. Beaurepaire, E. Chaigneau, J. Mertz, and S. Charpak, “Two-photon microscopy in brain tissue: parameters influencing the imaging depth,” J. Neurosci. Methods 111,29–37 (2001).
    [CrossRef] [PubMed]
  22. D. Débarre, W. Suppato, A. M. Pena, A. Fabre, T. Tordjmann, L. Combettes, M. C. Schanne-Klein, and E. Beaurepaire, “Imaging lipid bodies in cells and tissues using third-harmonic generation microscopy,” Nat. Methods 3,47 –53 (2006).
    [CrossRef]
  23. K. L. Kusser and T. D. Randall, “Simultaneous detection of EGFP and cell surface markers by fluorescence Microscopy in Lymphoid Tissues,” J. Histochem. Cytochem. 51,5–14 (2003).
    [CrossRef]
  24. W. Wang, J. B. Wyckoff, V. C. Frohlich, Y. Oleynikov, S. Hüttelmaier, J. Zavadil, L. Cermak, E. P. Bottinger, R. H. Singer, J. G. White, J. E. Segall, and J. S. Condeelis, “Single cell behavior in metastatic primary mammary tumors correlated with gene expressions patterns revealed by molecular profiling,” Cancer Res. 62,6278–6288 (2002).
    [PubMed]
  25. W. Lo, S-W. Teng, H-Y. Tan, K. H. Kim, H-C. Chen, H-S. Lee, Y-F. Chen, P. T. C. So, and C.-Y. Dong, “Intact corneal stroma visualization of GFP mouse revealed by multiphoton imaging,” Microsc. Res. Tech. 69,973–975 (2006)
    [CrossRef] [PubMed]
  26. Y. Yata, A. Scanga, A. Gillan, L. Yang, S. Reif, M. Breindl, D. A. Brenner, and R. A. Rippe, “DNase I-hypersensitive sites enhance a1(I) collagen gene expression in Hepatic Stellate Cells,” Hepatology 37,267–276 (2003).
    [CrossRef] [PubMed]
  27. J. Mertz and L. Moreaux, “Second-harmonic generation by focused excitation in inhomogeneously distributed scatterers,” Opt. Commun. 196,325–330 (2001).
    [CrossRef]
  28. A. K. Dunn, V. P. Wallace, M. Coleno, M. W. Berns, and B. J. Tromberg, “Influence of optical properties on two-photon fluorescence imaging in turbid samples,” Appl. Opt. 39,1194–1201 (2000).
    [CrossRef]
  29. B. M. Kim, J. Eichler, K. M. Reiser, A. M. Rubenchik, and L. B. Da Silva, “Collagen structure and nonlinear susceptibility: effects of heat, glycation, and enzymatic cleavage on second harmonic signal intensity,” Lasers Surg. Med. 27,329–335 (2000).
    [CrossRef] [PubMed]
  30. R. M. Williams, W. R. Zipfel, and W. W. Webb, “Interpreting second-harmonic generation images of collagen fibrils,” Biophys. J. 88,1377–1386 (2005).
    [CrossRef]
  31. M. Han, G. Giese, and J. F. Bille, “Second harmonic generation imaging of collagen fibrils in cornea and sclera,” Opt. Express 13,5791–5797 (2005).
    [CrossRef] [PubMed]
  32. D. J. S. Hulmes, “Building collagen molecules, fibrils, and suprafibrillar structures,” J. Struct. Biol. 137,2–10 (2002).
    [CrossRef] [PubMed]
  33. A. Fogo, J. A. Breyer, M. C. Smith, W. H. Cleveland, L. Agodoa, K. A. Kirk, and R. Glassock, “Accuracy of the diagnosis of hypertensive nephrosclerosis in African Americans: a report from the African American Study of Kidney Disease (AASK) Trial. AASK pilot study investigators,” Kidney Int.51 (1997).
    [CrossRef] [PubMed]
  34. K. A. Nath, “Tubulointerstitial changes as a major determinant in the progression of renal damage,” Am. J. Kidney Dis. 20,1–17 (1992).
    [PubMed]

2006 (5)

D. Débarre, W. Suppato, A. M. Pena, A. Fabre, T. Tordjmann, L. Combettes, M. C. Schanne-Klein, and E. Beaurepaire, “Imaging lipid bodies in cells and tissues using third-harmonic generation microscopy,” Nat. Methods 3,47 –53 (2006).
[CrossRef]

W. Lo, S-W. Teng, H-Y. Tan, K. H. Kim, H-C. Chen, H-S. Lee, Y-F. Chen, P. T. C. So, and C.-Y. Dong, “Intact corneal stroma visualization of GFP mouse revealed by multiphoton imaging,” Microsc. Res. Tech. 69,973–975 (2006)
[CrossRef] [PubMed]

T. Boulesteix, A. M. Pena, N. Pagès, G. Godeau, M.-P. Sauviat, E. Beaurepaire, and M. C. Schanne-Klein, “Micrometer scale ex vivo multiphoton imaging of unstained arterial wall structure,” Cytometry 69A,20–26 (2006).
[CrossRef]

J. A. Palero, H. S. D. Bruijn, A. V. D. P.-V. D. Heuvel, H. J. C. M. Sterenborg, and H. C. Gerritsen, “In vivo nonlinear spectral imaging in mouse skin,” Opt. Express 14,4395–4402 (2006).
[CrossRef] [PubMed]

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

2005 (6)

A.-M. Pena, T. Boulesteix, T. Dartigalongue, and M.-C. Schanne-Klein, “Chiroptical effects in the second harmonic signal of collagens I and IV,” J. Am. Chem. Soc. 127,10314–10322 (2005).
[CrossRef] [PubMed]

R. M. Williams, W. R. Zipfel, and W. W. Webb, “Interpreting second-harmonic generation images of collagen fibrils,” Biophys. J. 88,1377–1386 (2005).
[CrossRef]

S.-J. Lin, R.-Jr Wu, H.-Y. Tan, W. Lo, W.-C. Lin, T.-H. Young, C.-J. Hsu, J.-S. Chen, S.-H. Jee, and C.-Y. Dong, “Evaluating cutaneous photoaging by use of multiphoton fluorescence and second-harmonic generation microscopy,” Opt. Lett. 30,2275–2277 (2005).
[CrossRef] [PubMed]

M. Han, G. Giese, and J. F. Bille, “Second harmonic generation imaging of collagen fibrils in cornea and sclera,” Opt. Express 13,5791–5797 (2005).
[CrossRef] [PubMed]

A.-M. Pena, M. Strupler, T. Boulesteix, G. Godeau, and M.-C. Schanne-Klein, “Spectroscopic analysis of keratin endogenous signal for skin multiphoton microscopy,” Opt. Express 13,6268–6274; erratum: 13(17), 6667 (2005).
[CrossRef] [PubMed]

K. Schenke-Layland, I. Riemann, U. A. Stock, and K. König, “Imaging of cardiovascular structures using near-infrared femtosecond multiphoton laser scanning microscopy,” J. Biomed. Opt. 10,024017 (2005).
[CrossRef] [PubMed]

2004 (1)

A. Zoumi, X. Lu, G. S. Kassab, and B. J. Tromberg, “Imaging coronary artery microstructure using second-harmonic and two-photon fluorescence microscopy,” Biophys. J. 87,2778–2786 (2004).
[CrossRef] [PubMed]

2003 (7)

Y. Yata, A. Scanga, A. Gillan, L. Yang, S. Reif, M. Breindl, D. A. Brenner, and R. A. Rippe, “DNase I-hypersensitive sites enhance a1(I) collagen gene expression in Hepatic Stellate Cells,” Hepatology 37,267–276 (2003).
[CrossRef] [PubMed]

K. L. Kusser and T. D. Randall, “Simultaneous detection of EGFP and cell surface markers by fluorescence Microscopy in Lymphoid Tissues,” J. Histochem. Cytochem. 51,5–14 (2003).
[CrossRef]

G. Cox, E. Kable, A. Jones, I. Fraser, K. Marconi, and M. D. Gorrell, “3-dimensional imaging of collagen using second harmonic generation,” J. Struct. Biol. 141,53–62 (2003).
[CrossRef] [PubMed]

E. Brown, T. Mckee, E. Ditomaso, A. Pluen, B. Seed, Y. Boucher, and R. K. Jain, “Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation,” Nat. Med. 9,796–800 (2003).
[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. USA 100,7075–7080 (2003).
[CrossRef] [PubMed]

K. König and I. Riemann, “High-resolution multiphoton tomography of human skin with subcellular spatial resolution and picosecond time resolution,” J. Biomed. Opt. 8,432–439 (2003).
[CrossRef] [PubMed]

P. Stoller, P. M. Celliers, K. M. Reiser, and A. M. Rubenchik, “Quantitative second-harmonic generation microscopy in collagen,” Appl. Opt. 42,5209–5219 (2003).
[CrossRef] [PubMed]

2002 (4)

D. J. S. Hulmes, “Building collagen molecules, fibrils, and suprafibrillar structures,” J. Struct. Biol. 137,2–10 (2002).
[CrossRef] [PubMed]

P. J. Campagnola, A. C. Millard, M. Terasaki, P. E. Hoppe, C. J. Malone, and W. A. Mohler, “Three-dimensional high-resolution Second-Harmonic Generation imaging of endogenous structural proteins in biological tissues,” Biophys. J. 82,493–508 (2002).
[CrossRef]

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

W. Wang, J. B. Wyckoff, V. C. Frohlich, Y. Oleynikov, S. Hüttelmaier, J. Zavadil, L. Cermak, E. P. Bottinger, R. H. Singer, J. G. White, J. E. Segall, and J. S. Condeelis, “Single cell behavior in metastatic primary mammary tumors correlated with gene expressions patterns revealed by molecular profiling,” Cancer Res. 62,6278–6288 (2002).
[PubMed]

2001 (2)

J. Mertz and L. Moreaux, “Second-harmonic generation by focused excitation in inhomogeneously distributed scatterers,” Opt. Commun. 196,325–330 (2001).
[CrossRef]

M. Oheim, E. Beaurepaire, E. Chaigneau, J. Mertz, and S. Charpak, “Two-photon microscopy in brain tissue: parameters influencing the imaging depth,” J. Neurosci. Methods 111,29–37 (2001).
[CrossRef] [PubMed]

2000 (2)

A. K. Dunn, V. P. Wallace, M. Coleno, M. W. Berns, and B. J. Tromberg, “Influence of optical properties on two-photon fluorescence imaging in turbid samples,” Appl. Opt. 39,1194–1201 (2000).
[CrossRef]

B. M. Kim, J. Eichler, K. M. Reiser, A. M. Rubenchik, and L. B. Da Silva, “Collagen structure and nonlinear susceptibility: effects of heat, glycation, and enzymatic cleavage on second harmonic signal intensity,” Lasers Surg. Med. 27,329–335 (2000).
[CrossRef] [PubMed]

1995 (1)

M. S. Razzaque, M. Cheng, Y. Horita, M. Nishihara, T. Harada, and T. Taguchi, “Immunohistochemical analysis of type III and IV collagens in tubulointerstitial damage in human benign nephrosclerosis,” J. Int. Med. Res. 23,480–486 (1995).
[PubMed]

1994 (2)

P. Whittaker, R. A. Kloner, D. R. Boughner, and J. G. Pickering, “Quantitative assessment of myocardial collagen with picrosirius red staining and circularly polarized light,” Basic Res. Cardiol. 89,397–410 (1994).
[CrossRef] [PubMed]

N. Buyukbabani and D. Droz, “Distribution of the extracellular matrix components in human glomerular lesions,” J. Pathol. 172,199–207 (1994).
[CrossRef] [PubMed]

1992 (1)

K. A. Nath, “Tubulointerstitial changes as a major determinant in the progression of renal damage,” Am. J. Kidney Dis. 20,1–17 (1992).
[PubMed]

1979 (1)

L. C. U. Junqueira, G. Bignolas, and R. R. Brentani, “Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections,” Histochem. J. 11,447–155 (1979).
[CrossRef] [PubMed]

Agodoa, L.

A. Fogo, J. A. Breyer, M. C. Smith, W. H. Cleveland, L. Agodoa, K. A. Kirk, and R. Glassock, “Accuracy of the diagnosis of hypertensive nephrosclerosis in African Americans: a report from the African American Study of Kidney Disease (AASK) Trial. AASK pilot study investigators,” Kidney Int.51 (1997).
[CrossRef] [PubMed]

Beaurepaire, E.

T. Boulesteix, A. M. Pena, N. Pagès, G. Godeau, M.-P. Sauviat, E. Beaurepaire, and M. C. Schanne-Klein, “Micrometer scale ex vivo multiphoton imaging of unstained arterial wall structure,” Cytometry 69A,20–26 (2006).
[CrossRef]

D. Débarre, W. Suppato, A. M. Pena, A. Fabre, T. Tordjmann, L. Combettes, M. C. Schanne-Klein, and E. Beaurepaire, “Imaging lipid bodies in cells and tissues using third-harmonic generation microscopy,” Nat. Methods 3,47 –53 (2006).
[CrossRef]

M. Oheim, E. Beaurepaire, E. Chaigneau, J. Mertz, and S. Charpak, “Two-photon microscopy in brain tissue: parameters influencing the imaging depth,” J. Neurosci. Methods 111,29–37 (2001).
[CrossRef] [PubMed]

A.-M. Pena, A. Fabre, D. Débarre, J. Marchal-Somme, B. Crestani, J.-L. Martin, E. Beaurepaire, and M.-C. Schanne-Klein, “Three-dimensional investigation and scoring of extracellular matrix remodeling during lung fibrosis using multiphoton microscopy,” Microsc. Res. Tech. in press (2007).
[CrossRef]

Berns, M. W.

Bignolas, G.

L. C. U. Junqueira, G. Bignolas, and R. R. Brentani, “Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections,” Histochem. J. 11,447–155 (1979).
[CrossRef] [PubMed]

Bille, J. F.

Bottinger, E. P.

W. Wang, J. B. Wyckoff, V. C. Frohlich, Y. Oleynikov, S. Hüttelmaier, J. Zavadil, L. Cermak, E. P. Bottinger, R. H. Singer, J. G. White, J. E. Segall, and J. S. Condeelis, “Single cell behavior in metastatic primary mammary tumors correlated with gene expressions patterns revealed by molecular profiling,” Cancer Res. 62,6278–6288 (2002).
[PubMed]

Boucher, Y.

E. Brown, T. Mckee, E. Ditomaso, A. Pluen, B. Seed, Y. Boucher, and R. K. Jain, “Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation,” Nat. Med. 9,796–800 (2003).
[CrossRef] [PubMed]

Boughner, D. R.

P. Whittaker, R. A. Kloner, D. R. Boughner, and J. G. Pickering, “Quantitative assessment of myocardial collagen with picrosirius red staining and circularly polarized light,” Basic Res. Cardiol. 89,397–410 (1994).
[CrossRef] [PubMed]

Boulesteix, T.

T. Boulesteix, A. M. Pena, N. Pagès, G. Godeau, M.-P. Sauviat, E. Beaurepaire, and M. C. Schanne-Klein, “Micrometer scale ex vivo multiphoton imaging of unstained arterial wall structure,” Cytometry 69A,20–26 (2006).
[CrossRef]

A.-M. Pena, T. Boulesteix, T. Dartigalongue, and M.-C. Schanne-Klein, “Chiroptical effects in the second harmonic signal of collagens I and IV,” J. Am. Chem. Soc. 127,10314–10322 (2005).
[CrossRef] [PubMed]

A.-M. Pena, M. Strupler, T. Boulesteix, G. Godeau, and M.-C. Schanne-Klein, “Spectroscopic analysis of keratin endogenous signal for skin multiphoton microscopy,” Opt. Express 13,6268–6274; erratum: 13(17), 6667 (2005).
[CrossRef] [PubMed]

Breindl, M.

Y. Yata, A. Scanga, A. Gillan, L. Yang, S. Reif, M. Breindl, D. A. Brenner, and R. A. Rippe, “DNase I-hypersensitive sites enhance a1(I) collagen gene expression in Hepatic Stellate Cells,” Hepatology 37,267–276 (2003).
[CrossRef] [PubMed]

Brenner, D. A.

Y. Yata, A. Scanga, A. Gillan, L. Yang, S. Reif, M. Breindl, D. A. Brenner, and R. A. Rippe, “DNase I-hypersensitive sites enhance a1(I) collagen gene expression in Hepatic Stellate Cells,” Hepatology 37,267–276 (2003).
[CrossRef] [PubMed]

Brentani, R. R.

L. C. U. Junqueira, G. Bignolas, and R. R. Brentani, “Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections,” Histochem. J. 11,447–155 (1979).
[CrossRef] [PubMed]

Breyer, J. A.

A. Fogo, J. A. Breyer, M. C. Smith, W. H. Cleveland, L. Agodoa, K. A. Kirk, and R. Glassock, “Accuracy of the diagnosis of hypertensive nephrosclerosis in African Americans: a report from the African American Study of Kidney Disease (AASK) Trial. AASK pilot study investigators,” Kidney Int.51 (1997).
[CrossRef] [PubMed]

Brown, E.

E. Brown, T. Mckee, E. Ditomaso, A. Pluen, B. Seed, Y. Boucher, and R. K. Jain, “Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation,” Nat. Med. 9,796–800 (2003).
[CrossRef] [PubMed]

Bruijn, H. S. D.

Bückle, R.

Buyukbabani, N.

N. Buyukbabani and D. Droz, “Distribution of the extracellular matrix components in human glomerular lesions,” J. Pathol. 172,199–207 (1994).
[CrossRef] [PubMed]

Campagnola, P. J.

P. J. Campagnola, A. C. Millard, M. Terasaki, P. E. Hoppe, C. J. Malone, and W. A. Mohler, “Three-dimensional high-resolution Second-Harmonic Generation imaging of endogenous structural proteins in biological tissues,” Biophys. J. 82,493–508 (2002).
[CrossRef]

Celliers, P. M.

Cermak, L.

W. Wang, J. B. Wyckoff, V. C. Frohlich, Y. Oleynikov, S. Hüttelmaier, J. Zavadil, L. Cermak, E. P. Bottinger, R. H. Singer, J. G. White, J. E. Segall, and J. S. Condeelis, “Single cell behavior in metastatic primary mammary tumors correlated with gene expressions patterns revealed by molecular profiling,” Cancer Res. 62,6278–6288 (2002).
[PubMed]

Chaigneau, E.

M. Oheim, E. Beaurepaire, E. Chaigneau, J. Mertz, and S. Charpak, “Two-photon microscopy in brain tissue: parameters influencing the imaging depth,” J. Neurosci. Methods 111,29–37 (2001).
[CrossRef] [PubMed]

Charpak, S.

M. Oheim, E. Beaurepaire, E. Chaigneau, J. Mertz, and S. Charpak, “Two-photon microscopy in brain tissue: parameters influencing the imaging depth,” J. Neurosci. Methods 111,29–37 (2001).
[CrossRef] [PubMed]

Chen, H-C.

W. Lo, S-W. Teng, H-Y. Tan, K. H. Kim, H-C. Chen, H-S. Lee, Y-F. Chen, P. T. C. So, and C.-Y. Dong, “Intact corneal stroma visualization of GFP mouse revealed by multiphoton imaging,” Microsc. Res. Tech. 69,973–975 (2006)
[CrossRef] [PubMed]

Chen, J.-S.

Chen, Y-F.

W. Lo, S-W. Teng, H-Y. Tan, K. H. Kim, H-C. Chen, H-S. Lee, Y-F. Chen, P. T. C. So, and C.-Y. Dong, “Intact corneal stroma visualization of GFP mouse revealed by multiphoton imaging,” Microsc. Res. Tech. 69,973–975 (2006)
[CrossRef] [PubMed]

Cheng, M.

M. S. Razzaque, M. Cheng, Y. Horita, M. Nishihara, T. Harada, and T. Taguchi, “Immunohistochemical analysis of type III and IV collagens in tubulointerstitial damage in human benign nephrosclerosis,” J. Int. Med. Res. 23,480–486 (1995).
[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. USA 100,7075–7080 (2003).
[CrossRef] [PubMed]

Cleveland, W. H.

A. Fogo, J. A. Breyer, M. C. Smith, W. H. Cleveland, L. Agodoa, K. A. Kirk, and R. Glassock, “Accuracy of the diagnosis of hypertensive nephrosclerosis in African Americans: a report from the African American Study of Kidney Disease (AASK) Trial. AASK pilot study investigators,” Kidney Int.51 (1997).
[CrossRef] [PubMed]

Coleno, M.

Combettes, L.

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W. Wang, J. B. Wyckoff, V. C. Frohlich, Y. Oleynikov, S. Hüttelmaier, J. Zavadil, L. Cermak, E. P. Bottinger, R. H. Singer, J. G. White, J. E. Segall, and J. S. Condeelis, “Single cell behavior in metastatic primary mammary tumors correlated with gene expressions patterns revealed by molecular profiling,” Cancer Res. 62,6278–6288 (2002).
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G. Cox, E. Kable, A. Jones, I. Fraser, K. Marconi, and M. D. Gorrell, “3-dimensional imaging of collagen using second harmonic generation,” J. Struct. Biol. 141,53–62 (2003).
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Crestani, B.

A.-M. Pena, A. Fabre, D. Débarre, J. Marchal-Somme, B. Crestani, J.-L. Martin, E. Beaurepaire, and M.-C. Schanne-Klein, “Three-dimensional investigation and scoring of extracellular matrix remodeling during lung fibrosis using multiphoton microscopy,” Microsc. Res. Tech. in press (2007).
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Dartigalongue, T.

A.-M. Pena, T. Boulesteix, T. Dartigalongue, and M.-C. Schanne-Klein, “Chiroptical effects in the second harmonic signal of collagens I and IV,” J. Am. Chem. Soc. 127,10314–10322 (2005).
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Débarre, D.

D. Débarre, W. Suppato, A. M. Pena, A. Fabre, T. Tordjmann, L. Combettes, M. C. Schanne-Klein, and E. Beaurepaire, “Imaging lipid bodies in cells and tissues using third-harmonic generation microscopy,” Nat. Methods 3,47 –53 (2006).
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A.-M. Pena, A. Fabre, D. Débarre, J. Marchal-Somme, B. Crestani, J.-L. Martin, E. Beaurepaire, and M.-C. Schanne-Klein, “Three-dimensional investigation and scoring of extracellular matrix remodeling during lung fibrosis using multiphoton microscopy,” Microsc. Res. Tech. in press (2007).
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E. Brown, T. Mckee, E. Ditomaso, A. Pluen, B. Seed, Y. Boucher, and R. K. Jain, “Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation,” Nat. Med. 9,796–800 (2003).
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W. Lo, S-W. Teng, H-Y. Tan, K. H. Kim, H-C. Chen, H-S. Lee, Y-F. Chen, P. T. C. So, and C.-Y. Dong, “Intact corneal stroma visualization of GFP mouse revealed by multiphoton imaging,” Microsc. Res. Tech. 69,973–975 (2006)
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Fabre, A.

D. Débarre, W. Suppato, A. M. Pena, A. Fabre, T. Tordjmann, L. Combettes, M. C. Schanne-Klein, and E. Beaurepaire, “Imaging lipid bodies in cells and tissues using third-harmonic generation microscopy,” Nat. Methods 3,47 –53 (2006).
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A.-M. Pena, A. Fabre, D. Débarre, J. Marchal-Somme, B. Crestani, J.-L. Martin, E. Beaurepaire, and M.-C. Schanne-Klein, “Three-dimensional investigation and scoring of extracellular matrix remodeling during lung fibrosis using multiphoton microscopy,” Microsc. Res. Tech. in press (2007).
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A. Fogo, J. A. Breyer, M. C. Smith, W. H. Cleveland, L. Agodoa, K. A. Kirk, and R. Glassock, “Accuracy of the diagnosis of hypertensive nephrosclerosis in African Americans: a report from the African American Study of Kidney Disease (AASK) Trial. AASK pilot study investigators,” Kidney Int.51 (1997).
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G. Cox, E. Kable, A. Jones, I. Fraser, K. Marconi, and M. D. Gorrell, “3-dimensional imaging of collagen using second harmonic generation,” J. Struct. Biol. 141,53–62 (2003).
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W. Wang, J. B. Wyckoff, V. C. Frohlich, Y. Oleynikov, S. Hüttelmaier, J. Zavadil, L. Cermak, E. P. Bottinger, R. H. Singer, J. G. White, J. E. Segall, and J. S. Condeelis, “Single cell behavior in metastatic primary mammary tumors correlated with gene expressions patterns revealed by molecular profiling,” Cancer Res. 62,6278–6288 (2002).
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Giese, G.

Gillan, A.

Y. Yata, A. Scanga, A. Gillan, L. Yang, S. Reif, M. Breindl, D. A. Brenner, and R. A. Rippe, “DNase I-hypersensitive sites enhance a1(I) collagen gene expression in Hepatic Stellate Cells,” Hepatology 37,267–276 (2003).
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A. Fogo, J. A. Breyer, M. C. Smith, W. H. Cleveland, L. Agodoa, K. A. Kirk, and R. Glassock, “Accuracy of the diagnosis of hypertensive nephrosclerosis in African Americans: a report from the African American Study of Kidney Disease (AASK) Trial. AASK pilot study investigators,” Kidney Int.51 (1997).
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T. Boulesteix, A. M. Pena, N. Pagès, G. Godeau, M.-P. Sauviat, E. Beaurepaire, and M. C. Schanne-Klein, “Micrometer scale ex vivo multiphoton imaging of unstained arterial wall structure,” Cytometry 69A,20–26 (2006).
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A.-M. Pena, M. Strupler, T. Boulesteix, G. Godeau, and M.-C. Schanne-Klein, “Spectroscopic analysis of keratin endogenous signal for skin multiphoton microscopy,” Opt. Express 13,6268–6274; erratum: 13(17), 6667 (2005).
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Gorrell, M. D.

G. Cox, E. Kable, A. Jones, I. Fraser, K. Marconi, and M. D. Gorrell, “3-dimensional imaging of collagen using second harmonic generation,” J. Struct. Biol. 141,53–62 (2003).
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Harada, T.

M. S. Razzaque, M. Cheng, Y. Horita, M. Nishihara, T. Harada, and T. Taguchi, “Immunohistochemical analysis of type III and IV collagens in tubulointerstitial damage in human benign nephrosclerosis,” J. Int. Med. Res. 23,480–486 (1995).
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Hoppe, P. E.

P. J. Campagnola, A. C. Millard, M. Terasaki, P. E. Hoppe, C. J. Malone, and W. A. Mohler, “Three-dimensional high-resolution Second-Harmonic Generation imaging of endogenous structural proteins in biological tissues,” Biophys. J. 82,493–508 (2002).
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M. S. Razzaque, M. Cheng, Y. Horita, M. Nishihara, T. Harada, and T. Taguchi, “Immunohistochemical analysis of type III and IV collagens in tubulointerstitial damage in human benign nephrosclerosis,” J. Int. Med. Res. 23,480–486 (1995).
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W. Wang, J. B. Wyckoff, V. C. Frohlich, Y. Oleynikov, S. Hüttelmaier, J. Zavadil, L. Cermak, E. P. Bottinger, R. H. Singer, J. G. White, J. E. Segall, and J. S. Condeelis, “Single cell behavior in metastatic primary mammary tumors correlated with gene expressions patterns revealed by molecular profiling,” Cancer Res. 62,6278–6288 (2002).
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W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. USA 100,7075–7080 (2003).
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Jain, R. K.

E. Brown, T. Mckee, E. Ditomaso, A. Pluen, B. Seed, Y. Boucher, and R. K. Jain, “Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation,” Nat. Med. 9,796–800 (2003).
[CrossRef] [PubMed]

Jee, S.-H.

Jones, A.

G. Cox, E. Kable, A. Jones, I. Fraser, K. Marconi, and M. D. Gorrell, “3-dimensional imaging of collagen using second harmonic generation,” J. Struct. Biol. 141,53–62 (2003).
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Kable, E.

G. Cox, E. Kable, A. Jones, I. Fraser, K. Marconi, and M. D. Gorrell, “3-dimensional imaging of collagen using second harmonic generation,” J. Struct. Biol. 141,53–62 (2003).
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Kassab, G. S.

A. Zoumi, X. Lu, G. S. Kassab, and B. J. Tromberg, “Imaging coronary artery microstructure using second-harmonic and two-photon fluorescence microscopy,” Biophys. J. 87,2778–2786 (2004).
[CrossRef] [PubMed]

Kim, B. M.

B. M. Kim, J. Eichler, K. M. Reiser, A. M. Rubenchik, and L. B. Da Silva, “Collagen structure and nonlinear susceptibility: effects of heat, glycation, and enzymatic cleavage on second harmonic signal intensity,” Lasers Surg. Med. 27,329–335 (2000).
[CrossRef] [PubMed]

Kim, K. H.

W. Lo, S-W. Teng, H-Y. Tan, K. H. Kim, H-C. Chen, H-S. Lee, Y-F. Chen, P. T. C. So, and C.-Y. Dong, “Intact corneal stroma visualization of GFP mouse revealed by multiphoton imaging,” Microsc. Res. Tech. 69,973–975 (2006)
[CrossRef] [PubMed]

Kirk, K. A.

A. Fogo, J. A. Breyer, M. C. Smith, W. H. Cleveland, L. Agodoa, K. A. Kirk, and R. Glassock, “Accuracy of the diagnosis of hypertensive nephrosclerosis in African Americans: a report from the African American Study of Kidney Disease (AASK) Trial. AASK pilot study investigators,” Kidney Int.51 (1997).
[CrossRef] [PubMed]

Kloner, R. A.

P. Whittaker, R. A. Kloner, D. R. Boughner, and J. G. Pickering, “Quantitative assessment of myocardial collagen with picrosirius red staining and circularly polarized light,” Basic Res. Cardiol. 89,397–410 (1994).
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Koehler, M. J.

König, K

König, K.

K. Schenke-Layland, I. Riemann, U. A. Stock, and K. König, “Imaging of cardiovascular structures using near-infrared femtosecond multiphoton laser scanning microscopy,” J. Biomed. Opt. 10,024017 (2005).
[CrossRef] [PubMed]

K. König and I. Riemann, “High-resolution multiphoton tomography of human skin with subcellular spatial resolution and picosecond time resolution,” J. Biomed. Opt. 8,432–439 (2003).
[CrossRef] [PubMed]

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K. L. Kusser and T. D. Randall, “Simultaneous detection of EGFP and cell surface markers by fluorescence Microscopy in Lymphoid Tissues,” J. Histochem. Cytochem. 51,5–14 (2003).
[CrossRef]

Lee, H-S.

W. Lo, S-W. Teng, H-Y. Tan, K. H. Kim, H-C. Chen, H-S. Lee, Y-F. Chen, P. T. C. So, and C.-Y. Dong, “Intact corneal stroma visualization of GFP mouse revealed by multiphoton imaging,” Microsc. Res. Tech. 69,973–975 (2006)
[CrossRef] [PubMed]

Lin, S.-J.

Lin, W.-C.

Lo, W.

W. Lo, S-W. Teng, H-Y. Tan, K. H. Kim, H-C. Chen, H-S. Lee, Y-F. Chen, P. T. C. So, and C.-Y. Dong, “Intact corneal stroma visualization of GFP mouse revealed by multiphoton imaging,” Microsc. Res. Tech. 69,973–975 (2006)
[CrossRef] [PubMed]

S.-J. Lin, R.-Jr Wu, H.-Y. Tan, W. Lo, W.-C. Lin, T.-H. Young, C.-J. Hsu, J.-S. Chen, S.-H. Jee, and C.-Y. Dong, “Evaluating cutaneous photoaging by use of multiphoton fluorescence and second-harmonic generation microscopy,” Opt. Lett. 30,2275–2277 (2005).
[CrossRef] [PubMed]

Lu, X.

A. Zoumi, X. Lu, G. S. Kassab, and B. J. Tromberg, “Imaging coronary artery microstructure using second-harmonic and two-photon fluorescence microscopy,” Biophys. J. 87,2778–2786 (2004).
[CrossRef] [PubMed]

Malone, C. J.

P. J. Campagnola, A. C. Millard, M. Terasaki, P. E. Hoppe, C. J. Malone, and W. A. Mohler, “Three-dimensional high-resolution Second-Harmonic Generation imaging of endogenous structural proteins in biological tissues,” Biophys. J. 82,493–508 (2002).
[CrossRef]

Marchal-Somme, J.

A.-M. Pena, A. Fabre, D. Débarre, J. Marchal-Somme, B. Crestani, J.-L. Martin, E. Beaurepaire, and M.-C. Schanne-Klein, “Three-dimensional investigation and scoring of extracellular matrix remodeling during lung fibrosis using multiphoton microscopy,” Microsc. Res. Tech. in press (2007).
[CrossRef]

Marconi, K.

G. Cox, E. Kable, A. Jones, I. Fraser, K. Marconi, and M. D. Gorrell, “3-dimensional imaging of collagen using second harmonic generation,” J. Struct. Biol. 141,53–62 (2003).
[CrossRef] [PubMed]

Martin, J.-L.

A.-M. Pena, A. Fabre, D. Débarre, J. Marchal-Somme, B. Crestani, J.-L. Martin, E. Beaurepaire, and M.-C. Schanne-Klein, “Three-dimensional investigation and scoring of extracellular matrix remodeling during lung fibrosis using multiphoton microscopy,” Microsc. Res. Tech. in press (2007).
[CrossRef]

Mckee, T.

E. Brown, T. Mckee, E. Ditomaso, A. Pluen, B. Seed, Y. Boucher, and R. K. Jain, “Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation,” Nat. Med. 9,796–800 (2003).
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J. Mertz and L. Moreaux, “Second-harmonic generation by focused excitation in inhomogeneously distributed scatterers,” Opt. Commun. 196,325–330 (2001).
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M. Oheim, E. Beaurepaire, E. Chaigneau, J. Mertz, and S. Charpak, “Two-photon microscopy in brain tissue: parameters influencing the imaging depth,” J. Neurosci. Methods 111,29–37 (2001).
[CrossRef] [PubMed]

Millard, A. C.

P. J. Campagnola, A. C. Millard, M. Terasaki, P. E. Hoppe, C. J. Malone, and W. A. Mohler, “Three-dimensional high-resolution Second-Harmonic Generation imaging of endogenous structural proteins in biological tissues,” Biophys. J. 82,493–508 (2002).
[CrossRef]

Mohler, W. A.

P. J. Campagnola, A. C. Millard, M. Terasaki, P. E. Hoppe, C. J. Malone, and W. A. Mohler, “Three-dimensional high-resolution Second-Harmonic Generation imaging of endogenous structural proteins in biological tissues,” Biophys. J. 82,493–508 (2002).
[CrossRef]

Moreaux, L.

J. Mertz and L. Moreaux, “Second-harmonic generation by focused excitation in inhomogeneously distributed scatterers,” Opt. Commun. 196,325–330 (2001).
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K. A. Nath, “Tubulointerstitial changes as a major determinant in the progression of renal damage,” Am. J. Kidney Dis. 20,1–17 (1992).
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W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. USA 100,7075–7080 (2003).
[CrossRef] [PubMed]

Nishihara, M.

M. S. Razzaque, M. Cheng, Y. Horita, M. Nishihara, T. Harada, and T. Taguchi, “Immunohistochemical analysis of type III and IV collagens in tubulointerstitial damage in human benign nephrosclerosis,” J. Int. Med. Res. 23,480–486 (1995).
[PubMed]

Oheim, M.

M. Oheim, E. Beaurepaire, E. Chaigneau, J. Mertz, and S. Charpak, “Two-photon microscopy in brain tissue: parameters influencing the imaging depth,” J. Neurosci. Methods 111,29–37 (2001).
[CrossRef] [PubMed]

Oleynikov, Y.

W. Wang, J. B. Wyckoff, V. C. Frohlich, Y. Oleynikov, S. Hüttelmaier, J. Zavadil, L. Cermak, E. P. Bottinger, R. H. Singer, J. G. White, J. E. Segall, and J. S. Condeelis, “Single cell behavior in metastatic primary mammary tumors correlated with gene expressions patterns revealed by molecular profiling,” Cancer Res. 62,6278–6288 (2002).
[PubMed]

Pagès, N.

T. Boulesteix, A. M. Pena, N. Pagès, G. Godeau, M.-P. Sauviat, E. Beaurepaire, and M. C. Schanne-Klein, “Micrometer scale ex vivo multiphoton imaging of unstained arterial wall structure,” Cytometry 69A,20–26 (2006).
[CrossRef]

Palero, J. A.

Pena, A. M.

T. Boulesteix, A. M. Pena, N. Pagès, G. Godeau, M.-P. Sauviat, E. Beaurepaire, and M. C. Schanne-Klein, “Micrometer scale ex vivo multiphoton imaging of unstained arterial wall structure,” Cytometry 69A,20–26 (2006).
[CrossRef]

D. Débarre, W. Suppato, A. M. Pena, A. Fabre, T. Tordjmann, L. Combettes, M. C. Schanne-Klein, and E. Beaurepaire, “Imaging lipid bodies in cells and tissues using third-harmonic generation microscopy,” Nat. Methods 3,47 –53 (2006).
[CrossRef]

Pena, A.-M.

A.-M. Pena, T. Boulesteix, T. Dartigalongue, and M.-C. Schanne-Klein, “Chiroptical effects in the second harmonic signal of collagens I and IV,” J. Am. Chem. Soc. 127,10314–10322 (2005).
[CrossRef] [PubMed]

A.-M. Pena, M. Strupler, T. Boulesteix, G. Godeau, and M.-C. Schanne-Klein, “Spectroscopic analysis of keratin endogenous signal for skin multiphoton microscopy,” Opt. Express 13,6268–6274; erratum: 13(17), 6667 (2005).
[CrossRef] [PubMed]

A.-M. Pena, A. Fabre, D. Débarre, J. Marchal-Somme, B. Crestani, J.-L. Martin, E. Beaurepaire, and M.-C. Schanne-Klein, “Three-dimensional investigation and scoring of extracellular matrix remodeling during lung fibrosis using multiphoton microscopy,” Microsc. Res. Tech. in press (2007).
[CrossRef]

Pickering, J. G.

P. Whittaker, R. A. Kloner, D. R. Boughner, and J. G. Pickering, “Quantitative assessment of myocardial collagen with picrosirius red staining and circularly polarized light,” Basic Res. Cardiol. 89,397–410 (1994).
[CrossRef] [PubMed]

Pluen, A.

E. Brown, T. Mckee, E. Ditomaso, A. Pluen, B. Seed, Y. Boucher, and R. K. Jain, “Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation,” Nat. Med. 9,796–800 (2003).
[CrossRef] [PubMed]

Randall, T. D.

K. L. Kusser and T. D. Randall, “Simultaneous detection of EGFP and cell surface markers by fluorescence Microscopy in Lymphoid Tissues,” J. Histochem. Cytochem. 51,5–14 (2003).
[CrossRef]

Razzaque, M. S.

M. S. Razzaque, M. Cheng, Y. Horita, M. Nishihara, T. Harada, and T. Taguchi, “Immunohistochemical analysis of type III and IV collagens in tubulointerstitial damage in human benign nephrosclerosis,” J. Int. Med. Res. 23,480–486 (1995).
[PubMed]

Reif, S.

Y. Yata, A. Scanga, A. Gillan, L. Yang, S. Reif, M. Breindl, D. A. Brenner, and R. A. Rippe, “DNase I-hypersensitive sites enhance a1(I) collagen gene expression in Hepatic Stellate Cells,” Hepatology 37,267–276 (2003).
[CrossRef] [PubMed]

Reiser, K. M.

P. Stoller, P. M. Celliers, K. M. Reiser, and A. M. Rubenchik, “Quantitative second-harmonic generation microscopy in collagen,” Appl. Opt. 42,5209–5219 (2003).
[CrossRef] [PubMed]

B. M. Kim, J. Eichler, K. M. Reiser, A. M. Rubenchik, and L. B. Da Silva, “Collagen structure and nonlinear susceptibility: effects of heat, glycation, and enzymatic cleavage on second harmonic signal intensity,” Lasers Surg. Med. 27,329–335 (2000).
[CrossRef] [PubMed]

Riemann, I.

K. Schenke-Layland, I. Riemann, U. A. Stock, and K. König, “Imaging of cardiovascular structures using near-infrared femtosecond multiphoton laser scanning microscopy,” J. Biomed. Opt. 10,024017 (2005).
[CrossRef] [PubMed]

K. König and I. Riemann, “High-resolution multiphoton tomography of human skin with subcellular spatial resolution and picosecond time resolution,” J. Biomed. Opt. 8,432–439 (2003).
[CrossRef] [PubMed]

Rippe, R. A.

Y. Yata, A. Scanga, A. Gillan, L. Yang, S. Reif, M. Breindl, D. A. Brenner, and R. A. Rippe, “DNase I-hypersensitive sites enhance a1(I) collagen gene expression in Hepatic Stellate Cells,” Hepatology 37,267–276 (2003).
[CrossRef] [PubMed]

Rubenchik, A. M.

P. Stoller, P. M. Celliers, K. M. Reiser, and A. M. Rubenchik, “Quantitative second-harmonic generation microscopy in collagen,” Appl. Opt. 42,5209–5219 (2003).
[CrossRef] [PubMed]

B. M. Kim, J. Eichler, K. M. Reiser, A. M. Rubenchik, and L. B. Da Silva, “Collagen structure and nonlinear susceptibility: effects of heat, glycation, and enzymatic cleavage on second harmonic signal intensity,” Lasers Surg. Med. 27,329–335 (2000).
[CrossRef] [PubMed]

Sauviat, M.-P.

T. Boulesteix, A. M. Pena, N. Pagès, G. Godeau, M.-P. Sauviat, E. Beaurepaire, and M. C. Schanne-Klein, “Micrometer scale ex vivo multiphoton imaging of unstained arterial wall structure,” Cytometry 69A,20–26 (2006).
[CrossRef]

Scanga, A.

Y. Yata, A. Scanga, A. Gillan, L. Yang, S. Reif, M. Breindl, D. A. Brenner, and R. A. Rippe, “DNase I-hypersensitive sites enhance a1(I) collagen gene expression in Hepatic Stellate Cells,” Hepatology 37,267–276 (2003).
[CrossRef] [PubMed]

Schanne-Klein, M. C.

D. Débarre, W. Suppato, A. M. Pena, A. Fabre, T. Tordjmann, L. Combettes, M. C. Schanne-Klein, and E. Beaurepaire, “Imaging lipid bodies in cells and tissues using third-harmonic generation microscopy,” Nat. Methods 3,47 –53 (2006).
[CrossRef]

T. Boulesteix, A. M. Pena, N. Pagès, G. Godeau, M.-P. Sauviat, E. Beaurepaire, and M. C. Schanne-Klein, “Micrometer scale ex vivo multiphoton imaging of unstained arterial wall structure,” Cytometry 69A,20–26 (2006).
[CrossRef]

Schanne-Klein, M.-C.

A.-M. Pena, T. Boulesteix, T. Dartigalongue, and M.-C. Schanne-Klein, “Chiroptical effects in the second harmonic signal of collagens I and IV,” J. Am. Chem. Soc. 127,10314–10322 (2005).
[CrossRef] [PubMed]

A.-M. Pena, M. Strupler, T. Boulesteix, G. Godeau, and M.-C. Schanne-Klein, “Spectroscopic analysis of keratin endogenous signal for skin multiphoton microscopy,” Opt. Express 13,6268–6274; erratum: 13(17), 6667 (2005).
[CrossRef] [PubMed]

A.-M. Pena, A. Fabre, D. Débarre, J. Marchal-Somme, B. Crestani, J.-L. Martin, E. Beaurepaire, and M.-C. Schanne-Klein, “Three-dimensional investigation and scoring of extracellular matrix remodeling during lung fibrosis using multiphoton microscopy,” Microsc. Res. Tech. in press (2007).
[CrossRef]

Schenke-Layland, K.

K. Schenke-Layland, I. Riemann, U. A. Stock, and K. König, “Imaging of cardiovascular structures using near-infrared femtosecond multiphoton laser scanning microscopy,” J. Biomed. Opt. 10,024017 (2005).
[CrossRef] [PubMed]

Seed, B.

E. Brown, T. Mckee, E. Ditomaso, A. Pluen, B. Seed, Y. Boucher, and R. K. Jain, “Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation,” Nat. Med. 9,796–800 (2003).
[CrossRef] [PubMed]

Segall, J. E.

W. Wang, J. B. Wyckoff, V. C. Frohlich, Y. Oleynikov, S. Hüttelmaier, J. Zavadil, L. Cermak, E. P. Bottinger, R. H. Singer, J. G. White, J. E. Segall, and J. S. Condeelis, “Single cell behavior in metastatic primary mammary tumors correlated with gene expressions patterns revealed by molecular profiling,” Cancer Res. 62,6278–6288 (2002).
[PubMed]

Silva, L. B. Da

B. M. Kim, J. Eichler, K. M. Reiser, A. M. Rubenchik, and L. B. Da Silva, “Collagen structure and nonlinear susceptibility: effects of heat, glycation, and enzymatic cleavage on second harmonic signal intensity,” Lasers Surg. Med. 27,329–335 (2000).
[CrossRef] [PubMed]

Singer, R. H.

W. Wang, J. B. Wyckoff, V. C. Frohlich, Y. Oleynikov, S. Hüttelmaier, J. Zavadil, L. Cermak, E. P. Bottinger, R. H. Singer, J. G. White, J. E. Segall, and J. S. Condeelis, “Single cell behavior in metastatic primary mammary tumors correlated with gene expressions patterns revealed by molecular profiling,” Cancer Res. 62,6278–6288 (2002).
[PubMed]

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A. Fogo, J. A. Breyer, M. C. Smith, W. H. Cleveland, L. Agodoa, K. A. Kirk, and R. Glassock, “Accuracy of the diagnosis of hypertensive nephrosclerosis in African Americans: a report from the African American Study of Kidney Disease (AASK) Trial. AASK pilot study investigators,” Kidney Int.51 (1997).
[CrossRef] [PubMed]

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W. Lo, S-W. Teng, H-Y. Tan, K. H. Kim, H-C. Chen, H-S. Lee, Y-F. Chen, P. T. C. So, and C.-Y. Dong, “Intact corneal stroma visualization of GFP mouse revealed by multiphoton imaging,” Microsc. Res. Tech. 69,973–975 (2006)
[CrossRef] [PubMed]

Sterenborg, H. J. C. M.

Stock, U. A.

K. Schenke-Layland, I. Riemann, U. A. Stock, and K. König, “Imaging of cardiovascular structures using near-infrared femtosecond multiphoton laser scanning microscopy,” J. Biomed. Opt. 10,024017 (2005).
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Stoller, P.

Strupler, M.

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D. Débarre, W. Suppato, A. M. Pena, A. Fabre, T. Tordjmann, L. Combettes, M. C. Schanne-Klein, and E. Beaurepaire, “Imaging lipid bodies in cells and tissues using third-harmonic generation microscopy,” Nat. Methods 3,47 –53 (2006).
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W. Lo, S-W. Teng, H-Y. Tan, K. H. Kim, H-C. Chen, H-S. Lee, Y-F. Chen, P. T. C. So, and C.-Y. Dong, “Intact corneal stroma visualization of GFP mouse revealed by multiphoton imaging,” Microsc. Res. Tech. 69,973–975 (2006)
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Teng, S-W.

W. Lo, S-W. Teng, H-Y. Tan, K. H. Kim, H-C. Chen, H-S. Lee, Y-F. Chen, P. T. C. So, and C.-Y. Dong, “Intact corneal stroma visualization of GFP mouse revealed by multiphoton imaging,” Microsc. Res. Tech. 69,973–975 (2006)
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D. Débarre, W. Suppato, A. M. Pena, A. Fabre, T. Tordjmann, L. Combettes, M. C. Schanne-Klein, and E. Beaurepaire, “Imaging lipid bodies in cells and tissues using third-harmonic generation microscopy,” Nat. Methods 3,47 –53 (2006).
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W. Wang, J. B. Wyckoff, V. C. Frohlich, Y. Oleynikov, S. Hüttelmaier, J. Zavadil, L. Cermak, E. P. Bottinger, R. H. Singer, J. G. White, J. E. Segall, and J. S. Condeelis, “Single cell behavior in metastatic primary mammary tumors correlated with gene expressions patterns revealed by molecular profiling,” Cancer Res. 62,6278–6288 (2002).
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R. M. Williams, W. R. Zipfel, and W. W. Webb, “Interpreting second-harmonic generation images of collagen fibrils,” Biophys. J. 88,1377–1386 (2005).
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W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. USA 100,7075–7080 (2003).
[CrossRef] [PubMed]

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Wyckoff, J. B.

W. Wang, J. B. Wyckoff, V. C. Frohlich, Y. Oleynikov, S. Hüttelmaier, J. Zavadil, L. Cermak, E. P. Bottinger, R. H. Singer, J. G. White, J. E. Segall, and J. S. Condeelis, “Single cell behavior in metastatic primary mammary tumors correlated with gene expressions patterns revealed by molecular profiling,” Cancer Res. 62,6278–6288 (2002).
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[CrossRef] [PubMed]

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

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Zavadil, J.

W. Wang, J. B. Wyckoff, V. C. Frohlich, Y. Oleynikov, S. Hüttelmaier, J. Zavadil, L. Cermak, E. P. Bottinger, R. H. Singer, J. G. White, J. E. Segall, and J. S. Condeelis, “Single cell behavior in metastatic primary mammary tumors correlated with gene expressions patterns revealed by molecular profiling,” Cancer Res. 62,6278–6288 (2002).
[PubMed]

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R. M. Williams, W. R. Zipfel, and W. W. Webb, “Interpreting second-harmonic generation images of collagen fibrils,” Biophys. J. 88,1377–1386 (2005).
[CrossRef]

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

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A. Zoumi, X. Lu, G. S. Kassab, and B. J. Tromberg, “Imaging coronary artery microstructure using second-harmonic and two-photon fluorescence microscopy,” Biophys. J. 87,2778–2786 (2004).
[CrossRef] [PubMed]

A. Zoumi, A. Yeh, and B. J. Tromberg, “Imaging cells and extracellular matrix in vivo by using second-harmonic generation and two-photon excited fluorescence,” Proc. Natl. Acad. Sci. USA 99,11014–11019 (2002).
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P. J. Campagnola, A. C. Millard, M. Terasaki, P. E. Hoppe, C. J. Malone, and W. A. Mohler, “Three-dimensional high-resolution Second-Harmonic Generation imaging of endogenous structural proteins in biological tissues,” Biophys. J. 82,493–508 (2002).
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W. Wang, J. B. Wyckoff, V. C. Frohlich, Y. Oleynikov, S. Hüttelmaier, J. Zavadil, L. Cermak, E. P. Bottinger, R. H. Singer, J. G. White, J. E. Segall, and J. S. Condeelis, “Single cell behavior in metastatic primary mammary tumors correlated with gene expressions patterns revealed by molecular profiling,” Cancer Res. 62,6278–6288 (2002).
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T. Boulesteix, A. M. Pena, N. Pagès, G. Godeau, M.-P. Sauviat, E. Beaurepaire, and M. C. Schanne-Klein, “Micrometer scale ex vivo multiphoton imaging of unstained arterial wall structure,” Cytometry 69A,20–26 (2006).
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J. Biomed. Opt. (2)

K. Schenke-Layland, I. Riemann, U. A. Stock, and K. König, “Imaging of cardiovascular structures using near-infrared femtosecond multiphoton laser scanning microscopy,” J. Biomed. Opt. 10,024017 (2005).
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M. S. Razzaque, M. Cheng, Y. Horita, M. Nishihara, T. Harada, and T. Taguchi, “Immunohistochemical analysis of type III and IV collagens in tubulointerstitial damage in human benign nephrosclerosis,” J. Int. Med. Res. 23,480–486 (1995).
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B. M. Kim, J. Eichler, K. M. Reiser, A. M. Rubenchik, and L. B. Da Silva, “Collagen structure and nonlinear susceptibility: effects of heat, glycation, and enzymatic cleavage on second harmonic signal intensity,” Lasers Surg. Med. 27,329–335 (2000).
[CrossRef] [PubMed]

Microsc. Res. Tech. (1)

W. Lo, S-W. Teng, H-Y. Tan, K. H. Kim, H-C. Chen, H-S. Lee, Y-F. Chen, P. T. C. So, and C.-Y. Dong, “Intact corneal stroma visualization of GFP mouse revealed by multiphoton imaging,” Microsc. Res. Tech. 69,973–975 (2006)
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Nat. Methods (1)

D. Débarre, W. Suppato, A. M. Pena, A. Fabre, T. Tordjmann, L. Combettes, M. C. Schanne-Klein, and E. Beaurepaire, “Imaging lipid bodies in cells and tissues using third-harmonic generation microscopy,” Nat. Methods 3,47 –53 (2006).
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W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. USA 100,7075–7080 (2003).
[CrossRef] [PubMed]

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[CrossRef] [PubMed]

Other (2)

A.-M. Pena, A. Fabre, D. Débarre, J. Marchal-Somme, B. Crestani, J.-L. Martin, E. Beaurepaire, and M.-C. Schanne-Klein, “Three-dimensional investigation and scoring of extracellular matrix remodeling during lung fibrosis using multiphoton microscopy,” Microsc. Res. Tech. in press (2007).
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A. Fogo, J. A. Breyer, M. C. Smith, W. H. Cleveland, L. Agodoa, K. A. Kirk, and R. Glassock, “Accuracy of the diagnosis of hypertensive nephrosclerosis in African Americans: a report from the African American Study of Kidney Disease (AASK) Trial. AASK pilot study investigators,” Kidney Int.51 (1997).
[CrossRef] [PubMed]

Supplementary Material (3)

» Media 1: MOV (1327 KB)     
» Media 2: MOV (2277 KB)     
» Media 3: MOV (2219 KB)     

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Figures (6)

Fig. 1.
Fig. 1.

Comparison of SHG imaging to immunolabeling of collagens type I and type IV in serial frozen sections of murine renal tissue showing artery (A) and tubules (T). (a-c) 2PEF signals from FITC-coupled antibodies revealing (a) collagen I or (b) collagen IV, and (c) from endogenous chromophores such as elastin or cellular chromophores. (d-f) SHG signals in the adventitia. (g-h) Colocalization (white) of 2PEF (red) and SHG (green) signals showing that SHG arises from collagen I, not from collagen IV. (i) Merging of (c) and (f) showing the distribution of endogenous signals. Excitation: 25 mW at 800 nm, 20×0.9 NA objective, scale bar: 100 μm.

Fig. 2.
Fig. 2.

Comparison of histological staining and endogenous SHG in fibrotic kidney tissue: serial sections of mouse kidney (4 μm thick) visualized by (a-b) transmitted light microscopy, (c) polarized light microscopy, and (d,f) multiphoton microscopy (20 mW excitation at 860 nm, circular polarization, NA 0.9). G: glomerulus, A: artery, T: tubules, scale bar: 100 μm. (a) Masson’s trichrome staining; (b-c) Picrosirius red staining. (d) Multiphoton image showing SHG from collagen fibers (green) and endogenous 2PEF underlining the kidney morphology (red). (e) Spectra of these nonlinear endogenous signals (2PEF: red, and SHG: green), superimposed to the spectral transmittance of the SHG (blue) and 2PEF (pink) detection channels. (f) SHG image only (zoomed-in view in inset).

Fig. 3.
Fig. 3.

(a). (1.3 MB) Multimodal multiphoton z-stack of a fixed fibrotic transgenic mouse kidney: the endogenous 2PEF signals (red) reveal the morphology of the tissue, the SHG signals (green) map the distribution of fibrosis and the 2PEF signals from eGFP (white) evidence the collagen synthesis sites (860 nm excitation, 6 mW for the eGFP and 28 mW for the endogenous signals, 50 μm scale bar, 488×488×44 μm3, 13.4 s per image plane). [Media 1] (b) (2.3 MB) 3D reconstruction of SHG signal from collagen fibers in a fresh fibrotic mouse kidney (50 mW excitation at 860 nm, 477×406×58 μm3, 10.9 s per image plane). [Media 2]

Fig. 4.
Fig. 4.

Schematic of the image processing showing vignetting correction for 2PEF data, and vignetting correction, background correction and application of a threshold for SHG data. D stands for the mask image (pixel value=1 if significant SHG signal, 0 otherwise). S is the corrected SHG image where the pixels with no significant SHG signal are set to 0.

Fig. 5.
Fig. 5.

(2.2 MB) Corrected 2PEF/SHG image mapping 2.3×4.6 mm2 of an unlabeled fibrotic murine kidney with 0.8×0.8 μm2 pixel size (2967×5865 pixels scanned at 100 kHz, with 20×0.95-NA objective lens and 50 mW excitation at 860 nm, in a coronal fixed section). Intrinsic 2PEF signals (E700sp and GG455 filters, Chroma) arises from various cellular chromophores in the tubules and the collecting ducts, and SHG signals (E700sp and HQ430/20 filters, Chroma) map the distribution of fibrosis. The insets show the various distributions of collagen fibers scored in Table 1. [Media 3]

Fig. 6.
Fig. 6.

Morphological segmentation and SHG fibrosis scoring in the renal cortex of control versus treated mice. (a) Endogenous 2PEF image revealing the renal morphology and (b) SHG image evidencing collagen fibers, superimposed with the radial segmentation from the capsule (0 %) to the papilla (100 %) in the same unlabeled fibrotic kidney tissue as in Fig. 5(c) D score, expressed as a volume density of fibrosis, along the kidney cortex in control (light green) and Angiotensin II infused mice (dark green). Error bars correspond to standard errors of the mean.

Tables (2)

Tables Icon

Table 1. SHG scoring of areas enlarged in Fig. 5.

Tables Icon

Table 2. SHG scoring of control versus treated mice. Error bars correspond to standard errors of the mean.

Metrics