Abstract

We demonstrate the application of multiphoton microscopy in diagnosing toxin- CCl4 induced liver fibrosis in mice. Although hepatocyte autofluorescence does not vary significantly, different degrees of necrosis and stellate cell proliferation at necrotic sites in livers with fibrosis (ex vivo) can be detected easily from multiphoton-induced autofluorescence images by use of 780-nm excitation. Our result suggests that multiphoton microscopy can be developed into an effective technique for the detection and diagnosis of liver fibrosis in vivo.

© 2004 Optical Society of America

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    [CrossRef] [PubMed]
  2. P. T. C. So, C. Y. Dong, B. R. Masters, and K. M. Berland, Annu. Rev. Biomed. Eng. 2, 399 (2000).
    [CrossRef]
  3. B. Yu, C. Y. Dong, P. T. C. So, D. Blankschtein, and R. Langer, J. Invest. Dermatol. 117, 16 (2001).
    [CrossRef] [PubMed]
  4. Y. Sun, J. W. Su, W. Lo, S. J. Lin, S. H. Jee, and C. Y. Dong, Opt. Express 11, 3377 (2003), http://www.opticsexpress.org .
    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
  6. E. B. Brown, R. B. Campbell, Y. Tsuzuki, L. Xu, P. Carmeliet, D. Fukumura, and R. K. Jain, Nat. Med. 7, 864 (2001).
    [CrossRef] [PubMed]
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    [CrossRef]
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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
  10. M. H. Ross, G. I. Kaye, and W. Pawlina, Histology, 4th ed. (Lippincott Williams & Wilkins, Baltimore, 2003).
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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]

2004 (1)

2003 (1)

2002 (1)

B. Vollmar, S. Pradarutti, S. Richter, and M. D. Menger, Liver 22, 330 (2002).
[CrossRef] [PubMed]

2001 (3)

B. Yu, C. Y. Dong, P. T. C. So, D. Blankschtein, and R. Langer, J. Invest. Dermatol. 117, 16 (2001).
[CrossRef] [PubMed]

E. B. Brown, R. B. Campbell, Y. Tsuzuki, L. Xu, P. Carmeliet, D. Fukumura, and R. K. Jain, Nat. Med. 7, 864 (2001).
[CrossRef] [PubMed]

F. Helmchen, M. S. Fee, D. W. Tank, and W. Denk, Neuron 31, 903 (2001).
[CrossRef] [PubMed]

2000 (2)

P. T. C. So, C. Y. Dong, B. R. Masters, and K. M. Berland, Annu. Rev. Biomed. Eng. 2, 399 (2000).
[CrossRef]

S. L. Friedman, J. Biol. Chem. 275, 2247 (2000).
[CrossRef] [PubMed]

1999 (1)

J. M. Squirrell, D. L. Wokosin, J. G. White, and B. D. Bavister, Nat. Biotechnol. 17, 763 (1999).
[CrossRef] [PubMed]

1995 (1)

W. Denk, M. Sugimori, and R. Llinas, Proc. Natl. Acad. Sci. USA. 92, 8279 (1995).
[CrossRef]

1993 (1)

S. L. Friedman, N. Engl. J. Med. 328, 1828 (1993).
[CrossRef] [PubMed]

1990 (1)

W. Denk, J. H. Strickler, and W. W. Webb, Science 248, 73 (1990).
[CrossRef] [PubMed]

Bavister, B. D.

J. M. Squirrell, D. L. Wokosin, J. G. White, and B. D. Bavister, Nat. Biotechnol. 17, 763 (1999).
[CrossRef] [PubMed]

Berland, K. M.

P. T. C. So, C. Y. Dong, B. R. Masters, and K. M. Berland, Annu. Rev. Biomed. Eng. 2, 399 (2000).
[CrossRef]

Blankschtein, D.

B. Yu, C. Y. Dong, P. T. C. So, D. Blankschtein, and R. Langer, J. Invest. Dermatol. 117, 16 (2001).
[CrossRef] [PubMed]

Brown, E. B.

E. B. Brown, R. B. Campbell, Y. Tsuzuki, L. Xu, P. Carmeliet, D. Fukumura, and R. K. Jain, Nat. Med. 7, 864 (2001).
[CrossRef] [PubMed]

Campbell, R. B.

E. B. Brown, R. B. Campbell, Y. Tsuzuki, L. Xu, P. Carmeliet, D. Fukumura, and R. K. Jain, Nat. Med. 7, 864 (2001).
[CrossRef] [PubMed]

Carmeliet, P.

E. B. Brown, R. B. Campbell, Y. Tsuzuki, L. Xu, P. Carmeliet, D. Fukumura, and R. K. Jain, Nat. Med. 7, 864 (2001).
[CrossRef] [PubMed]

Denk, W.

F. Helmchen, M. S. Fee, D. W. Tank, and W. Denk, Neuron 31, 903 (2001).
[CrossRef] [PubMed]

W. Denk, M. Sugimori, and R. Llinas, Proc. Natl. Acad. Sci. USA. 92, 8279 (1995).
[CrossRef]

W. Denk, J. H. Strickler, and W. W. Webb, Science 248, 73 (1990).
[CrossRef] [PubMed]

Dong, C. Y.

Y. Sun, W. Lo, S. J. Lin, S. H. Jee, and C. Y. Dong, Opt. Lett. 29, 2013 (2004).
[CrossRef] [PubMed]

Y. Sun, J. W. Su, W. Lo, S. J. Lin, S. H. Jee, and C. Y. Dong, Opt. Express 11, 3377 (2003), http://www.opticsexpress.org .
[CrossRef] [PubMed]

B. Yu, C. Y. Dong, P. T. C. So, D. Blankschtein, and R. Langer, J. Invest. Dermatol. 117, 16 (2001).
[CrossRef] [PubMed]

P. T. C. So, C. Y. Dong, B. R. Masters, and K. M. Berland, Annu. Rev. Biomed. Eng. 2, 399 (2000).
[CrossRef]

Fee, M. S.

F. Helmchen, M. S. Fee, D. W. Tank, and W. Denk, Neuron 31, 903 (2001).
[CrossRef] [PubMed]

Friedman, S. L.

S. L. Friedman, J. Biol. Chem. 275, 2247 (2000).
[CrossRef] [PubMed]

S. L. Friedman, N. Engl. J. Med. 328, 1828 (1993).
[CrossRef] [PubMed]

Fukumura, D.

E. B. Brown, R. B. Campbell, Y. Tsuzuki, L. Xu, P. Carmeliet, D. Fukumura, and R. K. Jain, Nat. Med. 7, 864 (2001).
[CrossRef] [PubMed]

Helmchen, F.

F. Helmchen, M. S. Fee, D. W. Tank, and W. Denk, Neuron 31, 903 (2001).
[CrossRef] [PubMed]

Jain, R. K.

E. B. Brown, R. B. Campbell, Y. Tsuzuki, L. Xu, P. Carmeliet, D. Fukumura, and R. K. Jain, Nat. Med. 7, 864 (2001).
[CrossRef] [PubMed]

Jee, S. H.

Kaye, G. I.

M. H. Ross, G. I. Kaye, and W. Pawlina, Histology, 4th ed. (Lippincott Williams & Wilkins, Baltimore, 2003).

Langer, R.

B. Yu, C. Y. Dong, P. T. C. So, D. Blankschtein, and R. Langer, J. Invest. Dermatol. 117, 16 (2001).
[CrossRef] [PubMed]

Lin, S. J.

Llinas, R.

W. Denk, M. Sugimori, and R. Llinas, Proc. Natl. Acad. Sci. USA. 92, 8279 (1995).
[CrossRef]

Lo, W.

Masters, B. R.

P. T. C. So, C. Y. Dong, B. R. Masters, and K. M. Berland, Annu. Rev. Biomed. Eng. 2, 399 (2000).
[CrossRef]

Menger, M. D.

B. Vollmar, S. Pradarutti, S. Richter, and M. D. Menger, Liver 22, 330 (2002).
[CrossRef] [PubMed]

Pawlina, W.

M. H. Ross, G. I. Kaye, and W. Pawlina, Histology, 4th ed. (Lippincott Williams & Wilkins, Baltimore, 2003).

Pradarutti, S.

B. Vollmar, S. Pradarutti, S. Richter, and M. D. Menger, Liver 22, 330 (2002).
[CrossRef] [PubMed]

Richter, S.

B. Vollmar, S. Pradarutti, S. Richter, and M. D. Menger, Liver 22, 330 (2002).
[CrossRef] [PubMed]

Ross, M. H.

M. H. Ross, G. I. Kaye, and W. Pawlina, Histology, 4th ed. (Lippincott Williams & Wilkins, Baltimore, 2003).

So, P. T. C.

B. Yu, C. Y. Dong, P. T. C. So, D. Blankschtein, and R. Langer, J. Invest. Dermatol. 117, 16 (2001).
[CrossRef] [PubMed]

P. T. C. So, C. Y. Dong, B. R. Masters, and K. M. Berland, Annu. Rev. Biomed. Eng. 2, 399 (2000).
[CrossRef]

Squirrell, J. M.

J. M. Squirrell, D. L. Wokosin, J. G. White, and B. D. Bavister, Nat. Biotechnol. 17, 763 (1999).
[CrossRef] [PubMed]

Strickler, J. H.

W. Denk, J. H. Strickler, and W. W. Webb, Science 248, 73 (1990).
[CrossRef] [PubMed]

Su, J. W.

Sugimori, M.

W. Denk, M. Sugimori, and R. Llinas, Proc. Natl. Acad. Sci. USA. 92, 8279 (1995).
[CrossRef]

Sun, Y.

Tank, D. W.

F. Helmchen, M. S. Fee, D. W. Tank, and W. Denk, Neuron 31, 903 (2001).
[CrossRef] [PubMed]

Tsuzuki, Y.

E. B. Brown, R. B. Campbell, Y. Tsuzuki, L. Xu, P. Carmeliet, D. Fukumura, and R. K. Jain, Nat. Med. 7, 864 (2001).
[CrossRef] [PubMed]

Vollmar, B.

B. Vollmar, S. Pradarutti, S. Richter, and M. D. Menger, Liver 22, 330 (2002).
[CrossRef] [PubMed]

Webb, W. W.

W. Denk, J. H. Strickler, and W. W. Webb, Science 248, 73 (1990).
[CrossRef] [PubMed]

White, J. G.

J. M. Squirrell, D. L. Wokosin, J. G. White, and B. D. Bavister, Nat. Biotechnol. 17, 763 (1999).
[CrossRef] [PubMed]

Wokosin, D. L.

J. M. Squirrell, D. L. Wokosin, J. G. White, and B. D. Bavister, Nat. Biotechnol. 17, 763 (1999).
[CrossRef] [PubMed]

Xu, L.

E. B. Brown, R. B. Campbell, Y. Tsuzuki, L. Xu, P. Carmeliet, D. Fukumura, and R. K. Jain, Nat. Med. 7, 864 (2001).
[CrossRef] [PubMed]

Yu, B.

B. Yu, C. Y. Dong, P. T. C. So, D. Blankschtein, and R. Langer, J. Invest. Dermatol. 117, 16 (2001).
[CrossRef] [PubMed]

Annu. Rev. Biomed. Eng. (1)

P. T. C. So, C. Y. Dong, B. R. Masters, and K. M. Berland, Annu. Rev. Biomed. Eng. 2, 399 (2000).
[CrossRef]

J. Biol. Chem. (1)

S. L. Friedman, J. Biol. Chem. 275, 2247 (2000).
[CrossRef] [PubMed]

J. Invest. Dermatol. (1)

B. Yu, C. Y. Dong, P. T. C. So, D. Blankschtein, and R. Langer, J. Invest. Dermatol. 117, 16 (2001).
[CrossRef] [PubMed]

Liver (1)

B. Vollmar, S. Pradarutti, S. Richter, and M. D. Menger, Liver 22, 330 (2002).
[CrossRef] [PubMed]

N. Engl. J. Med. (1)

S. L. Friedman, N. Engl. J. Med. 328, 1828 (1993).
[CrossRef] [PubMed]

Nat. Biotechnol. (1)

J. M. Squirrell, D. L. Wokosin, J. G. White, and B. D. Bavister, Nat. Biotechnol. 17, 763 (1999).
[CrossRef] [PubMed]

Nat. Med. (1)

E. B. Brown, R. B. Campbell, Y. Tsuzuki, L. Xu, P. Carmeliet, D. Fukumura, and R. K. Jain, Nat. Med. 7, 864 (2001).
[CrossRef] [PubMed]

Neuron (1)

F. Helmchen, M. S. Fee, D. W. Tank, and W. Denk, Neuron 31, 903 (2001).
[CrossRef] [PubMed]

Opt. Express (1)

Opt. Lett. (1)

Proc. Natl. Acad. Sci. USA. (1)

W. Denk, M. Sugimori, and R. Llinas, Proc. Natl. Acad. Sci. USA. 92, 8279 (1995).
[CrossRef]

Science (1)

W. Denk, J. H. Strickler, and W. W. Webb, Science 248, 73 (1990).
[CrossRef] [PubMed]

Other (1)

M. H. Ross, G. I. Kaye, and W. Pawlina, Histology, 4th ed. (Lippincott Williams & Wilkins, Baltimore, 2003).

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Figures (2)

Fig. 1
Fig. 1

Distribution of hepatocytes (elliptically enclosed regions) and stellate cells in normal mouse liver (yellow arrow, a stellate cell). Left, magnified multiphoton image. Center, large-area multiphoton scan 1.27 mm×1.21 mm. Right, histological images (hepatocyte nuclei, purple; stellate cells, red). The scale bar is 100 µm.

Fig. 2
Fig. 2

From top to bottom: mouse liver treated with 1, 2, and 3 weeks of CCl4. Left, magnified multiphoton image. Shown are the distribution of hepatocytes (elliptically enclosed regions) and stellate cells (yellow arrows). Center, large-area multiphoton scan 1.27 mm×1.21 mm. Necrotic sites are indicated by white arrows. Right, histological images (hepatocyte nuclei, purple; stellate cells, red). The scale bar is 100 µm.

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