Abstract

Simultaneous backward and forward second harmonic generations from isolated type-I collagen matrix are observed. Optical interference behaviors of these nonlinear optical signals are studied with accurately determined fibril thickness by an atomic force microscope. The nonlinear emission directions are strongly dependent on the coherent interaction within and between collagen fibrils. A linear relationship is obtained to estimate collagen fibril thickness with nanometer precision noninvasively by evaluating the forward/backward second harmonic generation ratio.

© 2007 Optical Society of America

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  1. Y. C. Guo, H. E. Savage, F. Liu, S. P. Schantz, P. P. Ho, and R. R. Alfano, “Subsurface tumor progression investigated by noninvasive optical second harmonic tomography,” Proc. Natl. Acad. Sci. U. S. A. 96, 10854–10856 (1999).
    [CrossRef] [PubMed]
  2. P. Stoller, B. M. Kim, A. M. Rubenchik, K. M. Reiser, and L. B. Da Silva, “Polarization-dependent optical second-harmonic imaging of a rat-tail tendon,” J. Biomed. Opt. 7, 205–214 (2002).
    [CrossRef] [PubMed]
  3. 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]
  4. A. Zoumi, A. Yeh, and B. J. Tromberg, “Imaging cells and extracellular matrix in vivo by using secondharmonic generation and two-photon excited fluorescence,” Proc. Natl. Acad. Sci. U. S. A. 99, 11014–11019 (2002).
    [CrossRef] [PubMed]
  5. G. Cox, E. Kable, A. Jones, I. K. Fraser, F. Manconi, and M. D. Gorrell, “3-dimensional imaging of collagen using second harmonic generation,” J. Struct. Biol. 141, 53–62 (2003).
    [CrossRef] [PubMed]
  6. P. J. Campagnola and L. M. Loew, “Second-harmonic imaging microscopy for visualizing biomolecular arrays in cells, tissues and organisms,” Nat. Biotechnol. 21, 1356–1360 (2003).
    [CrossRef] [PubMed]
  7. S. W. Chu, I. H. Chen, T. M. Liu, C. K. Sun, S. P. Lee, B. L. Lin, P. C. Cheng, D. J. M. X., H. L. Lin, and Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc.-Oxf.  208, 190–200 (2002).
    [CrossRef]
  8. M. Both, M. Vogel, O. Friedrich, F. von Wegner, T. Kunsting, R. H. A. Fink, and D. Uttenweiler, “Second harmonic imaging of intrinsic signals in muscle fibers in situ,” J. Biomed. Opt. 9, 882–892 (2004).
    [CrossRef] [PubMed]
  9. G. Peleg, A. Lewis, M. Linial, and L. M. Loew, “Nonlinear optical measurement of membrane potential around single molecules at selected cellular sites,” Proc. Natl. Acad. Sci. U. S. A. 96, 6700–6704 (1999).
    [CrossRef] [PubMed]
  10. 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. 100, 7075–7080 (2003).
    [CrossRef] [PubMed]
  11. L. Moreaux, O. Sandre, S. Charpak, M. Blanchard-Desce, and J. Mertz, “Coherent scattering in multi-harmonic light microscopy,” Biophys. J. 80, 1568–1574 (2001).
    [CrossRef] [PubMed]
  12. J. Mertz and L. Moreaux, “Second-harmonic generation by focused excitation of inhomogeneously distributed scatterers,” Opt. Commun. 196, 325–330 (2001).
    [CrossRef]
  13. E. S. Tasheva, A. Koester, A. Q. Paulsen, A. S. Garrett, D. L. Boyle, H. J. Davidson, M. Song, N. Fox, and G. W. Conrad, “Mimecan/osteoglycin-deficient mice have collagen fibril abnormalities,” Mol. Vis. 8, 407–415 (2002).
    [PubMed]
  14. R. Fleischmajer, B. R. Olsen, R. Timpl, J. S. Perlish, and O. Lovelace, “Collagen fibril formation during embryogenesis,” Proc. Natl. Acad. Sci. 80, 3354–3358 (1983).
    [CrossRef] [PubMed]
  15. S. W. Chu, S. Y. Chen, G. W. Chern, T. H. Tsai, Y. C. Chen, B. L. Lin, and C. K. Sun, “Studies of χ(2)/χ(3) tensors in submicron-scaled bio-tissues by polarization harmonics optical microscopy,” Biophys. J. 86, 3914–3922 (2004).
    [CrossRef] [PubMed]
  16. S. W. Chu, S. P. Tai, C. L. Ho, C. H. Lin, and C. K. Sun, “High-resolution simultaneous three-photon fluorescence and third-harmonic-generation microscopy,” Microsc. Res. Tech. 66, 193–197 (2005).
    [CrossRef] [PubMed]
  17. R. M. Williams, W. R. Zipfel, and W. W. Webb, “Interpreting second-harmonic generation images of collagen I fibrils,” Biophys. J. 88, 1377–1386 (2005).
    [CrossRef]
  18. Y. R. Shen, The Principles of Nonlinear Optics (John Wiley & Sons, Hoboken, NJ, 2002).
  19. E. Claridge, S. Cotton, P. Hall, and M. Moncrieff, “From colour to tissue histology: physics-based interpretation of images of pigmented skin lesions,” Med. Image Anal. 7, 489–502 (2003).
    [CrossRef] [PubMed]
  20. T. Gutsmann, G. E. Fantner, M. Venturoni, A. Ekani-Nkodo, J. B. Thompson, J. H. Kindt, D. E. Morse, D. K. Fygenson, and P. K. Hansma, “Evidence that collagen fibrils in tendons are inhomogeneously structured in a tubelike manner,” Biophys. J. 84, 2593–2598 (2003).
    [CrossRef] [PubMed]

2005 (2)

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

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

2004 (2)

M. Both, M. Vogel, O. Friedrich, F. von Wegner, T. Kunsting, R. H. A. Fink, and D. Uttenweiler, “Second harmonic imaging of intrinsic signals in muscle fibers in situ,” J. Biomed. Opt. 9, 882–892 (2004).
[CrossRef] [PubMed]

S. W. Chu, S. Y. Chen, G. W. Chern, T. H. Tsai, Y. C. Chen, B. L. Lin, and C. K. Sun, “Studies of χ(2)/χ(3) tensors in submicron-scaled bio-tissues by polarization harmonics optical microscopy,” Biophys. J. 86, 3914–3922 (2004).
[CrossRef] [PubMed]

2003 (6)

G. Cox, E. Kable, A. Jones, I. K. Fraser, F. Manconi, and M. D. Gorrell, “3-dimensional imaging of collagen using second harmonic generation,” J. Struct. Biol. 141, 53–62 (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, 1356–1360 (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]

E. Claridge, S. Cotton, P. Hall, and M. Moncrieff, “From colour to tissue histology: physics-based interpretation of images of pigmented skin lesions,” Med. Image Anal. 7, 489–502 (2003).
[CrossRef] [PubMed]

T. Gutsmann, G. E. Fantner, M. Venturoni, A. Ekani-Nkodo, J. B. Thompson, J. H. Kindt, D. E. Morse, D. K. Fygenson, and P. K. Hansma, “Evidence that collagen fibrils in tendons are inhomogeneously structured in a tubelike manner,” Biophys. J. 84, 2593–2598 (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. 100, 7075–7080 (2003).
[CrossRef] [PubMed]

2002 (4)

E. S. Tasheva, A. Koester, A. Q. Paulsen, A. S. Garrett, D. L. Boyle, H. J. Davidson, M. Song, N. Fox, and G. W. Conrad, “Mimecan/osteoglycin-deficient mice have collagen fibril abnormalities,” Mol. Vis. 8, 407–415 (2002).
[PubMed]

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

P. Stoller, B. M. Kim, A. M. Rubenchik, K. M. Reiser, and L. B. Da Silva, “Polarization-dependent optical second-harmonic imaging of a rat-tail tendon,” J. Biomed. Opt. 7, 205–214 (2002).
[CrossRef] [PubMed]

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

2001 (2)

L. Moreaux, O. Sandre, S. Charpak, M. Blanchard-Desce, and J. Mertz, “Coherent scattering in multi-harmonic light microscopy,” Biophys. J. 80, 1568–1574 (2001).
[CrossRef] [PubMed]

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

1999 (2)

G. Peleg, A. Lewis, M. Linial, and L. M. Loew, “Nonlinear optical measurement of membrane potential around single molecules at selected cellular sites,” Proc. Natl. Acad. Sci. U. S. A. 96, 6700–6704 (1999).
[CrossRef] [PubMed]

Y. C. Guo, H. E. Savage, F. Liu, S. P. Schantz, P. P. Ho, and R. R. Alfano, “Subsurface tumor progression investigated by noninvasive optical second harmonic tomography,” Proc. Natl. Acad. Sci. U. S. A. 96, 10854–10856 (1999).
[CrossRef] [PubMed]

1983 (1)

R. Fleischmajer, B. R. Olsen, R. Timpl, J. S. Perlish, and O. Lovelace, “Collagen fibril formation during embryogenesis,” Proc. Natl. Acad. Sci. 80, 3354–3358 (1983).
[CrossRef] [PubMed]

Alfano, R. R.

Y. C. Guo, H. E. Savage, F. Liu, S. P. Schantz, P. P. Ho, and R. R. Alfano, “Subsurface tumor progression investigated by noninvasive optical second harmonic tomography,” Proc. Natl. Acad. Sci. U. S. A. 96, 10854–10856 (1999).
[CrossRef] [PubMed]

Blanchard-Desce, M.

L. Moreaux, O. Sandre, S. Charpak, M. Blanchard-Desce, and J. Mertz, “Coherent scattering in multi-harmonic light microscopy,” Biophys. J. 80, 1568–1574 (2001).
[CrossRef] [PubMed]

Both, M.

M. Both, M. Vogel, O. Friedrich, F. von Wegner, T. Kunsting, R. H. A. Fink, and D. Uttenweiler, “Second harmonic imaging of intrinsic signals in muscle fibers in situ,” J. Biomed. Opt. 9, 882–892 (2004).
[CrossRef] [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]

Boyle, D. L.

E. S. Tasheva, A. Koester, A. Q. Paulsen, A. S. Garrett, D. L. Boyle, H. J. Davidson, M. Song, N. Fox, and G. W. Conrad, “Mimecan/osteoglycin-deficient mice have collagen fibril abnormalities,” Mol. Vis. 8, 407–415 (2002).
[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]

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, 1356–1360 (2003).
[CrossRef] [PubMed]

Charpak, S.

L. Moreaux, O. Sandre, S. Charpak, M. Blanchard-Desce, and J. Mertz, “Coherent scattering in multi-harmonic light microscopy,” Biophys. J. 80, 1568–1574 (2001).
[CrossRef] [PubMed]

Chen, I. H.

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

Chen, S. Y.

S. W. Chu, S. Y. Chen, G. W. Chern, T. H. Tsai, Y. C. Chen, B. L. Lin, and C. K. Sun, “Studies of χ(2)/χ(3) tensors in submicron-scaled bio-tissues by polarization harmonics optical microscopy,” Biophys. J. 86, 3914–3922 (2004).
[CrossRef] [PubMed]

Chen, Y. C.

S. W. Chu, S. Y. Chen, G. W. Chern, T. H. Tsai, Y. C. Chen, B. L. Lin, and C. K. Sun, “Studies of χ(2)/χ(3) tensors in submicron-scaled bio-tissues by polarization harmonics optical microscopy,” Biophys. J. 86, 3914–3922 (2004).
[CrossRef] [PubMed]

Cheng, P. C.

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

Chern, G. W.

S. W. Chu, S. Y. Chen, G. W. Chern, T. H. Tsai, Y. C. Chen, B. L. Lin, and C. K. Sun, “Studies of χ(2)/χ(3) tensors in submicron-scaled bio-tissues by polarization harmonics optical microscopy,” Biophys. J. 86, 3914–3922 (2004).
[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. 100, 7075–7080 (2003).
[CrossRef] [PubMed]

Chu, S. W.

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

S. W. Chu, S. Y. Chen, G. W. Chern, T. H. Tsai, Y. C. Chen, B. L. Lin, and C. K. Sun, “Studies of χ(2)/χ(3) tensors in submicron-scaled bio-tissues by polarization harmonics optical microscopy,” Biophys. J. 86, 3914–3922 (2004).
[CrossRef] [PubMed]

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

Claridge, E.

E. Claridge, S. Cotton, P. Hall, and M. Moncrieff, “From colour to tissue histology: physics-based interpretation of images of pigmented skin lesions,” Med. Image Anal. 7, 489–502 (2003).
[CrossRef] [PubMed]

Conrad, G. W.

E. S. Tasheva, A. Koester, A. Q. Paulsen, A. S. Garrett, D. L. Boyle, H. J. Davidson, M. Song, N. Fox, and G. W. Conrad, “Mimecan/osteoglycin-deficient mice have collagen fibril abnormalities,” Mol. Vis. 8, 407–415 (2002).
[PubMed]

Cotton, S.

E. Claridge, S. Cotton, P. Hall, and M. Moncrieff, “From colour to tissue histology: physics-based interpretation of images of pigmented skin lesions,” Med. Image Anal. 7, 489–502 (2003).
[CrossRef] [PubMed]

Cox, G.

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

Davidson, H. J.

E. S. Tasheva, A. Koester, A. Q. Paulsen, A. S. Garrett, D. L. Boyle, H. J. Davidson, M. Song, N. Fox, and G. W. Conrad, “Mimecan/osteoglycin-deficient mice have collagen fibril abnormalities,” Mol. Vis. 8, 407–415 (2002).
[PubMed]

diTomaso, 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]

Ekani-Nkodo, A.

T. Gutsmann, G. E. Fantner, M. Venturoni, A. Ekani-Nkodo, J. B. Thompson, J. H. Kindt, D. E. Morse, D. K. Fygenson, and P. K. Hansma, “Evidence that collagen fibrils in tendons are inhomogeneously structured in a tubelike manner,” Biophys. J. 84, 2593–2598 (2003).
[CrossRef] [PubMed]

Fantner, G. E.

T. Gutsmann, G. E. Fantner, M. Venturoni, A. Ekani-Nkodo, J. B. Thompson, J. H. Kindt, D. E. Morse, D. K. Fygenson, and P. K. Hansma, “Evidence that collagen fibrils in tendons are inhomogeneously structured in a tubelike manner,” Biophys. J. 84, 2593–2598 (2003).
[CrossRef] [PubMed]

Fink, R. H. A.

M. Both, M. Vogel, O. Friedrich, F. von Wegner, T. Kunsting, R. H. A. Fink, and D. Uttenweiler, “Second harmonic imaging of intrinsic signals in muscle fibers in situ,” J. Biomed. Opt. 9, 882–892 (2004).
[CrossRef] [PubMed]

Fleischmajer, R.

R. Fleischmajer, B. R. Olsen, R. Timpl, J. S. Perlish, and O. Lovelace, “Collagen fibril formation during embryogenesis,” Proc. Natl. Acad. Sci. 80, 3354–3358 (1983).
[CrossRef] [PubMed]

Fox, N.

E. S. Tasheva, A. Koester, A. Q. Paulsen, A. S. Garrett, D. L. Boyle, H. J. Davidson, M. Song, N. Fox, and G. W. Conrad, “Mimecan/osteoglycin-deficient mice have collagen fibril abnormalities,” Mol. Vis. 8, 407–415 (2002).
[PubMed]

Fraser, I. K.

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

Friedrich, O.

M. Both, M. Vogel, O. Friedrich, F. von Wegner, T. Kunsting, R. H. A. Fink, and D. Uttenweiler, “Second harmonic imaging of intrinsic signals in muscle fibers in situ,” J. Biomed. Opt. 9, 882–892 (2004).
[CrossRef] [PubMed]

Fygenson, D. K.

T. Gutsmann, G. E. Fantner, M. Venturoni, A. Ekani-Nkodo, J. B. Thompson, J. H. Kindt, D. E. Morse, D. K. Fygenson, and P. K. Hansma, “Evidence that collagen fibrils in tendons are inhomogeneously structured in a tubelike manner,” Biophys. J. 84, 2593–2598 (2003).
[CrossRef] [PubMed]

Garrett, A. S.

E. S. Tasheva, A. Koester, A. Q. Paulsen, A. S. Garrett, D. L. Boyle, H. J. Davidson, M. Song, N. Fox, and G. W. Conrad, “Mimecan/osteoglycin-deficient mice have collagen fibril abnormalities,” Mol. Vis. 8, 407–415 (2002).
[PubMed]

Gorrell, M. D.

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

Guo, Y. C.

Y. C. Guo, H. E. Savage, F. Liu, S. P. Schantz, P. P. Ho, and R. R. Alfano, “Subsurface tumor progression investigated by noninvasive optical second harmonic tomography,” Proc. Natl. Acad. Sci. U. S. A. 96, 10854–10856 (1999).
[CrossRef] [PubMed]

Gutsmann, T.

T. Gutsmann, G. E. Fantner, M. Venturoni, A. Ekani-Nkodo, J. B. Thompson, J. H. Kindt, D. E. Morse, D. K. Fygenson, and P. K. Hansma, “Evidence that collagen fibrils in tendons are inhomogeneously structured in a tubelike manner,” Biophys. J. 84, 2593–2598 (2003).
[CrossRef] [PubMed]

Hall, P.

E. Claridge, S. Cotton, P. Hall, and M. Moncrieff, “From colour to tissue histology: physics-based interpretation of images of pigmented skin lesions,” Med. Image Anal. 7, 489–502 (2003).
[CrossRef] [PubMed]

Hansma, P. K.

T. Gutsmann, G. E. Fantner, M. Venturoni, A. Ekani-Nkodo, J. B. Thompson, J. H. Kindt, D. E. Morse, D. K. Fygenson, and P. K. Hansma, “Evidence that collagen fibrils in tendons are inhomogeneously structured in a tubelike manner,” Biophys. J. 84, 2593–2598 (2003).
[CrossRef] [PubMed]

Ho, C. L.

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

Ho, P. P.

Y. C. Guo, H. E. Savage, F. Liu, S. P. Schantz, P. P. Ho, and R. R. Alfano, “Subsurface tumor progression investigated by noninvasive optical second harmonic tomography,” Proc. Natl. Acad. Sci. U. S. A. 96, 10854–10856 (1999).
[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. 100, 7075–7080 (2003).
[CrossRef] [PubMed]

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]

Jones, A.

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

Kable, E.

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

Kim, B. M.

P. Stoller, B. M. Kim, A. M. Rubenchik, K. M. Reiser, and L. B. Da Silva, “Polarization-dependent optical second-harmonic imaging of a rat-tail tendon,” J. Biomed. Opt. 7, 205–214 (2002).
[CrossRef] [PubMed]

Kindt, J. H.

T. Gutsmann, G. E. Fantner, M. Venturoni, A. Ekani-Nkodo, J. B. Thompson, J. H. Kindt, D. E. Morse, D. K. Fygenson, and P. K. Hansma, “Evidence that collagen fibrils in tendons are inhomogeneously structured in a tubelike manner,” Biophys. J. 84, 2593–2598 (2003).
[CrossRef] [PubMed]

Koester, A.

E. S. Tasheva, A. Koester, A. Q. Paulsen, A. S. Garrett, D. L. Boyle, H. J. Davidson, M. Song, N. Fox, and G. W. Conrad, “Mimecan/osteoglycin-deficient mice have collagen fibril abnormalities,” Mol. Vis. 8, 407–415 (2002).
[PubMed]

Kunsting, T.

M. Both, M. Vogel, O. Friedrich, F. von Wegner, T. Kunsting, R. H. A. Fink, and D. Uttenweiler, “Second harmonic imaging of intrinsic signals in muscle fibers in situ,” J. Biomed. Opt. 9, 882–892 (2004).
[CrossRef] [PubMed]

Lee, S. P.

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

Lewis, A.

G. Peleg, A. Lewis, M. Linial, and L. M. Loew, “Nonlinear optical measurement of membrane potential around single molecules at selected cellular sites,” Proc. Natl. Acad. Sci. U. S. A. 96, 6700–6704 (1999).
[CrossRef] [PubMed]

Lin, B. L.

S. W. Chu, S. Y. Chen, G. W. Chern, T. H. Tsai, Y. C. Chen, B. L. Lin, and C. K. Sun, “Studies of χ(2)/χ(3) tensors in submicron-scaled bio-tissues by polarization harmonics optical microscopy,” Biophys. J. 86, 3914–3922 (2004).
[CrossRef] [PubMed]

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

Lin, C. H.

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

Lin, H. L.

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

Linial, M.

G. Peleg, A. Lewis, M. Linial, and L. M. Loew, “Nonlinear optical measurement of membrane potential around single molecules at selected cellular sites,” Proc. Natl. Acad. Sci. U. S. A. 96, 6700–6704 (1999).
[CrossRef] [PubMed]

Liu,

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

Liu, F.

Y. C. Guo, H. E. Savage, F. Liu, S. P. Schantz, P. P. Ho, and R. R. Alfano, “Subsurface tumor progression investigated by noninvasive optical second harmonic tomography,” Proc. Natl. Acad. Sci. U. S. A. 96, 10854–10856 (1999).
[CrossRef] [PubMed]

Liu, T. M.

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

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, 1356–1360 (2003).
[CrossRef] [PubMed]

G. Peleg, A. Lewis, M. Linial, and L. M. Loew, “Nonlinear optical measurement of membrane potential around single molecules at selected cellular sites,” Proc. Natl. Acad. Sci. U. S. A. 96, 6700–6704 (1999).
[CrossRef] [PubMed]

Lovelace, O.

R. Fleischmajer, B. R. Olsen, R. Timpl, J. S. Perlish, and O. Lovelace, “Collagen fibril formation during embryogenesis,” Proc. Natl. Acad. Sci. 80, 3354–3358 (1983).
[CrossRef] [PubMed]

M. X., D. J.

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

Manconi, F.

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

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).
[CrossRef] [PubMed]

Mertz, J.

L. Moreaux, O. Sandre, S. Charpak, M. Blanchard-Desce, and J. Mertz, “Coherent scattering in multi-harmonic light microscopy,” Biophys. J. 80, 1568–1574 (2001).
[CrossRef] [PubMed]

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

Moncrieff, M.

E. Claridge, S. Cotton, P. Hall, and M. Moncrieff, “From colour to tissue histology: physics-based interpretation of images of pigmented skin lesions,” Med. Image Anal. 7, 489–502 (2003).
[CrossRef] [PubMed]

Moreaux, L.

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

L. Moreaux, O. Sandre, S. Charpak, M. Blanchard-Desce, and J. Mertz, “Coherent scattering in multi-harmonic light microscopy,” Biophys. J. 80, 1568–1574 (2001).
[CrossRef] [PubMed]

Morse, D. E.

T. Gutsmann, G. E. Fantner, M. Venturoni, A. Ekani-Nkodo, J. B. Thompson, J. H. Kindt, D. E. Morse, D. K. Fygenson, and P. K. Hansma, “Evidence that collagen fibrils in tendons are inhomogeneously structured in a tubelike manner,” Biophys. J. 84, 2593–2598 (2003).
[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. 100, 7075–7080 (2003).
[CrossRef] [PubMed]

Olsen, B. R.

R. Fleischmajer, B. R. Olsen, R. Timpl, J. S. Perlish, and O. Lovelace, “Collagen fibril formation during embryogenesis,” Proc. Natl. Acad. Sci. 80, 3354–3358 (1983).
[CrossRef] [PubMed]

Paulsen, A. Q.

E. S. Tasheva, A. Koester, A. Q. Paulsen, A. S. Garrett, D. L. Boyle, H. J. Davidson, M. Song, N. Fox, and G. W. Conrad, “Mimecan/osteoglycin-deficient mice have collagen fibril abnormalities,” Mol. Vis. 8, 407–415 (2002).
[PubMed]

Peleg, G.

G. Peleg, A. Lewis, M. Linial, and L. M. Loew, “Nonlinear optical measurement of membrane potential around single molecules at selected cellular sites,” Proc. Natl. Acad. Sci. U. S. A. 96, 6700–6704 (1999).
[CrossRef] [PubMed]

Perlish, J. S.

R. Fleischmajer, B. R. Olsen, R. Timpl, J. S. Perlish, and O. Lovelace, “Collagen fibril formation during embryogenesis,” Proc. Natl. Acad. Sci. 80, 3354–3358 (1983).
[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]

Reiser, K. M.

P. Stoller, B. M. Kim, A. M. Rubenchik, K. M. Reiser, and L. B. Da Silva, “Polarization-dependent optical second-harmonic imaging of a rat-tail tendon,” J. Biomed. Opt. 7, 205–214 (2002).
[CrossRef] [PubMed]

Rubenchik, A. M.

P. Stoller, B. M. Kim, A. M. Rubenchik, K. M. Reiser, and L. B. Da Silva, “Polarization-dependent optical second-harmonic imaging of a rat-tail tendon,” J. Biomed. Opt. 7, 205–214 (2002).
[CrossRef] [PubMed]

Sandre, O.

L. Moreaux, O. Sandre, S. Charpak, M. Blanchard-Desce, and J. Mertz, “Coherent scattering in multi-harmonic light microscopy,” Biophys. J. 80, 1568–1574 (2001).
[CrossRef] [PubMed]

Savage, H. E.

Y. C. Guo, H. E. Savage, F. Liu, S. P. Schantz, P. P. Ho, and R. R. Alfano, “Subsurface tumor progression investigated by noninvasive optical second harmonic tomography,” Proc. Natl. Acad. Sci. U. S. A. 96, 10854–10856 (1999).
[CrossRef] [PubMed]

Schantz, S. P.

Y. C. Guo, H. E. Savage, F. Liu, S. P. Schantz, P. P. Ho, and R. R. Alfano, “Subsurface tumor progression investigated by noninvasive optical second harmonic tomography,” Proc. Natl. Acad. Sci. U. S. A. 96, 10854–10856 (1999).
[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]

Shen, Y. R.

Y. R. Shen, The Principles of Nonlinear Optics (John Wiley & Sons, Hoboken, NJ, 2002).

Silva, L. B. Da

P. Stoller, B. M. Kim, A. M. Rubenchik, K. M. Reiser, and L. B. Da Silva, “Polarization-dependent optical second-harmonic imaging of a rat-tail tendon,” J. Biomed. Opt. 7, 205–214 (2002).
[CrossRef] [PubMed]

Song, M.

E. S. Tasheva, A. Koester, A. Q. Paulsen, A. S. Garrett, D. L. Boyle, H. J. Davidson, M. Song, N. Fox, and G. W. Conrad, “Mimecan/osteoglycin-deficient mice have collagen fibril abnormalities,” Mol. Vis. 8, 407–415 (2002).
[PubMed]

Stoller, P.

P. Stoller, B. M. Kim, A. M. Rubenchik, K. M. Reiser, and L. B. Da Silva, “Polarization-dependent optical second-harmonic imaging of a rat-tail tendon,” J. Biomed. Opt. 7, 205–214 (2002).
[CrossRef] [PubMed]

Sun, C. K.

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

S. W. Chu, S. Y. Chen, G. W. Chern, T. H. Tsai, Y. C. Chen, B. L. Lin, and C. K. Sun, “Studies of χ(2)/χ(3) tensors in submicron-scaled bio-tissues by polarization harmonics optical microscopy,” Biophys. J. 86, 3914–3922 (2004).
[CrossRef] [PubMed]

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

Tai, S. P.

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

Tasheva, E. S.

E. S. Tasheva, A. Koester, A. Q. Paulsen, A. S. Garrett, D. L. Boyle, H. J. Davidson, M. Song, N. Fox, and G. W. Conrad, “Mimecan/osteoglycin-deficient mice have collagen fibril abnormalities,” Mol. Vis. 8, 407–415 (2002).
[PubMed]

Thompson, J. B.

T. Gutsmann, G. E. Fantner, M. Venturoni, A. Ekani-Nkodo, J. B. Thompson, J. H. Kindt, D. E. Morse, D. K. Fygenson, and P. K. Hansma, “Evidence that collagen fibrils in tendons are inhomogeneously structured in a tubelike manner,” Biophys. J. 84, 2593–2598 (2003).
[CrossRef] [PubMed]

Timpl, R.

R. Fleischmajer, B. R. Olsen, R. Timpl, J. S. Perlish, and O. Lovelace, “Collagen fibril formation during embryogenesis,” Proc. Natl. Acad. Sci. 80, 3354–3358 (1983).
[CrossRef] [PubMed]

Tromberg, B. J.

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

Tsai, T. H.

S. W. Chu, S. Y. Chen, G. W. Chern, T. H. Tsai, Y. C. Chen, B. L. Lin, and C. K. Sun, “Studies of χ(2)/χ(3) tensors in submicron-scaled bio-tissues by polarization harmonics optical microscopy,” Biophys. J. 86, 3914–3922 (2004).
[CrossRef] [PubMed]

Uttenweiler, D.

M. Both, M. Vogel, O. Friedrich, F. von Wegner, T. Kunsting, R. H. A. Fink, and D. Uttenweiler, “Second harmonic imaging of intrinsic signals in muscle fibers in situ,” J. Biomed. Opt. 9, 882–892 (2004).
[CrossRef] [PubMed]

Venturoni, M.

T. Gutsmann, G. E. Fantner, M. Venturoni, A. Ekani-Nkodo, J. B. Thompson, J. H. Kindt, D. E. Morse, D. K. Fygenson, and P. K. Hansma, “Evidence that collagen fibrils in tendons are inhomogeneously structured in a tubelike manner,” Biophys. J. 84, 2593–2598 (2003).
[CrossRef] [PubMed]

Vogel, M.

M. Both, M. Vogel, O. Friedrich, F. von Wegner, T. Kunsting, R. H. A. Fink, and D. Uttenweiler, “Second harmonic imaging of intrinsic signals in muscle fibers in situ,” J. Biomed. Opt. 9, 882–892 (2004).
[CrossRef] [PubMed]

Webb, W. W.

R. M. Williams, W. R. Zipfel, and W. W. Webb, “Interpreting second-harmonic generation images of collagen I 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. 100, 7075–7080 (2003).
[CrossRef] [PubMed]

Wegner, F. von

M. Both, M. Vogel, O. Friedrich, F. von Wegner, T. Kunsting, R. H. A. Fink, and D. Uttenweiler, “Second harmonic imaging of intrinsic signals in muscle fibers in situ,” J. Biomed. Opt. 9, 882–892 (2004).
[CrossRef] [PubMed]

Williams, R. M.

R. M. Williams, W. R. Zipfel, and W. W. Webb, “Interpreting second-harmonic generation images of collagen I 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. 100, 7075–7080 (2003).
[CrossRef] [PubMed]

Yeh, A.

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

Zipfel, W. R.

R. M. Williams, W. R. Zipfel, and W. W. Webb, “Interpreting second-harmonic generation images of collagen I 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. 100, 7075–7080 (2003).
[CrossRef] [PubMed]

Zoumi, A.

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

Biophys. J. (4)

L. Moreaux, O. Sandre, S. Charpak, M. Blanchard-Desce, and J. Mertz, “Coherent scattering in multi-harmonic light microscopy,” Biophys. J. 80, 1568–1574 (2001).
[CrossRef] [PubMed]

S. W. Chu, S. Y. Chen, G. W. Chern, T. H. Tsai, Y. C. Chen, B. L. Lin, and C. K. Sun, “Studies of χ(2)/χ(3) tensors in submicron-scaled bio-tissues by polarization harmonics optical microscopy,” Biophys. J. 86, 3914–3922 (2004).
[CrossRef] [PubMed]

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

T. Gutsmann, G. E. Fantner, M. Venturoni, A. Ekani-Nkodo, J. B. Thompson, J. H. Kindt, D. E. Morse, D. K. Fygenson, and P. K. Hansma, “Evidence that collagen fibrils in tendons are inhomogeneously structured in a tubelike manner,” Biophys. J. 84, 2593–2598 (2003).
[CrossRef] [PubMed]

J. Biomed. Opt. (2)

P. Stoller, B. M. Kim, A. M. Rubenchik, K. M. Reiser, and L. B. Da Silva, “Polarization-dependent optical second-harmonic imaging of a rat-tail tendon,” J. Biomed. Opt. 7, 205–214 (2002).
[CrossRef] [PubMed]

M. Both, M. Vogel, O. Friedrich, F. von Wegner, T. Kunsting, R. H. A. Fink, and D. Uttenweiler, “Second harmonic imaging of intrinsic signals in muscle fibers in situ,” J. Biomed. Opt. 9, 882–892 (2004).
[CrossRef] [PubMed]

J. Microsc.-Oxf. (1)

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

J. Struct. Biol. (1)

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

Med. Image Anal. (1)

E. Claridge, S. Cotton, P. Hall, and M. Moncrieff, “From colour to tissue histology: physics-based interpretation of images of pigmented skin lesions,” Med. Image Anal. 7, 489–502 (2003).
[CrossRef] [PubMed]

Microsc. Res. Tech. (1)

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

Mol. Vis. (1)

E. S. Tasheva, A. Koester, A. Q. Paulsen, A. S. Garrett, D. L. Boyle, H. J. Davidson, M. Song, N. Fox, and G. W. Conrad, “Mimecan/osteoglycin-deficient mice have collagen fibril abnormalities,” Mol. Vis. 8, 407–415 (2002).
[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, 1356–1360 (2003).
[CrossRef] [PubMed]

Nat. Med. (1)

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]

Opt. Commun. (1)

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

Proc. Natl. Acad. Sci. (2)

R. Fleischmajer, B. R. Olsen, R. Timpl, J. S. Perlish, and O. Lovelace, “Collagen fibril formation during embryogenesis,” Proc. Natl. Acad. Sci. 80, 3354–3358 (1983).
[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. 100, 7075–7080 (2003).
[CrossRef] [PubMed]

Proc. Natl. Acad. Sci. U. S. A. (3)

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

Y. C. Guo, H. E. Savage, F. Liu, S. P. Schantz, P. P. Ho, and R. R. Alfano, “Subsurface tumor progression investigated by noninvasive optical second harmonic tomography,” Proc. Natl. Acad. Sci. U. S. A. 96, 10854–10856 (1999).
[CrossRef] [PubMed]

G. Peleg, A. Lewis, M. Linial, and L. M. Loew, “Nonlinear optical measurement of membrane potential around single molecules at selected cellular sites,” Proc. Natl. Acad. Sci. U. S. A. 96, 6700–6704 (1999).
[CrossRef] [PubMed]

Other (1)

Y. R. Shen, The Principles of Nonlinear Optics (John Wiley & Sons, Hoboken, NJ, 2002).

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Figures (3)

Fig. 1.
Fig. 1.

(A) AFM, (B) BSHG, and (C) FSHG images of a collagen fibril matrix on a cover glass. The selected fibril is marked with a rectangle. Several arrows in the AFM image indicate the points of discussion. Laser polarization is shown as double-sided arrows in (B) and (C). Scale bar: 3-µm.

Fig. 2.
Fig. 2.

(A). The integrated line graph of the rectangular area for BSHG (solid rectangles) and FSHG (hollow circles), showing the SHG power variation along the selected fibril. (B) F/B variation along the same fibril. The arrows show the location correspondence to the AFM image.

Fig. 3.
Fig. 3.

Solid circles are measured F/B ratio relative to collagen fibril thickness. If the collagen molecules all act as active SHG scatterers, the calculated F/B ratio is plotted as the solid line. Dashed line is F/B calculation based on active cluster sizes, indicating that only a fraction of the collagen molecules inside a fibril produce SHG effectively. Inset: an empirical linear relation on F/B ratio over collagen thickness is obtained.

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