Abstract

Second Harmonic Generation (SHG) microscopy offers the opportunity to image collagen of type I without staining. We recently showed that a simple scoring method, based on SHG images of histological human liver biopsies, correlates well with the Metavir assessment of fibrosis level (Gailhouste et al., J. Hepatol., 2010). In this article, we present a detailed study of this new scoring method with two different objective lenses. By using measurements of the objectives point spread functions and of the photomultiplier gain, and a simple model of the SHG intensity, we show that our scoring method, applied to human liver biopsies, is robust to the objective’s numerical aperture (NA) for low NA, the choice of the reference sample and laser power, and the spatial sampling rate. The simplicity and robustness of our collagen scoring method may open new opportunities in the quantification of collagen content in different organs, which is of main importance in providing diagnostic information and evaluation of therapeutic efficiency.

© 2010 Optical Society of America

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    [CrossRef]
  2. R. Bataller, and D. A. Brenner, “Liver fibrosis,” J. Clin. Invest. 115, 209–218 (2005).
    [PubMed]
  3. N. H. Afdhal, and D. Nunes, “Evaluation of liver fibrosis: a concise review,” Am. J. Gastroenterol. 99, 1160–1174 (2004).
    [CrossRef] [PubMed]
  4. G. L. Davis, J. E. Albright, S. F. Cook, and D. M. Rosenberg, “Projecting future complications of chronic hepatitis C in the United States,” Liver Transpl. 9, 331–338 (2003).
    [CrossRef] [PubMed]
  5. F. Oberti, E. Valsesia, C. Pilette, M. C. Rousselet, P. Bedossa, C. Aub, Y. Gallois, H. Rifflet, M. Y. Maga, D. Penneau-Fontbonne, and P. Cals, “Noninvasive diagnosis of hepatic fibrosis or cirrhosis,” Gastroenterology 113, 1609–1616 (1997).
    [CrossRef] [PubMed]
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    [CrossRef]
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  19. 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).
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  20. W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21, 1369–1377 (2003).
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  26. C. Odin, Y. Le Grand, A. Renault, L. Gailhouste, and G. Baffet, “Orientation fields of nonlinear biological fibrils by second harmonic generation microscopy,” J. Microsc. 229, 32–38 (2008).
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    [CrossRef]
  36. P. Bedossa, “Harmony in liver fibrosis.,” J. Hepatol. 52, 313–314 (2010).
    [CrossRef]
  37. J. Mertz, and L. Moreaux, “Second-harmonic generation by focused excitation of inhomogeneously distributed scatterers,” Opt. Commun. 196, 325–330 (2001).
    [CrossRef]
  38. L. I.-K. Lin, “A concordance correlation coefficient to evaluate reproducibility,” Biometrics 45, 255–268 (1989).
    [CrossRef]
  39. L. I.-K. Lin, “A note on the concordance correlation coefficient,” Biometrics 56, 324–325 (2000).
  40. H. Bao, A. Boussioutas, R. Jeremy, S. Russell, and M. Gu, “Second harmonic generation imaging via nonlinear endomicroscopy,” Opt. Express 18, 1255–1260 (2010).
    [CrossRef] [PubMed]

2010 (3)

L. Gailhouste, Y. Le Grand, C. Odin, D. Guyader, B. Turlin, F. Ezan, Y. Dsille, T. Guilbert, A. Bessard, C. Frmin, N. Theret, and G. Baffet, “Fibrillar Collagen Scoring by Second Harmonic Microscopy as a New Tool in the Assessment of Liver Fibrosis,” J. Hepatol. 52, 398–406 (2010).
[CrossRef]

P. Bedossa, “Harmony in liver fibrosis.,” J. Hepatol. 52, 313–314 (2010).
[CrossRef]

H. Bao, A. Boussioutas, R. Jeremy, S. Russell, and M. Gu, “Second harmonic generation imaging via nonlinear endomicroscopy,” Opt. Express 18, 1255–1260 (2010).
[CrossRef] [PubMed]

2009 (5)

D. C. S. Tai, N. Tan, S. Xu, C. H. Kang, S. M. Chia, C. L. Cheng, A. Wee, C. Li Wei, A. M. Raja, G. Xiao, S. Chang, J. C. Rajapakse, P. T. C. So, H.-H. Tang, C. Shing Chen, and H. Yu, “Fibro-C-Index: comprehensive, morphology-based quantification of liver fibrosis using second harmonic generation and two-photon microscopy,” J. Biomed. Opt. 14(4), 044013 (2009), doi:10.1117/1.3183811.
[CrossRef] [PubMed]

C. Odin, C. Heichette, D. Chretien, and Y. Le Grand, “Second harmonic microscopy of axonemes,” Opt. Express 17, 9235–9240 (2009).
[CrossRef] [PubMed]

S. Psilodimitrakopoulos, D. Artigas, G. Soria, I. Amat-Roldan, A. Planas, and P. Loza-Alvarez, “Quantitative discrimination between endogenousSHG sources in mammalian tissue, based ontheir polarization response,” Opt. Express 17, 10168–10176 (2009).
[CrossRef] [PubMed]

S. Psilodimitrakopoulos, V. Petegnief, G. Soria, I. Amat-Roldan, D. Artigas, A. Planas, and P. Loza-Alvarez, “Estimation of the effective orientation of the SHG source in primary cortical neurons,” Opt. Express 17, 14418–14425 (2009).
[CrossRef] [PubMed]

S. C. Faria, K. Ganesan, I. Mwangi, M. Shiehmorteza, B. Viamonte, S. Mazhar, M. Peterson, Y. Kono, C. Santillan, G. Casola, and C. B. Sirlin, “MR Imaging of Liver Fibrosis: Current State of the Art,” Radiographics 29, 1615–1635 (2009).
[CrossRef] [PubMed]

2008 (3)

C. Odin, Y. Le Grand, A. Renault, L. Gailhouste, and G. Baffet, “Orientation fields of nonlinear biological fibrils by second harmonic generation microscopy,” J. Microsc. 229, 32–38 (2008).
[CrossRef]

C. Odin, T. Guilbert, A. Alkilani, O. Boryskina, V. Fleury, and Y. Le Grand, “Collagen and myosin characterization by orientation field second harmonic microscopy,” Opt. Express 16, 16151–16165 (2008).
[CrossRef] [PubMed]

X. Han, R. M. Burke, M. L. Zettel, P. Tang, and E. B. Brown, “Second harmonic properties of tumor collagen: determining the structural relationship between reactive stroma and healthy stroma,” Opt. Express 16, 1846–1859 (2008), http://www.opticsinfobase.org/abstract.cfm?URI=oe-16-3-1846.
[CrossRef] [PubMed]

2007 (3)

M. Strupler, A. Pena, M. Hernest, P. Tharaux, J. Martin, E. Beaurepaire, and M. Schanne-Klein, “Second harmonic imaging and scoring of collagen in fibrotic tissues,” Opt. Express 15, 4054–4065 (2007).
[CrossRef] [PubMed]

A.-M. Pena, A. Fabre, D. Dbarre, 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. 70, 162–170 (2007).
[CrossRef]

H. A. Saleh, and A. H. Abu-Rashed, “Liver Biopsy Remains the Gold Standard for Evaluation of Chronic Hepatitis and Fibrosis,” J. Gastrointestin. Liver Dis. 16, 425–426 (2007).

2006 (1)

S. V. Plotnikov, A. C. Millard, and P. J. Campagnola, and W. A. Mohler, “Characterization of the myosin-based source for second-harmonic generation from muscle sarcomeres,” Biophys. J. 90, 693–703 (2006).
[CrossRef]

2005 (3)

R. Bataller, and D. A. Brenner, “Liver fibrosis,” J. Clin. Invest. 115, 209–218 (2005).
[PubMed]

M. A. Friedenberg, L. Miller, C. Y. Chung, F. Fleszler, F. L. Banson, R. Thomas, K. P. Swartz, and F. K. Friedenberg, “Simplified method of hepatic fibrosis quantification: design of a new morphometric analysis application,” Liver Int. 25, 1156–1161 (2005).
[CrossRef]

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 (3)

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]

A. Y. Hui, C.-T. Liew, M. Y.-Y. Go, A. M.-L. Chim, H. L.-Y. Chan, N. W.-Y. Leung, and J. J.-Y. Sung, “Quantitative assessment of fibrosis in liver biopsies from patients with chronic hepatitis B,” Liver Int. 24, 611–618 (2004).
[CrossRef]

N. H. Afdhal, and D. Nunes, “Evaluation of liver fibrosis: a concise review,” Am. J. Gastroenterol. 99, 1160–1174 (2004).
[CrossRef] [PubMed]

2003 (6)

G. L. Davis, J. E. Albright, S. F. Cook, and D. M. Rosenberg, “Projecting future complications of chronic hepatitis C in the United States,” Liver Transpl. 9, 331–338 (2003).
[CrossRef] [PubMed]

P. Bedossa, D. Dargre, and V. Paradis, “Sampling variability of liver fibrosis in chronic hepatitis C,” J. Hepatol. 38, 1356–1358 (2003).

S. L. Friedman, “Liver fibrosis - from bench to bedside,” J. Hepatol. 38, 38–53 (2003).
[CrossRef]

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]

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21, 1369–1377 (2003).
[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. U.S.A. 100, 7075–7080 (2003).
[CrossRef] [PubMed]

2002 (1)

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. U.S.A.. 20, 11014–11019 (2002).
[CrossRef]

2001 (1)

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

2000 (3)

K. König, “Multiphoton microscopy in life sciences,” J. Microsc. 200, 83–104 (2000).
[CrossRef] [PubMed]

M. Masseroli, and T. Caballero, “F. OValle, R. M. Del Moral, A. Perez-Milena, and R. G. Del Moral “Automatic quantification of liver fibrosis design and validation of a new image analysis method: comparison with semiquantitative indexes of fibrosis,”,” J. Hepatol. 32, 453–464 (2000).
[CrossRef] [PubMed]

L. I.-K. Lin, “A note on the concordance correlation coefficient,” Biometrics 56, 324–325 (2000).

1999 (1)

C. Aube, F. Oberti, N. Koralin, M.-A. Namour, D. Loisel, M. C. Rousselet, P. Bedossa, H. Rifflet, M. Y. Maga, C. Penneau, C. Caron, and P. Cals, “Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis,” J. Hepatol. 30, 472–478 (1999).
[CrossRef] [PubMed]

1997 (2)

F. Oberti, E. Valsesia, C. Pilette, M. C. Rousselet, P. Bedossa, C. Aub, Y. Gallois, H. Rifflet, M. Y. Maga, D. Penneau-Fontbonne, and P. Cals, “Noninvasive diagnosis of hepatic fibrosis or cirrhosis,” Gastroenterology 113, 1609–1616 (1997).
[CrossRef] [PubMed]

N. H. Afdhal, A. P. Keaveny, S. B. Cohen, D. P. Nunes, N. Maldonado, M. O’Brien, and P. J. Stone, “Urinary assays for desmosine and hydroxylysylpyridinoline in the detection of cirrhosis,” J. Hepatol. 27, 993–1002 (1997).
[CrossRef]

1995 (2)

K. Ishak, A. Baptista, L. Bianchi, F. Callea, J. De Groote, F. Gudat, H. Denk, V. Desmet, G. Korb, and R. N. MacSween, “Histological grading and staging of chronic hepatitis,” J. Hepatol. 22, 696–699 (1995).
[CrossRef] [PubMed]

The French METAVIR Cooperative Study Group, “Intraobserver, interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C,” J. Hepatol. 20, 15–20 (1995).

1991 (1)

P. J. Scheuer, “Classification of of chronic viral hepatitis: a need for reassessment,” J. Hepatol. 13, 372–374 (1991).
[CrossRef] [PubMed]

1989 (1)

L. I.-K. Lin, “A concordance correlation coefficient to evaluate reproducibility,” Biometrics 45, 255–268 (1989).
[CrossRef]

1979 (1)

S. Roth, and I. Freund, “Second harmonic generation in collagen,” J. Chem. Phys. 70, 1637–1643 (1979).
[CrossRef]

Abu-Rashed, A. H.

H. A. Saleh, and A. H. Abu-Rashed, “Liver Biopsy Remains the Gold Standard for Evaluation of Chronic Hepatitis and Fibrosis,” J. Gastrointestin. Liver Dis. 16, 425–426 (2007).

Afdhal, N. H.

N. H. Afdhal, and D. Nunes, “Evaluation of liver fibrosis: a concise review,” Am. J. Gastroenterol. 99, 1160–1174 (2004).
[CrossRef] [PubMed]

N. H. Afdhal, A. P. Keaveny, S. B. Cohen, D. P. Nunes, N. Maldonado, M. O’Brien, and P. J. Stone, “Urinary assays for desmosine and hydroxylysylpyridinoline in the detection of cirrhosis,” J. Hepatol. 27, 993–1002 (1997).
[CrossRef]

Albright, J. E.

G. L. Davis, J. E. Albright, S. F. Cook, and D. M. Rosenberg, “Projecting future complications of chronic hepatitis C in the United States,” Liver Transpl. 9, 331–338 (2003).
[CrossRef] [PubMed]

Alkilani, A.

C. Odin, T. Guilbert, A. Alkilani, O. Boryskina, V. Fleury, and Y. Le Grand, “Collagen and myosin characterization by orientation field second harmonic microscopy,” Opt. Express 16, 16151–16165 (2008).
[CrossRef] [PubMed]

Amat-Roldan, I.

S. Psilodimitrakopoulos, D. Artigas, G. Soria, I. Amat-Roldan, A. Planas, and P. Loza-Alvarez, “Quantitative discrimination between endogenousSHG sources in mammalian tissue, based ontheir polarization response,” Opt. Express 17, 10168–10176 (2009).
[CrossRef] [PubMed]

S. Psilodimitrakopoulos, V. Petegnief, G. Soria, I. Amat-Roldan, D. Artigas, A. Planas, and P. Loza-Alvarez, “Estimation of the effective orientation of the SHG source in primary cortical neurons,” Opt. Express 17, 14418–14425 (2009).
[CrossRef] [PubMed]

Artigas, D.

S. Psilodimitrakopoulos, V. Petegnief, G. Soria, I. Amat-Roldan, D. Artigas, A. Planas, and P. Loza-Alvarez, “Estimation of the effective orientation of the SHG source in primary cortical neurons,” Opt. Express 17, 14418–14425 (2009).
[CrossRef] [PubMed]

S. Psilodimitrakopoulos, D. Artigas, G. Soria, I. Amat-Roldan, A. Planas, and P. Loza-Alvarez, “Quantitative discrimination between endogenousSHG sources in mammalian tissue, based ontheir polarization response,” Opt. Express 17, 10168–10176 (2009).
[CrossRef] [PubMed]

Aub, C.

F. Oberti, E. Valsesia, C. Pilette, M. C. Rousselet, P. Bedossa, C. Aub, Y. Gallois, H. Rifflet, M. Y. Maga, D. Penneau-Fontbonne, and P. Cals, “Noninvasive diagnosis of hepatic fibrosis or cirrhosis,” Gastroenterology 113, 1609–1616 (1997).
[CrossRef] [PubMed]

Aube, C.

C. Aube, F. Oberti, N. Koralin, M.-A. Namour, D. Loisel, M. C. Rousselet, P. Bedossa, H. Rifflet, M. Y. Maga, C. Penneau, C. Caron, and P. Cals, “Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis,” J. Hepatol. 30, 472–478 (1999).
[CrossRef] [PubMed]

Baffet, G.

L. Gailhouste, Y. Le Grand, C. Odin, D. Guyader, B. Turlin, F. Ezan, Y. Dsille, T. Guilbert, A. Bessard, C. Frmin, N. Theret, and G. Baffet, “Fibrillar Collagen Scoring by Second Harmonic Microscopy as a New Tool in the Assessment of Liver Fibrosis,” J. Hepatol. 52, 398–406 (2010).
[CrossRef]

C. Odin, Y. Le Grand, A. Renault, L. Gailhouste, and G. Baffet, “Orientation fields of nonlinear biological fibrils by second harmonic generation microscopy,” J. Microsc. 229, 32–38 (2008).
[CrossRef]

Banson, F. L.

M. A. Friedenberg, L. Miller, C. Y. Chung, F. Fleszler, F. L. Banson, R. Thomas, K. P. Swartz, and F. K. Friedenberg, “Simplified method of hepatic fibrosis quantification: design of a new morphometric analysis application,” Liver Int. 25, 1156–1161 (2005).
[CrossRef]

Bao, H.

H. Bao, A. Boussioutas, R. Jeremy, S. Russell, and M. Gu, “Second harmonic generation imaging via nonlinear endomicroscopy,” Opt. Express 18, 1255–1260 (2010).
[CrossRef] [PubMed]

Baptista, A.

K. Ishak, A. Baptista, L. Bianchi, F. Callea, J. De Groote, F. Gudat, H. Denk, V. Desmet, G. Korb, and R. N. MacSween, “Histological grading and staging of chronic hepatitis,” J. Hepatol. 22, 696–699 (1995).
[CrossRef] [PubMed]

Bataller, R.

R. Bataller, and D. A. Brenner, “Liver fibrosis,” J. Clin. Invest. 115, 209–218 (2005).
[PubMed]

Beaurepaire, E.

M. Strupler, A. Pena, M. Hernest, P. Tharaux, J. Martin, E. Beaurepaire, and M. Schanne-Klein, “Second harmonic imaging and scoring of collagen in fibrotic tissues,” Opt. Express 15, 4054–4065 (2007).
[CrossRef] [PubMed]

A.-M. Pena, A. Fabre, D. Dbarre, 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. 70, 162–170 (2007).
[CrossRef]

Bedossa, P.

P. Bedossa, “Harmony in liver fibrosis.,” J. Hepatol. 52, 313–314 (2010).
[CrossRef]

P. Bedossa, D. Dargre, and V. Paradis, “Sampling variability of liver fibrosis in chronic hepatitis C,” J. Hepatol. 38, 1356–1358 (2003).

C. Aube, F. Oberti, N. Koralin, M.-A. Namour, D. Loisel, M. C. Rousselet, P. Bedossa, H. Rifflet, M. Y. Maga, C. Penneau, C. Caron, and P. Cals, “Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis,” J. Hepatol. 30, 472–478 (1999).
[CrossRef] [PubMed]

F. Oberti, E. Valsesia, C. Pilette, M. C. Rousselet, P. Bedossa, C. Aub, Y. Gallois, H. Rifflet, M. Y. Maga, D. Penneau-Fontbonne, and P. Cals, “Noninvasive diagnosis of hepatic fibrosis or cirrhosis,” Gastroenterology 113, 1609–1616 (1997).
[CrossRef] [PubMed]

Bessard, A.

L. Gailhouste, Y. Le Grand, C. Odin, D. Guyader, B. Turlin, F. Ezan, Y. Dsille, T. Guilbert, A. Bessard, C. Frmin, N. Theret, and G. Baffet, “Fibrillar Collagen Scoring by Second Harmonic Microscopy as a New Tool in the Assessment of Liver Fibrosis,” J. Hepatol. 52, 398–406 (2010).
[CrossRef]

Bianchi, L.

K. Ishak, A. Baptista, L. Bianchi, F. Callea, J. De Groote, F. Gudat, H. Denk, V. Desmet, G. Korb, and R. N. MacSween, “Histological grading and staging of chronic hepatitis,” J. Hepatol. 22, 696–699 (1995).
[CrossRef] [PubMed]

Boryskina, O.

C. Odin, T. Guilbert, A. Alkilani, O. Boryskina, V. Fleury, and Y. Le Grand, “Collagen and myosin characterization by orientation field second harmonic microscopy,” Opt. Express 16, 16151–16165 (2008).
[CrossRef] [PubMed]

Boussioutas, A.

H. Bao, A. Boussioutas, R. Jeremy, S. Russell, and M. Gu, “Second harmonic generation imaging via nonlinear endomicroscopy,” Opt. Express 18, 1255–1260 (2010).
[CrossRef] [PubMed]

Brenner, D. A.

R. Bataller, and D. A. Brenner, “Liver fibrosis,” J. Clin. Invest. 115, 209–218 (2005).
[PubMed]

Brown, E. B.

X. Han, R. M. Burke, M. L. Zettel, P. Tang, and E. B. Brown, “Second harmonic properties of tumor collagen: determining the structural relationship between reactive stroma and healthy stroma,” Opt. Express 16, 1846–1859 (2008), http://www.opticsinfobase.org/abstract.cfm?URI=oe-16-3-1846.
[CrossRef] [PubMed]

Burke, R. M.

X. Han, R. M. Burke, M. L. Zettel, P. Tang, and E. B. Brown, “Second harmonic properties of tumor collagen: determining the structural relationship between reactive stroma and healthy stroma,” Opt. Express 16, 1846–1859 (2008), http://www.opticsinfobase.org/abstract.cfm?URI=oe-16-3-1846.
[CrossRef] [PubMed]

Caballero, T.

M. Masseroli, and T. Caballero, “F. OValle, R. M. Del Moral, A. Perez-Milena, and R. G. Del Moral “Automatic quantification of liver fibrosis design and validation of a new image analysis method: comparison with semiquantitative indexes of fibrosis,”,” J. Hepatol. 32, 453–464 (2000).
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Callea, F.

K. Ishak, A. Baptista, L. Bianchi, F. Callea, J. De Groote, F. Gudat, H. Denk, V. Desmet, G. Korb, and R. N. MacSween, “Histological grading and staging of chronic hepatitis,” J. Hepatol. 22, 696–699 (1995).
[CrossRef] [PubMed]

Cals, P.

C. Aube, F. Oberti, N. Koralin, M.-A. Namour, D. Loisel, M. C. Rousselet, P. Bedossa, H. Rifflet, M. Y. Maga, C. Penneau, C. Caron, and P. Cals, “Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis,” J. Hepatol. 30, 472–478 (1999).
[CrossRef] [PubMed]

F. Oberti, E. Valsesia, C. Pilette, M. C. Rousselet, P. Bedossa, C. Aub, Y. Gallois, H. Rifflet, M. Y. Maga, D. Penneau-Fontbonne, and P. Cals, “Noninvasive diagnosis of hepatic fibrosis or cirrhosis,” Gastroenterology 113, 1609–1616 (1997).
[CrossRef] [PubMed]

Campagnola, P. J.

S. V. Plotnikov, A. C. Millard, and P. J. Campagnola, and W. A. Mohler, “Characterization of the myosin-based source for second-harmonic generation from muscle sarcomeres,” Biophys. J. 90, 693–703 (2006).
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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]

Caron, C.

C. Aube, F. Oberti, N. Koralin, M.-A. Namour, D. Loisel, M. C. Rousselet, P. Bedossa, H. Rifflet, M. Y. Maga, C. Penneau, C. Caron, and P. Cals, “Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis,” J. Hepatol. 30, 472–478 (1999).
[CrossRef] [PubMed]

Casola, G.

S. C. Faria, K. Ganesan, I. Mwangi, M. Shiehmorteza, B. Viamonte, S. Mazhar, M. Peterson, Y. Kono, C. Santillan, G. Casola, and C. B. Sirlin, “MR Imaging of Liver Fibrosis: Current State of the Art,” Radiographics 29, 1615–1635 (2009).
[CrossRef] [PubMed]

Chan, H. L.-Y.

A. Y. Hui, C.-T. Liew, M. Y.-Y. Go, A. M.-L. Chim, H. L.-Y. Chan, N. W.-Y. Leung, and J. J.-Y. Sung, “Quantitative assessment of fibrosis in liver biopsies from patients with chronic hepatitis B,” Liver Int. 24, 611–618 (2004).
[CrossRef]

Chang, S.

D. C. S. Tai, N. Tan, S. Xu, C. H. Kang, S. M. Chia, C. L. Cheng, A. Wee, C. Li Wei, A. M. Raja, G. Xiao, S. Chang, J. C. Rajapakse, P. T. C. So, H.-H. Tang, C. Shing Chen, and H. Yu, “Fibro-C-Index: comprehensive, morphology-based quantification of liver fibrosis using second harmonic generation and two-photon microscopy,” J. Biomed. Opt. 14(4), 044013 (2009), doi:10.1117/1.3183811.
[CrossRef] [PubMed]

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, C. L.

D. C. S. Tai, N. Tan, S. Xu, C. H. Kang, S. M. Chia, C. L. Cheng, A. Wee, C. Li Wei, A. M. Raja, G. Xiao, S. Chang, J. C. Rajapakse, P. T. C. So, H.-H. Tang, C. Shing Chen, and H. Yu, “Fibro-C-Index: comprehensive, morphology-based quantification of liver fibrosis using second harmonic generation and two-photon microscopy,” J. Biomed. Opt. 14(4), 044013 (2009), doi:10.1117/1.3183811.
[CrossRef] [PubMed]

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]

Chia, S. M.

D. C. S. Tai, N. Tan, S. Xu, C. H. Kang, S. M. Chia, C. L. Cheng, A. Wee, C. Li Wei, A. M. Raja, G. Xiao, S. Chang, J. C. Rajapakse, P. T. C. So, H.-H. Tang, C. Shing Chen, and H. Yu, “Fibro-C-Index: comprehensive, morphology-based quantification of liver fibrosis using second harmonic generation and two-photon microscopy,” J. Biomed. Opt. 14(4), 044013 (2009), doi:10.1117/1.3183811.
[CrossRef] [PubMed]

Chim, A. M.-L.

A. Y. Hui, C.-T. Liew, M. Y.-Y. Go, A. M.-L. Chim, H. L.-Y. Chan, N. W.-Y. Leung, and J. J.-Y. Sung, “Quantitative assessment of fibrosis in liver biopsies from patients with chronic hepatitis B,” Liver Int. 24, 611–618 (2004).
[CrossRef]

Chretien, D.

C. Odin, C. Heichette, D. Chretien, and Y. Le Grand, “Second harmonic microscopy of axonemes,” Opt. Express 17, 9235–9240 (2009).
[CrossRef] [PubMed]

Christie, R.

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

Chu, S. 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]

Chung, C. Y.

M. A. Friedenberg, L. Miller, C. Y. Chung, F. Fleszler, F. L. Banson, R. Thomas, K. P. Swartz, and F. K. Friedenberg, “Simplified method of hepatic fibrosis quantification: design of a new morphometric analysis application,” Liver Int. 25, 1156–1161 (2005).
[CrossRef]

Cohen, S. B.

N. H. Afdhal, A. P. Keaveny, S. B. Cohen, D. P. Nunes, N. Maldonado, M. O’Brien, and P. J. Stone, “Urinary assays for desmosine and hydroxylysylpyridinoline in the detection of cirrhosis,” J. Hepatol. 27, 993–1002 (1997).
[CrossRef]

Cook, S. F.

G. L. Davis, J. E. Albright, S. F. Cook, and D. M. Rosenberg, “Projecting future complications of chronic hepatitis C in the United States,” Liver Transpl. 9, 331–338 (2003).
[CrossRef] [PubMed]

Crestani, B.

A.-M. Pena, A. Fabre, D. Dbarre, 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. 70, 162–170 (2007).
[CrossRef]

Dargre, D.

P. Bedossa, D. Dargre, and V. Paradis, “Sampling variability of liver fibrosis in chronic hepatitis C,” J. Hepatol. 38, 1356–1358 (2003).

Davis, G. L.

G. L. Davis, J. E. Albright, S. F. Cook, and D. M. Rosenberg, “Projecting future complications of chronic hepatitis C in the United States,” Liver Transpl. 9, 331–338 (2003).
[CrossRef] [PubMed]

Dbarre, D.

A.-M. Pena, A. Fabre, D. Dbarre, 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. 70, 162–170 (2007).
[CrossRef]

De Groote, J.

K. Ishak, A. Baptista, L. Bianchi, F. Callea, J. De Groote, F. Gudat, H. Denk, V. Desmet, G. Korb, and R. N. MacSween, “Histological grading and staging of chronic hepatitis,” J. Hepatol. 22, 696–699 (1995).
[CrossRef] [PubMed]

Denk, H.

K. Ishak, A. Baptista, L. Bianchi, F. Callea, J. De Groote, F. Gudat, H. Denk, V. Desmet, G. Korb, and R. N. MacSween, “Histological grading and staging of chronic hepatitis,” J. Hepatol. 22, 696–699 (1995).
[CrossRef] [PubMed]

Desmet, V.

K. Ishak, A. Baptista, L. Bianchi, F. Callea, J. De Groote, F. Gudat, H. Denk, V. Desmet, G. Korb, and R. N. MacSween, “Histological grading and staging of chronic hepatitis,” J. Hepatol. 22, 696–699 (1995).
[CrossRef] [PubMed]

Dsille, Y.

L. Gailhouste, Y. Le Grand, C. Odin, D. Guyader, B. Turlin, F. Ezan, Y. Dsille, T. Guilbert, A. Bessard, C. Frmin, N. Theret, and G. Baffet, “Fibrillar Collagen Scoring by Second Harmonic Microscopy as a New Tool in the Assessment of Liver Fibrosis,” J. Hepatol. 52, 398–406 (2010).
[CrossRef]

Ezan, F.

L. Gailhouste, Y. Le Grand, C. Odin, D. Guyader, B. Turlin, F. Ezan, Y. Dsille, T. Guilbert, A. Bessard, C. Frmin, N. Theret, and G. Baffet, “Fibrillar Collagen Scoring by Second Harmonic Microscopy as a New Tool in the Assessment of Liver Fibrosis,” J. Hepatol. 52, 398–406 (2010).
[CrossRef]

Fabre, A.

A.-M. Pena, A. Fabre, D. Dbarre, 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. 70, 162–170 (2007).
[CrossRef]

Faria, S. C.

S. C. Faria, K. Ganesan, I. Mwangi, M. Shiehmorteza, B. Viamonte, S. Mazhar, M. Peterson, Y. Kono, C. Santillan, G. Casola, and C. B. Sirlin, “MR Imaging of Liver Fibrosis: Current State of the Art,” Radiographics 29, 1615–1635 (2009).
[CrossRef] [PubMed]

Fleszler, F.

M. A. Friedenberg, L. Miller, C. Y. Chung, F. Fleszler, F. L. Banson, R. Thomas, K. P. Swartz, and F. K. Friedenberg, “Simplified method of hepatic fibrosis quantification: design of a new morphometric analysis application,” Liver Int. 25, 1156–1161 (2005).
[CrossRef]

Fleury, V.

C. Odin, T. Guilbert, A. Alkilani, O. Boryskina, V. Fleury, and Y. Le Grand, “Collagen and myosin characterization by orientation field second harmonic microscopy,” Opt. Express 16, 16151–16165 (2008).
[CrossRef] [PubMed]

Freund, I.

S. Roth, and I. Freund, “Second harmonic generation in collagen,” J. Chem. Phys. 70, 1637–1643 (1979).
[CrossRef]

Friedenberg, F. K.

M. A. Friedenberg, L. Miller, C. Y. Chung, F. Fleszler, F. L. Banson, R. Thomas, K. P. Swartz, and F. K. Friedenberg, “Simplified method of hepatic fibrosis quantification: design of a new morphometric analysis application,” Liver Int. 25, 1156–1161 (2005).
[CrossRef]

Friedenberg, M. A.

M. A. Friedenberg, L. Miller, C. Y. Chung, F. Fleszler, F. L. Banson, R. Thomas, K. P. Swartz, and F. K. Friedenberg, “Simplified method of hepatic fibrosis quantification: design of a new morphometric analysis application,” Liver Int. 25, 1156–1161 (2005).
[CrossRef]

Friedman, S. L.

S. L. Friedman, “Liver fibrosis - from bench to bedside,” J. Hepatol. 38, 38–53 (2003).
[CrossRef]

Frmin, C.

L. Gailhouste, Y. Le Grand, C. Odin, D. Guyader, B. Turlin, F. Ezan, Y. Dsille, T. Guilbert, A. Bessard, C. Frmin, N. Theret, and G. Baffet, “Fibrillar Collagen Scoring by Second Harmonic Microscopy as a New Tool in the Assessment of Liver Fibrosis,” J. Hepatol. 52, 398–406 (2010).
[CrossRef]

Gailhouste, L.

L. Gailhouste, Y. Le Grand, C. Odin, D. Guyader, B. Turlin, F. Ezan, Y. Dsille, T. Guilbert, A. Bessard, C. Frmin, N. Theret, and G. Baffet, “Fibrillar Collagen Scoring by Second Harmonic Microscopy as a New Tool in the Assessment of Liver Fibrosis,” J. Hepatol. 52, 398–406 (2010).
[CrossRef]

C. Odin, Y. Le Grand, A. Renault, L. Gailhouste, and G. Baffet, “Orientation fields of nonlinear biological fibrils by second harmonic generation microscopy,” J. Microsc. 229, 32–38 (2008).
[CrossRef]

Gallois, Y.

F. Oberti, E. Valsesia, C. Pilette, M. C. Rousselet, P. Bedossa, C. Aub, Y. Gallois, H. Rifflet, M. Y. Maga, D. Penneau-Fontbonne, and P. Cals, “Noninvasive diagnosis of hepatic fibrosis or cirrhosis,” Gastroenterology 113, 1609–1616 (1997).
[CrossRef] [PubMed]

Ganesan, K.

S. C. Faria, K. Ganesan, I. Mwangi, M. Shiehmorteza, B. Viamonte, S. Mazhar, M. Peterson, Y. Kono, C. Santillan, G. Casola, and C. B. Sirlin, “MR Imaging of Liver Fibrosis: Current State of the Art,” Radiographics 29, 1615–1635 (2009).
[CrossRef] [PubMed]

Go, M. Y.-Y.

A. Y. Hui, C.-T. Liew, M. Y.-Y. Go, A. M.-L. Chim, H. L.-Y. Chan, N. W.-Y. Leung, and J. J.-Y. Sung, “Quantitative assessment of fibrosis in liver biopsies from patients with chronic hepatitis B,” Liver Int. 24, 611–618 (2004).
[CrossRef]

Gu, M.

H. Bao, A. Boussioutas, R. Jeremy, S. Russell, and M. Gu, “Second harmonic generation imaging via nonlinear endomicroscopy,” Opt. Express 18, 1255–1260 (2010).
[CrossRef] [PubMed]

Gudat, F.

K. Ishak, A. Baptista, L. Bianchi, F. Callea, J. De Groote, F. Gudat, H. Denk, V. Desmet, G. Korb, and R. N. MacSween, “Histological grading and staging of chronic hepatitis,” J. Hepatol. 22, 696–699 (1995).
[CrossRef] [PubMed]

Guilbert, T.

L. Gailhouste, Y. Le Grand, C. Odin, D. Guyader, B. Turlin, F. Ezan, Y. Dsille, T. Guilbert, A. Bessard, C. Frmin, N. Theret, and G. Baffet, “Fibrillar Collagen Scoring by Second Harmonic Microscopy as a New Tool in the Assessment of Liver Fibrosis,” J. Hepatol. 52, 398–406 (2010).
[CrossRef]

C. Odin, T. Guilbert, A. Alkilani, O. Boryskina, V. Fleury, and Y. Le Grand, “Collagen and myosin characterization by orientation field second harmonic microscopy,” Opt. Express 16, 16151–16165 (2008).
[CrossRef] [PubMed]

Guyader, D.

L. Gailhouste, Y. Le Grand, C. Odin, D. Guyader, B. Turlin, F. Ezan, Y. Dsille, T. Guilbert, A. Bessard, C. Frmin, N. Theret, and G. Baffet, “Fibrillar Collagen Scoring by Second Harmonic Microscopy as a New Tool in the Assessment of Liver Fibrosis,” J. Hepatol. 52, 398–406 (2010).
[CrossRef]

Han, X.

X. Han, R. M. Burke, M. L. Zettel, P. Tang, and E. B. Brown, “Second harmonic properties of tumor collagen: determining the structural relationship between reactive stroma and healthy stroma,” Opt. Express 16, 1846–1859 (2008), http://www.opticsinfobase.org/abstract.cfm?URI=oe-16-3-1846.
[CrossRef] [PubMed]

Heichette, C.

C. Odin, C. Heichette, D. Chretien, and Y. Le Grand, “Second harmonic microscopy of axonemes,” Opt. Express 17, 9235–9240 (2009).
[CrossRef] [PubMed]

Hernest, M.

M. Strupler, A. Pena, M. Hernest, P. Tharaux, J. Martin, E. Beaurepaire, and M. Schanne-Klein, “Second harmonic imaging and scoring of collagen in fibrotic tissues,” Opt. Express 15, 4054–4065 (2007).
[CrossRef] [PubMed]

Hui, A. Y.

A. Y. Hui, C.-T. Liew, M. Y.-Y. Go, A. M.-L. Chim, H. L.-Y. Chan, N. W.-Y. Leung, and J. J.-Y. Sung, “Quantitative assessment of fibrosis in liver biopsies from patients with chronic hepatitis B,” Liver Int. 24, 611–618 (2004).
[CrossRef]

Hyman, B. T.

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

Ishak, K.

K. Ishak, A. Baptista, L. Bianchi, F. Callea, J. De Groote, F. Gudat, H. Denk, V. Desmet, G. Korb, and R. N. MacSween, “Histological grading and staging of chronic hepatitis,” J. Hepatol. 22, 696–699 (1995).
[CrossRef] [PubMed]

Jeremy, R.

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N. H. Afdhal, A. P. Keaveny, S. B. Cohen, D. P. Nunes, N. Maldonado, M. O’Brien, and P. J. Stone, “Urinary assays for desmosine and hydroxylysylpyridinoline in the detection of cirrhosis,” J. Hepatol. 27, 993–1002 (1997).
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S. Psilodimitrakopoulos, D. Artigas, G. Soria, I. Amat-Roldan, A. Planas, and P. Loza-Alvarez, “Quantitative discrimination between endogenousSHG sources in mammalian tissue, based ontheir polarization response,” Opt. Express 17, 10168–10176 (2009).
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K. Ishak, A. Baptista, L. Bianchi, F. Callea, J. De Groote, F. Gudat, H. Denk, V. Desmet, G. Korb, and R. N. MacSween, “Histological grading and staging of chronic hepatitis,” J. Hepatol. 22, 696–699 (1995).
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C. Aube, F. Oberti, N. Koralin, M.-A. Namour, D. Loisel, M. C. Rousselet, P. Bedossa, H. Rifflet, M. Y. Maga, C. Penneau, C. Caron, and P. Cals, “Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis,” J. Hepatol. 30, 472–478 (1999).
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N. H. Afdhal, A. P. Keaveny, S. B. Cohen, D. P. Nunes, N. Maldonado, M. O’Brien, and P. J. Stone, “Urinary assays for desmosine and hydroxylysylpyridinoline in the detection of cirrhosis,” J. Hepatol. 27, 993–1002 (1997).
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N. H. Afdhal, A. P. Keaveny, S. B. Cohen, D. P. Nunes, N. Maldonado, M. O’Brien, and P. J. Stone, “Urinary assays for desmosine and hydroxylysylpyridinoline in the detection of cirrhosis,” J. Hepatol. 27, 993–1002 (1997).
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L. Gailhouste, Y. Le Grand, C. Odin, D. Guyader, B. Turlin, F. Ezan, Y. Dsille, T. Guilbert, A. Bessard, C. Frmin, N. Theret, and G. Baffet, “Fibrillar Collagen Scoring by Second Harmonic Microscopy as a New Tool in the Assessment of Liver Fibrosis,” J. Hepatol. 52, 398–406 (2010).
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C. Odin, C. Heichette, D. Chretien, and Y. Le Grand, “Second harmonic microscopy of axonemes,” Opt. Express 17, 9235–9240 (2009).
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C. Odin, T. Guilbert, A. Alkilani, O. Boryskina, V. Fleury, and Y. Le Grand, “Collagen and myosin characterization by orientation field second harmonic microscopy,” Opt. Express 16, 16151–16165 (2008).
[CrossRef] [PubMed]

C. Odin, Y. Le Grand, A. Renault, L. Gailhouste, and G. Baffet, “Orientation fields of nonlinear biological fibrils by second harmonic generation microscopy,” J. Microsc. 229, 32–38 (2008).
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M. Strupler, A. Pena, M. Hernest, P. Tharaux, J. Martin, E. Beaurepaire, and M. Schanne-Klein, “Second harmonic imaging and scoring of collagen in fibrotic tissues,” Opt. Express 15, 4054–4065 (2007).
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A.-M. Pena, A. Fabre, D. Dbarre, 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. 70, 162–170 (2007).
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C. Aube, F. Oberti, N. Koralin, M.-A. Namour, D. Loisel, M. C. Rousselet, P. Bedossa, H. Rifflet, M. Y. Maga, C. Penneau, C. Caron, and P. Cals, “Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis,” J. Hepatol. 30, 472–478 (1999).
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S. Psilodimitrakopoulos, V. Petegnief, G. Soria, I. Amat-Roldan, D. Artigas, A. Planas, and P. Loza-Alvarez, “Estimation of the effective orientation of the SHG source in primary cortical neurons,” Opt. Express 17, 14418–14425 (2009).
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S. C. Faria, K. Ganesan, I. Mwangi, M. Shiehmorteza, B. Viamonte, S. Mazhar, M. Peterson, Y. Kono, C. Santillan, G. Casola, and C. B. Sirlin, “MR Imaging of Liver Fibrosis: Current State of the Art,” Radiographics 29, 1615–1635 (2009).
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F. Oberti, E. Valsesia, C. Pilette, M. C. Rousselet, P. Bedossa, C. Aub, Y. Gallois, H. Rifflet, M. Y. Maga, D. Penneau-Fontbonne, and P. Cals, “Noninvasive diagnosis of hepatic fibrosis or cirrhosis,” Gastroenterology 113, 1609–1616 (1997).
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S. Psilodimitrakopoulos, V. Petegnief, G. Soria, I. Amat-Roldan, D. Artigas, A. Planas, and P. Loza-Alvarez, “Estimation of the effective orientation of the SHG source in primary cortical neurons,” Opt. Express 17, 14418–14425 (2009).
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S. Psilodimitrakopoulos, D. Artigas, G. Soria, I. Amat-Roldan, A. Planas, and P. Loza-Alvarez, “Quantitative discrimination between endogenousSHG sources in mammalian tissue, based ontheir polarization response,” Opt. Express 17, 10168–10176 (2009).
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S. V. Plotnikov, A. C. Millard, and P. J. Campagnola, and W. A. Mohler, “Characterization of the myosin-based source for second-harmonic generation from muscle sarcomeres,” Biophys. J. 90, 693–703 (2006).
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S. Psilodimitrakopoulos, V. Petegnief, G. Soria, I. Amat-Roldan, D. Artigas, A. Planas, and P. Loza-Alvarez, “Estimation of the effective orientation of the SHG source in primary cortical neurons,” Opt. Express 17, 14418–14425 (2009).
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S. Psilodimitrakopoulos, D. Artigas, G. Soria, I. Amat-Roldan, A. Planas, and P. Loza-Alvarez, “Quantitative discrimination between endogenousSHG sources in mammalian tissue, based ontheir polarization response,” Opt. Express 17, 10168–10176 (2009).
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D. C. S. Tai, N. Tan, S. Xu, C. H. Kang, S. M. Chia, C. L. Cheng, A. Wee, C. Li Wei, A. M. Raja, G. Xiao, S. Chang, J. C. Rajapakse, P. T. C. So, H.-H. Tang, C. Shing Chen, and H. Yu, “Fibro-C-Index: comprehensive, morphology-based quantification of liver fibrosis using second harmonic generation and two-photon microscopy,” J. Biomed. Opt. 14(4), 044013 (2009), doi:10.1117/1.3183811.
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D. C. S. Tai, N. Tan, S. Xu, C. H. Kang, S. M. Chia, C. L. Cheng, A. Wee, C. Li Wei, A. M. Raja, G. Xiao, S. Chang, J. C. Rajapakse, P. T. C. So, H.-H. Tang, C. Shing Chen, and H. Yu, “Fibro-C-Index: comprehensive, morphology-based quantification of liver fibrosis using second harmonic generation and two-photon microscopy,” J. Biomed. Opt. 14(4), 044013 (2009), doi:10.1117/1.3183811.
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C. Odin, Y. Le Grand, A. Renault, L. Gailhouste, and G. Baffet, “Orientation fields of nonlinear biological fibrils by second harmonic generation microscopy,” J. Microsc. 229, 32–38 (2008).
[CrossRef]

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C. Aube, F. Oberti, N. Koralin, M.-A. Namour, D. Loisel, M. C. Rousselet, P. Bedossa, H. Rifflet, M. Y. Maga, C. Penneau, C. Caron, and P. Cals, “Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis,” J. Hepatol. 30, 472–478 (1999).
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H. Bao, A. Boussioutas, R. Jeremy, S. Russell, and M. Gu, “Second harmonic generation imaging via nonlinear endomicroscopy,” Opt. Express 18, 1255–1260 (2010).
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M. Strupler, A. Pena, M. Hernest, P. Tharaux, J. Martin, E. Beaurepaire, and M. Schanne-Klein, “Second harmonic imaging and scoring of collagen in fibrotic tissues,” Opt. Express 15, 4054–4065 (2007).
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A.-M. Pena, A. Fabre, D. Dbarre, 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. 70, 162–170 (2007).
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Shing Chen, C.

D. C. S. Tai, N. Tan, S. Xu, C. H. Kang, S. M. Chia, C. L. Cheng, A. Wee, C. Li Wei, A. M. Raja, G. Xiao, S. Chang, J. C. Rajapakse, P. T. C. So, H.-H. Tang, C. Shing Chen, and H. Yu, “Fibro-C-Index: comprehensive, morphology-based quantification of liver fibrosis using second harmonic generation and two-photon microscopy,” J. Biomed. Opt. 14(4), 044013 (2009), doi:10.1117/1.3183811.
[CrossRef] [PubMed]

Sirlin, C. B.

S. C. Faria, K. Ganesan, I. Mwangi, M. Shiehmorteza, B. Viamonte, S. Mazhar, M. Peterson, Y. Kono, C. Santillan, G. Casola, and C. B. Sirlin, “MR Imaging of Liver Fibrosis: Current State of the Art,” Radiographics 29, 1615–1635 (2009).
[CrossRef] [PubMed]

So, P. T. C.

D. C. S. Tai, N. Tan, S. Xu, C. H. Kang, S. M. Chia, C. L. Cheng, A. Wee, C. Li Wei, A. M. Raja, G. Xiao, S. Chang, J. C. Rajapakse, P. T. C. So, H.-H. Tang, C. Shing Chen, and H. Yu, “Fibro-C-Index: comprehensive, morphology-based quantification of liver fibrosis using second harmonic generation and two-photon microscopy,” J. Biomed. Opt. 14(4), 044013 (2009), doi:10.1117/1.3183811.
[CrossRef] [PubMed]

Soria, G.

S. Psilodimitrakopoulos, D. Artigas, G. Soria, I. Amat-Roldan, A. Planas, and P. Loza-Alvarez, “Quantitative discrimination between endogenousSHG sources in mammalian tissue, based ontheir polarization response,” Opt. Express 17, 10168–10176 (2009).
[CrossRef] [PubMed]

S. Psilodimitrakopoulos, V. Petegnief, G. Soria, I. Amat-Roldan, D. Artigas, A. Planas, and P. Loza-Alvarez, “Estimation of the effective orientation of the SHG source in primary cortical neurons,” Opt. Express 17, 14418–14425 (2009).
[CrossRef] [PubMed]

Stone, P. J.

N. H. Afdhal, A. P. Keaveny, S. B. Cohen, D. P. Nunes, N. Maldonado, M. O’Brien, and P. J. Stone, “Urinary assays for desmosine and hydroxylysylpyridinoline in the detection of cirrhosis,” J. Hepatol. 27, 993–1002 (1997).
[CrossRef]

Strupler, M.

M. Strupler, A. Pena, M. Hernest, P. Tharaux, J. Martin, E. Beaurepaire, and M. Schanne-Klein, “Second harmonic imaging and scoring of collagen in fibrotic tissues,” Opt. Express 15, 4054–4065 (2007).
[CrossRef] [PubMed]

Sun, C. K.

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]

Sung, J. J.-Y.

A. Y. Hui, C.-T. Liew, M. Y.-Y. Go, A. M.-L. Chim, H. L.-Y. Chan, N. W.-Y. Leung, and J. J.-Y. Sung, “Quantitative assessment of fibrosis in liver biopsies from patients with chronic hepatitis B,” Liver Int. 24, 611–618 (2004).
[CrossRef]

Swartz, K. P.

M. A. Friedenberg, L. Miller, C. Y. Chung, F. Fleszler, F. L. Banson, R. Thomas, K. P. Swartz, and F. K. Friedenberg, “Simplified method of hepatic fibrosis quantification: design of a new morphometric analysis application,” Liver Int. 25, 1156–1161 (2005).
[CrossRef]

Tai, D. C. S.

D. C. S. Tai, N. Tan, S. Xu, C. H. Kang, S. M. Chia, C. L. Cheng, A. Wee, C. Li Wei, A. M. Raja, G. Xiao, S. Chang, J. C. Rajapakse, P. T. C. So, H.-H. Tang, C. Shing Chen, and H. Yu, “Fibro-C-Index: comprehensive, morphology-based quantification of liver fibrosis using second harmonic generation and two-photon microscopy,” J. Biomed. Opt. 14(4), 044013 (2009), doi:10.1117/1.3183811.
[CrossRef] [PubMed]

Tan, N.

D. C. S. Tai, N. Tan, S. Xu, C. H. Kang, S. M. Chia, C. L. Cheng, A. Wee, C. Li Wei, A. M. Raja, G. Xiao, S. Chang, J. C. Rajapakse, P. T. C. So, H.-H. Tang, C. Shing Chen, and H. Yu, “Fibro-C-Index: comprehensive, morphology-based quantification of liver fibrosis using second harmonic generation and two-photon microscopy,” J. Biomed. Opt. 14(4), 044013 (2009), doi:10.1117/1.3183811.
[CrossRef] [PubMed]

Tang, H.-H.

D. C. S. Tai, N. Tan, S. Xu, C. H. Kang, S. M. Chia, C. L. Cheng, A. Wee, C. Li Wei, A. M. Raja, G. Xiao, S. Chang, J. C. Rajapakse, P. T. C. So, H.-H. Tang, C. Shing Chen, and H. Yu, “Fibro-C-Index: comprehensive, morphology-based quantification of liver fibrosis using second harmonic generation and two-photon microscopy,” J. Biomed. Opt. 14(4), 044013 (2009), doi:10.1117/1.3183811.
[CrossRef] [PubMed]

Tang, P.

X. Han, R. M. Burke, M. L. Zettel, P. Tang, and E. B. Brown, “Second harmonic properties of tumor collagen: determining the structural relationship between reactive stroma and healthy stroma,” Opt. Express 16, 1846–1859 (2008), http://www.opticsinfobase.org/abstract.cfm?URI=oe-16-3-1846.
[CrossRef] [PubMed]

Tharaux, P.

M. Strupler, A. Pena, M. Hernest, P. Tharaux, J. Martin, E. Beaurepaire, and M. Schanne-Klein, “Second harmonic imaging and scoring of collagen in fibrotic tissues,” Opt. Express 15, 4054–4065 (2007).
[CrossRef] [PubMed]

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L. Gailhouste, Y. Le Grand, C. Odin, D. Guyader, B. Turlin, F. Ezan, Y. Dsille, T. Guilbert, A. Bessard, C. Frmin, N. Theret, and G. Baffet, “Fibrillar Collagen Scoring by Second Harmonic Microscopy as a New Tool in the Assessment of Liver Fibrosis,” J. Hepatol. 52, 398–406 (2010).
[CrossRef]

Thomas, R.

M. A. Friedenberg, L. Miller, C. Y. Chung, F. Fleszler, F. L. Banson, R. Thomas, K. P. Swartz, and F. K. Friedenberg, “Simplified method of hepatic fibrosis quantification: design of a new morphometric analysis application,” Liver Int. 25, 1156–1161 (2005).
[CrossRef]

Tromberg, B. J.

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. U.S.A.. 20, 11014–11019 (2002).
[CrossRef]

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]

Turlin, B.

L. Gailhouste, Y. Le Grand, C. Odin, D. Guyader, B. Turlin, F. Ezan, Y. Dsille, T. Guilbert, A. Bessard, C. Frmin, N. Theret, and G. Baffet, “Fibrillar Collagen Scoring by Second Harmonic Microscopy as a New Tool in the Assessment of Liver Fibrosis,” J. Hepatol. 52, 398–406 (2010).
[CrossRef]

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F. Oberti, E. Valsesia, C. Pilette, M. C. Rousselet, P. Bedossa, C. Aub, Y. Gallois, H. Rifflet, M. Y. Maga, D. Penneau-Fontbonne, and P. Cals, “Noninvasive diagnosis of hepatic fibrosis or cirrhosis,” Gastroenterology 113, 1609–1616 (1997).
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S. C. Faria, K. Ganesan, I. Mwangi, M. Shiehmorteza, B. Viamonte, S. Mazhar, M. Peterson, Y. Kono, C. Santillan, G. Casola, and C. B. Sirlin, “MR Imaging of Liver Fibrosis: Current State of the Art,” Radiographics 29, 1615–1635 (2009).
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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).
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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. U.S.A. 100, 7075–7080 (2003).
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W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21, 1369–1377 (2003).
[CrossRef]

Wee, A.

D. C. S. Tai, N. Tan, S. Xu, C. H. Kang, S. M. Chia, C. L. Cheng, A. Wee, C. Li Wei, A. M. Raja, G. Xiao, S. Chang, J. C. Rajapakse, P. T. C. So, H.-H. Tang, C. Shing Chen, and H. Yu, “Fibro-C-Index: comprehensive, morphology-based quantification of liver fibrosis using second harmonic generation and two-photon microscopy,” J. Biomed. Opt. 14(4), 044013 (2009), doi:10.1117/1.3183811.
[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. U.S.A. 100, 7075–7080 (2003).
[CrossRef] [PubMed]

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21, 1369–1377 (2003).
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Xiao, G.

D. C. S. Tai, N. Tan, S. Xu, C. H. Kang, S. M. Chia, C. L. Cheng, A. Wee, C. Li Wei, A. M. Raja, G. Xiao, S. Chang, J. C. Rajapakse, P. T. C. So, H.-H. Tang, C. Shing Chen, and H. Yu, “Fibro-C-Index: comprehensive, morphology-based quantification of liver fibrosis using second harmonic generation and two-photon microscopy,” J. Biomed. Opt. 14(4), 044013 (2009), doi:10.1117/1.3183811.
[CrossRef] [PubMed]

Xu, S.

D. C. S. Tai, N. Tan, S. Xu, C. H. Kang, S. M. Chia, C. L. Cheng, A. Wee, C. Li Wei, A. M. Raja, G. Xiao, S. Chang, J. C. Rajapakse, P. T. C. So, H.-H. Tang, C. Shing Chen, and H. Yu, “Fibro-C-Index: comprehensive, morphology-based quantification of liver fibrosis using second harmonic generation and two-photon microscopy,” J. Biomed. Opt. 14(4), 044013 (2009), doi:10.1117/1.3183811.
[CrossRef] [PubMed]

Yeh, A.

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. U.S.A.. 20, 11014–11019 (2002).
[CrossRef]

Yu, H.

D. C. S. Tai, N. Tan, S. Xu, C. H. Kang, S. M. Chia, C. L. Cheng, A. Wee, C. Li Wei, A. M. Raja, G. Xiao, S. Chang, J. C. Rajapakse, P. T. C. So, H.-H. Tang, C. Shing Chen, and H. Yu, “Fibro-C-Index: comprehensive, morphology-based quantification of liver fibrosis using second harmonic generation and two-photon microscopy,” J. Biomed. Opt. 14(4), 044013 (2009), doi:10.1117/1.3183811.
[CrossRef] [PubMed]

Zettel, M. L.

X. Han, R. M. Burke, M. L. Zettel, P. Tang, and E. B. Brown, “Second harmonic properties of tumor collagen: determining the structural relationship between reactive stroma and healthy stroma,” Opt. Express 16, 1846–1859 (2008), http://www.opticsinfobase.org/abstract.cfm?URI=oe-16-3-1846.
[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. U.S.A. 100, 7075–7080 (2003).
[CrossRef] [PubMed]

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol. 21, 1369–1377 (2003).
[CrossRef]

Zoumi, A.

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. U.S.A.. 20, 11014–11019 (2002).
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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).
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F. Oberti, E. Valsesia, C. Pilette, M. C. Rousselet, P. Bedossa, C. Aub, Y. Gallois, H. Rifflet, M. Y. Maga, D. Penneau-Fontbonne, and P. Cals, “Noninvasive diagnosis of hepatic fibrosis or cirrhosis,” Gastroenterology 113, 1609–1616 (1997).
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J. Biomed. Opt. (1)

D. C. S. Tai, N. Tan, S. Xu, C. H. Kang, S. M. Chia, C. L. Cheng, A. Wee, C. Li Wei, A. M. Raja, G. Xiao, S. Chang, J. C. Rajapakse, P. T. C. So, H.-H. Tang, C. Shing Chen, and H. Yu, “Fibro-C-Index: comprehensive, morphology-based quantification of liver fibrosis using second harmonic generation and two-photon microscopy,” J. Biomed. Opt. 14(4), 044013 (2009), doi:10.1117/1.3183811.
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A. Y. Hui, C.-T. Liew, M. Y.-Y. Go, A. M.-L. Chim, H. L.-Y. Chan, N. W.-Y. Leung, and J. J.-Y. Sung, “Quantitative assessment of fibrosis in liver biopsies from patients with chronic hepatitis B,” Liver Int. 24, 611–618 (2004).
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M. A. Friedenberg, L. Miller, C. Y. Chung, F. Fleszler, F. L. Banson, R. Thomas, K. P. Swartz, and F. K. Friedenberg, “Simplified method of hepatic fibrosis quantification: design of a new morphometric analysis application,” Liver Int. 25, 1156–1161 (2005).
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Microsc. Res. Tech. (1)

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C. Odin, T. Guilbert, A. Alkilani, O. Boryskina, V. Fleury, and Y. Le Grand, “Collagen and myosin characterization by orientation field second harmonic microscopy,” Opt. Express 16, 16151–16165 (2008).
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S. Psilodimitrakopoulos, D. Artigas, G. Soria, I. Amat-Roldan, A. Planas, and P. Loza-Alvarez, “Quantitative discrimination between endogenousSHG sources in mammalian tissue, based ontheir polarization response,” Opt. Express 17, 10168–10176 (2009).
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S. Psilodimitrakopoulos, V. Petegnief, G. Soria, I. Amat-Roldan, D. Artigas, A. Planas, and P. Loza-Alvarez, “Estimation of the effective orientation of the SHG source in primary cortical neurons,” Opt. Express 17, 14418–14425 (2009).
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M. Strupler, A. Pena, M. Hernest, P. Tharaux, J. Martin, E. Beaurepaire, and M. Schanne-Klein, “Second harmonic imaging and scoring of collagen in fibrotic tissues,” Opt. Express 15, 4054–4065 (2007).
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X. Han, R. M. Burke, M. L. Zettel, P. Tang, and E. B. Brown, “Second harmonic properties of tumor collagen: determining the structural relationship between reactive stroma and healthy stroma,” Opt. Express 16, 1846–1859 (2008), http://www.opticsinfobase.org/abstract.cfm?URI=oe-16-3-1846.
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Proc. Natl. Acad. Sci. U.S.A. (1)

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A. 100, 7075–7080 (2003).
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Proc. Natl. Acad. Sci. U.S.A.. (1)

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. U.S.A.. 20, 11014–11019 (2002).
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Radiographics (1)

S. C. Faria, K. Ganesan, I. Mwangi, M. Shiehmorteza, B. Viamonte, S. Mazhar, M. Peterson, Y. Kono, C. Santillan, G. Casola, and C. B. Sirlin, “MR Imaging of Liver Fibrosis: Current State of the Art,” Radiographics 29, 1615–1635 (2009).
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Figures (7)

Fig. 1
Fig. 1

(Color inline) SHG images acquired with a 4x-objective of a F1 biopsies. (a) PMT gain g1 was set to obtain an image with almost no saturated pixels (3.5×3.5mm2) ; (b) Same image as in a), but multiplied by 4.7 and shown with a scale limited to the 12-bits range [0 4095];(c) Experimental image with a PMT gain set to 4.7×g1 ;(d) Comparison of image intensity histograms for three PMT gains g1, 2.15 × g1, and 4.7 × g1.

Fig. 2
Fig. 2

(Color inline) (a) Schematic representation of the PSF2 of the objectives (1/e contour lines) as compared to the sample thickness ; (b) Experimental z-profiles of the PSF2 of the 4x(•) and 10x (♦) objectives. Intensity z-profile (▪) of a 50μm thick sample reconstructed from slices acquired with the 10x objective. Continuous lines are fits as explained in the text. (c) Typical images of a z-stack recorded with the 10x objective (scale bar=400μm).

Fig. 3
Fig. 3

a) Example of non fibrotic ECM on a F4 sample, delineated by white boxes ; b) Boxplot of mean intensities of different non-fibrotic ECM ROIs selected from different Metavir-graded samples. The PMT gain is the same for all samples, and was set to obtain r =4%(<ISHG>= 164, horizontal line) on a F0 sample with the 4x objective.

Fig. 4
Fig. 4

Images of non-fibrotic ECM ROIs for different PMT gains corresponding to r =2,3,4,5% : (a) for the 4x objective lens ; (b) 10x objective lens. c) Corresponding PMT gains ; (d) Correlation between the PMT gains of the 10x and 4x objective lens.

Fig. 5
Fig. 5

SHG images of histological serial sections of a surgical biopsie of a F4 patient, with thicknesses : (a)5μm,(b) 15μm,(c) 50μm. d) Correlation between the PMT gain and the inverse of the geometrical factor f (Eq. (3)).

Fig. 6
Fig. 6

Example of 4x (first line) and 10x (second line) images when r=4%, for the same field of view 3525×3525μm2 (4x : 512×512 pixels; 10x : 1300×1300 pixels).(a,b,c,d) F1 Metavir grade. (e,f,g,h) F4 Metavir grade. (a,b,e,f) 4x-obj. (c,d,g,h) 10x-obj

Fig. 7
Fig. 7

Comparison of the scores obtained at r =2,3,5% with the score at r =4% for :(a) the 4x lens ; (b) the 10x lens. (c) Comparison of 4x and 10x scores.

Tables (3)

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Table 1 (1) : Estimation of the lateral and axial 1/e radii of the diffraction-limited PSF2 of the two objective lenses used in the experiments, assuming a Gaussian shape, from ref. [20]. (2) Measured value. Excitation wavelength=810nm; FOV=Field of View of our microscope.

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Table 2 Data of the experimental set up.(1) : Average laser power at the focal plane measured with a calibrated power-meter OPHIR PD300; (2) PMT supplied voltage used for experiments performed with 4% SHG mean intensity from the basal collagen of the ECM.

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Table 3 Slope from a least-square linear fit Y = a × X and Pearson’s linear correlation coefficient R between different scores, and the sample concordance correlation coefficient ρL proposed by Lin (1989) [38].

Equations (6)

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S ¯ ( t ) = 1 N 2 i , j = 1 N H ( I i j t )
I SHG g PMT T 2 I o 2 d 3 r P ( r ) C ¯
f Ω N A 2 e / 2 e / 2 exp ( z 2 / w z 2 ) d z N A 2 w z erf ( e 2 w z ) N A 4 erf ( e 2 w z )
I S H G g P M T T 2 f C ¯
I S H G = r I S a t C ¯ C r e f
g P M T 10 x = ( T 4 x T 10 x ) 2 f 4 x g P M T 4 x

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