Abstract

Conventional histopathology involves sampling, sectioning and staining of tissue specimens prior to microscopic evaluation, and provides diagnostic information at a single location and point in time. In vivo microscopy and molecular-targeted optical labeling are two rapidly developing fields, which together have the potential to provide anatomical and functional indications of disease by staining and imaging tissue in situ. To address the need for high-resolution imaging instrumentation, we have developed a compact, robust, and inexpensive fiber-optic microendoscopy system based around wide-field LED illumination, a flexible 1 mm diameter fiber-optic bundle, and a color CCD camera. We demonstrate the subcellular resolution imaging capabilities of the system through a series of experiments, beginning with simultaneous imaging of three different cancer cell lines in culture, each targeted with a distinct fluorescent label. We used the narrow diameter probe to access subcutaneous tumors in an in vivo murine model, allowing direct comparison of microendoscopy images with macroscopic images and histopathology. A surgically resected tissue specimen from the human oral cavity was imaged across the clinical margin, demonstrating qualitative and quantitative distinction between normal and cancerous tissue based on sub-cellular image features. Finally, the fiber-optic microendoscope was used on topically-stained normal human oral mucosa in vivo, resolving epithelial cell nuclei and membranes in real-time fluorescence images. Our results demonstrate that this imaging system can potentially complement conventional diagnostic techniques, and support efforts to translate emerging molecular-diagnostic and therapeutic agents into clinical use.

© 2007 Optical Society of America

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  4. A. Becker, C. Hessenius, K. Licha, B. Ebert, U. Sukowski, W. Semmler, B. Wiedenmann, and C. Grötzinger, "Receptor-targeted optical imaging of tumors with near-infrared fluorescent ligands," Nat. Biotechnol. 19, 327-331 (2001).
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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
  30. K.-B. Sung, R. Richards-Kortum, M. Follen, A. Malpica, C. Liang, and M. Descour, "Fiber optic confocal reflectance microscopy: a new real-time technique to view nuclear morphology in cervical squamous epithelium in vivo," Opt. Express 11, 3171-3181 (2003).
    [CrossRef] [PubMed]
  31. A. R. Rouse, A. Kano, J. A. Udovich, S. M. Kroto, and A. F. Gmitro, "Design and Demonstration of a Miniature Catheter for a Confocal Microendoscope," Appl. Opt. 43, 5763-5771 (2004).
    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
  33. G. R. Poe, D. M. Rector, and R. M. Harper, "Hippocampal reflected optical patterns during sleep and waking states in the freely behaving cat," J. Neurosci. 14, 2933-2942 (1994).
    [PubMed]

2007 (6)

T. F. Massoud and S. S. Gambhir, "Integrating noninvasive molecular imaging into molecular medicine: an evolving paradigm," Trends Mol. Med. 13, 183-191 (2007).
[CrossRef] [PubMed]

J. T. C. Liu, M. J. Mandella, H. Ra, L. K. Wong, O. Solgaard, G. S. Kino, W. Piyawattanametha, C. H. Contag, and T. D. Wang, "Miniature near-infrared dual-axes confocal microscope utilizing a two-dimensional microelectromechanical systems scanner," Opt. Lett. 32, 256-258 (2007).
[CrossRef] [PubMed]

H.-J. Shin, M. C. Pierce, D. Lee, H. Ra, O. Solgaard, and R. Richards-Kortum, "Fiber-optic confocal microscope using a MEMS scanner and miniature objective lens" Opt. Express 15, 9113-9122 (2007).
[CrossRef] [PubMed]

R. Kiesslich, M. Goetz, M. Vieth, P. R. Galle, and M. F. Neurath, "Technology insight: confocal laser endoscopy for in vivo diagnosis of colorectal cancer," Nat. Clin. Pract. Oncol. 4, 480-490 (2007).
[CrossRef] [PubMed]

F. Jean, G. Bourg-Heckly, and B. Viellerobe, "Fibered confocal spectroscopy and multicolor imaging system for in vivo fluorescence analysis," Opt. Express 15, 4008-4017 (2007).
[CrossRef] [PubMed]

T. Collier, M. Guillaud, M. Follen, A. Malpica, and R. Richards-Kortum, "Real-time reflectance confocal microscopy: comparison of two-dimensional images and three-dimensional image stacks for detection of cervical precancer," J. Biomed. Opt. 12, 024021 (2007).
[CrossRef] [PubMed]

2006 (1)

D. Yelin, I. Rizvi, W. M. White, J. T. Motz, T. Hasan, B. E. Bouma, and G. J. Tearney, "Three-dimensional miniature endoscopy" Nature 443, 765 (2006).
[CrossRef] [PubMed]

2005 (3)

A. L. Polglase, W. J. McLaren, S. A. Skinner, R. Kiesslich, M. F. Neurath, and P. M. Delaney, "Fluorescence confocal endomicroscope for in vivo microscopy of the upper and lower gastrointestinal tract," Gastrointest. Endosc. 62, 686-695 (2005).
[CrossRef] [PubMed]

F. A. Jaffer and R. Weissleder, "Molecular imaging in the clinical arena," JAMA 293, 855-862 (2005).
[CrossRef] [PubMed]

B. A. Flusberg, E. D. Cocker, W. Piyawattanametha, J. C. Jung, E. L. Cheung, and M. J. Schnitzer, "Fiber-optic fluorescence imaging," Nat. Methods 2, 941-950 (2005).
[CrossRef] [PubMed]

2004 (3)

X. Gao, Y. Cui, R. M. Levenson, L. W. K. Chung, and S. Nie, "In vivo cancer targeting and imaging with semiconductor quantum dots," Nat. Biotechnol. 22, 969-976 (2004).
[CrossRef] [PubMed]

A. R. Rouse, A. Kano, J. A. Udovich, S. M. Kroto, and A. F. Gmitro, "Design and Demonstration of a Miniature Catheter for a Confocal Microendoscope," Appl. Opt. 43, 5763-5771 (2004).
[CrossRef] [PubMed]

E. Laemmel, M. Genet, G. Le Goualher, A. Perchant, J.-F. Le Gargasson, and E. Vicaut, "Fibered confocal fluorescence microscopy (Cell-viZio) facilitates extended imaging in the field of microcirculation. A comparison with intravital microscopy," J. Vasc. Res. 41, 400-411 (2004).
[CrossRef] [PubMed]

2003 (2)

K.-B. Sung, R. Richards-Kortum, M. Follen, A. Malpica, C. Liang, and M. Descour, "Fiber optic confocal reflectance microscopy: a new real-time technique to view nuclear morphology in cervical squamous epithelium in vivo," Opt. Express 11, 3171-3181 (2003).
[CrossRef] [PubMed]

S. Ke, W. Xiaoxia, M. Gurfinkel, C. Charnsangavej, S. Wallace, E. M. Sevick-Muraca, and C. Li, "Near-infrared optical imaging of epidermal growth factor receptor in breast cancer xenografts," Cancer Res. 63, 7870-7875 (2003).
[PubMed]

2002 (2)

E. J. Seibel and Q. Y. J. Smithwick, "Unique features of optical scanning, single fiber Endoscopy," Lasers Surg. Med. 30, 177-183 (2002).
[CrossRef] [PubMed]

V. Dubaj, A. Mazzolini, A. Wood, and M. Harris, "Optic fibre bundle contact imaging probe employing a laser scanning confocal microscope," J. Microsc. 207, 108-117 (2002).
[CrossRef] [PubMed]

2001 (2)

C. Liang, M. Descour, K.-B. Sung, and R. Richards-Kortum, "Fiber confocal reflectance microscope (FCRM) for in-vivo imaging," Opt. Express 9, 821-830 (2001).
[CrossRef] [PubMed]

A. Becker, C. Hessenius, K. Licha, B. Ebert, U. Sukowski, W. Semmler, B. Wiedenmann, and C. Grötzinger, "Receptor-targeted optical imaging of tumors with near-infrared fluorescent ligands," Nat. Biotechnol. 19, 327-331 (2001).
[CrossRef] [PubMed]

2000 (1)

1999 (2)

Y. S. Sabharwal, A. R. Rouse, L. Donaldson, M. F. Hopkins, and A. F. Gmitro, "Slit-scanning confocal microendoscope for high-resolution in Vivo Imaging," Appl. Opt. 38, 7133-7144 (1999).
[CrossRef]

R. Weissleder, C. H. Tung, U. Mahmood, and A. Bogdanov, Jr, "In vivo imaging of tumors with protease-activated near-infrared fluorescent probes," Nat. Biotechnol 17, 375-378 (1999).
[CrossRef] [PubMed]

1997 (1)

R. Juškaitis, T. Wilson, and T. F. Watson, "Real-time white light reflection confocal microscopy using a fibre-optic bundle," Scanning 19, 15-19 (1997).

1996 (2)

D. L. Dickensheets and G. S. Kino, "Micromachined scanning confocal optical microscope," Opt. Lett. 21, 764-766 (1996).
[CrossRef] [PubMed]

M. Hirano, Y. Yamashita, and A. Miyakawa, "In vivo visualization of hippocampal cells and dynamics of Ca2+ concentration during anoxia: feasibility of a fiber-optic plate microscope system for in vivo experiments," Brain. Res. 732, 61-68 (1996).
[CrossRef] [PubMed]

1994 (2)

G. R. Poe, D. M. Rector, and R. M. Harper, "Hippocampal reflected optical patterns during sleep and waking states in the freely behaving cat," J. Neurosci. 14, 2933-2942 (1994).
[PubMed]

P. M. Delaney, M. R. Harris, and R. G. King, "Fibre-optic laser scanning confocal microscope suitable for fluorescence imaging," Appl. Opt. 33, 573-577 (1994).
[CrossRef] [PubMed]

1993 (1)

1991 (2)

S. Kimura and T. Wilson, "Confocal scanning optical microscope using single-mode fiber for signal detection," Appl. Opt. 30, 2143-2150 (1991).
[CrossRef] [PubMed]

L. Giniunas, R. Juškaitis, and S. V. Shatalin, "Scanning fiber-optic microscope" Electron Lett. 27, 724-726 (1991).
[CrossRef]

1968 (1)

R. R. Steinman, "Pharmacologic control of dentinal fluid movement and dental caries in rats," J. Dent. Res. 47, 720-724 (1968).
[CrossRef] [PubMed]

Aziz, D. J.

Becker, A.

A. Becker, C. Hessenius, K. Licha, B. Ebert, U. Sukowski, W. Semmler, B. Wiedenmann, and C. Grötzinger, "Receptor-targeted optical imaging of tumors with near-infrared fluorescent ligands," Nat. Biotechnol. 19, 327-331 (2001).
[CrossRef] [PubMed]

Bogdanov, A.

R. Weissleder, C. H. Tung, U. Mahmood, and A. Bogdanov, Jr, "In vivo imaging of tumors with protease-activated near-infrared fluorescent probes," Nat. Biotechnol 17, 375-378 (1999).
[CrossRef] [PubMed]

Bouma, B. E.

D. Yelin, I. Rizvi, W. M. White, J. T. Motz, T. Hasan, B. E. Bouma, and G. J. Tearney, "Three-dimensional miniature endoscopy" Nature 443, 765 (2006).
[CrossRef] [PubMed]

Bourg-Heckly, G.

Charnsangavej, C.

S. Ke, W. Xiaoxia, M. Gurfinkel, C. Charnsangavej, S. Wallace, E. M. Sevick-Muraca, and C. Li, "Near-infrared optical imaging of epidermal growth factor receptor in breast cancer xenografts," Cancer Res. 63, 7870-7875 (2003).
[PubMed]

Cheung, E. L.

B. A. Flusberg, E. D. Cocker, W. Piyawattanametha, J. C. Jung, E. L. Cheung, and M. J. Schnitzer, "Fiber-optic fluorescence imaging," Nat. Methods 2, 941-950 (2005).
[CrossRef] [PubMed]

Chung, L. W. K.

X. Gao, Y. Cui, R. M. Levenson, L. W. K. Chung, and S. Nie, "In vivo cancer targeting and imaging with semiconductor quantum dots," Nat. Biotechnol. 22, 969-976 (2004).
[CrossRef] [PubMed]

Cocker, E. D.

B. A. Flusberg, E. D. Cocker, W. Piyawattanametha, J. C. Jung, E. L. Cheung, and M. J. Schnitzer, "Fiber-optic fluorescence imaging," Nat. Methods 2, 941-950 (2005).
[CrossRef] [PubMed]

Collier, T.

T. Collier, M. Guillaud, M. Follen, A. Malpica, and R. Richards-Kortum, "Real-time reflectance confocal microscopy: comparison of two-dimensional images and three-dimensional image stacks for detection of cervical precancer," J. Biomed. Opt. 12, 024021 (2007).
[CrossRef] [PubMed]

Contag, C. H.

Cui, Y.

X. Gao, Y. Cui, R. M. Levenson, L. W. K. Chung, and S. Nie, "In vivo cancer targeting and imaging with semiconductor quantum dots," Nat. Biotechnol. 22, 969-976 (2004).
[CrossRef] [PubMed]

Delaney, P. M.

A. L. Polglase, W. J. McLaren, S. A. Skinner, R. Kiesslich, M. F. Neurath, and P. M. Delaney, "Fluorescence confocal endomicroscope for in vivo microscopy of the upper and lower gastrointestinal tract," Gastrointest. Endosc. 62, 686-695 (2005).
[CrossRef] [PubMed]

P. M. Delaney, M. R. Harris, and R. G. King, "Fibre-optic laser scanning confocal microscope suitable for fluorescence imaging," Appl. Opt. 33, 573-577 (1994).
[CrossRef] [PubMed]

Descour, M.

K.-B. Sung, R. Richards-Kortum, M. Follen, A. Malpica, C. Liang, and M. Descour, "Fiber optic confocal reflectance microscopy: a new real-time technique to view nuclear morphology in cervical squamous epithelium in vivo," Opt. Express 11, 3171-3181 (2003).
[CrossRef] [PubMed]

C. Liang, M. Descour, K.-B. Sung, and R. Richards-Kortum, "Fiber confocal reflectance microscope (FCRM) for in-vivo imaging," Opt. Express 9, 821-830 (2001).
[CrossRef] [PubMed]

Dickensheets, D. L.

Donaldson, L.

Dubaj, V.

V. Dubaj, A. Mazzolini, A. Wood, and M. Harris, "Optic fibre bundle contact imaging probe employing a laser scanning confocal microscope," J. Microsc. 207, 108-117 (2002).
[CrossRef] [PubMed]

Ebert, B.

A. Becker, C. Hessenius, K. Licha, B. Ebert, U. Sukowski, W. Semmler, B. Wiedenmann, and C. Grötzinger, "Receptor-targeted optical imaging of tumors with near-infrared fluorescent ligands," Nat. Biotechnol. 19, 327-331 (2001).
[CrossRef] [PubMed]

Flusberg, B. A.

B. A. Flusberg, E. D. Cocker, W. Piyawattanametha, J. C. Jung, E. L. Cheung, and M. J. Schnitzer, "Fiber-optic fluorescence imaging," Nat. Methods 2, 941-950 (2005).
[CrossRef] [PubMed]

Follen, M.

T. Collier, M. Guillaud, M. Follen, A. Malpica, and R. Richards-Kortum, "Real-time reflectance confocal microscopy: comparison of two-dimensional images and three-dimensional image stacks for detection of cervical precancer," J. Biomed. Opt. 12, 024021 (2007).
[CrossRef] [PubMed]

K.-B. Sung, R. Richards-Kortum, M. Follen, A. Malpica, C. Liang, and M. Descour, "Fiber optic confocal reflectance microscopy: a new real-time technique to view nuclear morphology in cervical squamous epithelium in vivo," Opt. Express 11, 3171-3181 (2003).
[CrossRef] [PubMed]

Galle, P. R.

R. Kiesslich, M. Goetz, M. Vieth, P. R. Galle, and M. F. Neurath, "Technology insight: confocal laser endoscopy for in vivo diagnosis of colorectal cancer," Nat. Clin. Pract. Oncol. 4, 480-490 (2007).
[CrossRef] [PubMed]

Gambhir, S. S.

T. F. Massoud and S. S. Gambhir, "Integrating noninvasive molecular imaging into molecular medicine: an evolving paradigm," Trends Mol. Med. 13, 183-191 (2007).
[CrossRef] [PubMed]

Gao, X.

X. Gao, Y. Cui, R. M. Levenson, L. W. K. Chung, and S. Nie, "In vivo cancer targeting and imaging with semiconductor quantum dots," Nat. Biotechnol. 22, 969-976 (2004).
[CrossRef] [PubMed]

Genet, M.

E. Laemmel, M. Genet, G. Le Goualher, A. Perchant, J.-F. Le Gargasson, and E. Vicaut, "Fibered confocal fluorescence microscopy (Cell-viZio) facilitates extended imaging in the field of microcirculation. A comparison with intravital microscopy," J. Vasc. Res. 41, 400-411 (2004).
[CrossRef] [PubMed]

Giniunas, L.

L. Giniunas, R. Juškaitis, and S. V. Shatalin, "Scanning fiber-optic microscope" Electron Lett. 27, 724-726 (1991).
[CrossRef]

Gmitro, A. F.

Goetz, M.

R. Kiesslich, M. Goetz, M. Vieth, P. R. Galle, and M. F. Neurath, "Technology insight: confocal laser endoscopy for in vivo diagnosis of colorectal cancer," Nat. Clin. Pract. Oncol. 4, 480-490 (2007).
[CrossRef] [PubMed]

Grötzinger, C.

A. Becker, C. Hessenius, K. Licha, B. Ebert, U. Sukowski, W. Semmler, B. Wiedenmann, and C. Grötzinger, "Receptor-targeted optical imaging of tumors with near-infrared fluorescent ligands," Nat. Biotechnol. 19, 327-331 (2001).
[CrossRef] [PubMed]

Guillaud, M.

T. Collier, M. Guillaud, M. Follen, A. Malpica, and R. Richards-Kortum, "Real-time reflectance confocal microscopy: comparison of two-dimensional images and three-dimensional image stacks for detection of cervical precancer," J. Biomed. Opt. 12, 024021 (2007).
[CrossRef] [PubMed]

Gurfinkel, M.

S. Ke, W. Xiaoxia, M. Gurfinkel, C. Charnsangavej, S. Wallace, E. M. Sevick-Muraca, and C. Li, "Near-infrared optical imaging of epidermal growth factor receptor in breast cancer xenografts," Cancer Res. 63, 7870-7875 (2003).
[PubMed]

Harper, R. M.

G. R. Poe, D. M. Rector, and R. M. Harper, "Hippocampal reflected optical patterns during sleep and waking states in the freely behaving cat," J. Neurosci. 14, 2933-2942 (1994).
[PubMed]

Harris, M.

V. Dubaj, A. Mazzolini, A. Wood, and M. Harris, "Optic fibre bundle contact imaging probe employing a laser scanning confocal microscope," J. Microsc. 207, 108-117 (2002).
[CrossRef] [PubMed]

Harris, M. R.

Hasan, T.

D. Yelin, I. Rizvi, W. M. White, J. T. Motz, T. Hasan, B. E. Bouma, and G. J. Tearney, "Three-dimensional miniature endoscopy" Nature 443, 765 (2006).
[CrossRef] [PubMed]

Hessenius, C.

A. Becker, C. Hessenius, K. Licha, B. Ebert, U. Sukowski, W. Semmler, B. Wiedenmann, and C. Grötzinger, "Receptor-targeted optical imaging of tumors with near-infrared fluorescent ligands," Nat. Biotechnol. 19, 327-331 (2001).
[CrossRef] [PubMed]

Hirano, M.

M. Hirano, Y. Yamashita, and A. Miyakawa, "In vivo visualization of hippocampal cells and dynamics of Ca2+ concentration during anoxia: feasibility of a fiber-optic plate microscope system for in vivo experiments," Brain. Res. 732, 61-68 (1996).
[CrossRef] [PubMed]

Hopkins, M. F.

Jaffer, F. A.

F. A. Jaffer and R. Weissleder, "Molecular imaging in the clinical arena," JAMA 293, 855-862 (2005).
[CrossRef] [PubMed]

Jean, F.

Jung, J. C.

B. A. Flusberg, E. D. Cocker, W. Piyawattanametha, J. C. Jung, E. L. Cheung, and M. J. Schnitzer, "Fiber-optic fluorescence imaging," Nat. Methods 2, 941-950 (2005).
[CrossRef] [PubMed]

Juškaitis, R.

R. Juškaitis, T. Wilson, and T. F. Watson, "Real-time white light reflection confocal microscopy using a fibre-optic bundle," Scanning 19, 15-19 (1997).

L. Giniunas, R. Juškaitis, and S. V. Shatalin, "Scanning fiber-optic microscope" Electron Lett. 27, 724-726 (1991).
[CrossRef]

Kano, A.

Ke, S.

S. Ke, W. Xiaoxia, M. Gurfinkel, C. Charnsangavej, S. Wallace, E. M. Sevick-Muraca, and C. Li, "Near-infrared optical imaging of epidermal growth factor receptor in breast cancer xenografts," Cancer Res. 63, 7870-7875 (2003).
[PubMed]

Kiesslich, R.

R. Kiesslich, M. Goetz, M. Vieth, P. R. Galle, and M. F. Neurath, "Technology insight: confocal laser endoscopy for in vivo diagnosis of colorectal cancer," Nat. Clin. Pract. Oncol. 4, 480-490 (2007).
[CrossRef] [PubMed]

A. L. Polglase, W. J. McLaren, S. A. Skinner, R. Kiesslich, M. F. Neurath, and P. M. Delaney, "Fluorescence confocal endomicroscope for in vivo microscopy of the upper and lower gastrointestinal tract," Gastrointest. Endosc. 62, 686-695 (2005).
[CrossRef] [PubMed]

Kimura, S.

King, R. G.

Kino, G. S.

Kroto, S. M.

Laemmel, E.

E. Laemmel, M. Genet, G. Le Goualher, A. Perchant, J.-F. Le Gargasson, and E. Vicaut, "Fibered confocal fluorescence microscopy (Cell-viZio) facilitates extended imaging in the field of microcirculation. A comparison with intravital microscopy," J. Vasc. Res. 41, 400-411 (2004).
[CrossRef] [PubMed]

Le Gargasson, J.-F.

E. Laemmel, M. Genet, G. Le Goualher, A. Perchant, J.-F. Le Gargasson, and E. Vicaut, "Fibered confocal fluorescence microscopy (Cell-viZio) facilitates extended imaging in the field of microcirculation. A comparison with intravital microscopy," J. Vasc. Res. 41, 400-411 (2004).
[CrossRef] [PubMed]

Le Goualher, G.

E. Laemmel, M. Genet, G. Le Goualher, A. Perchant, J.-F. Le Gargasson, and E. Vicaut, "Fibered confocal fluorescence microscopy (Cell-viZio) facilitates extended imaging in the field of microcirculation. A comparison with intravital microscopy," J. Vasc. Res. 41, 400-411 (2004).
[CrossRef] [PubMed]

Lee, D.

Levenson, R. M.

X. Gao, Y. Cui, R. M. Levenson, L. W. K. Chung, and S. Nie, "In vivo cancer targeting and imaging with semiconductor quantum dots," Nat. Biotechnol. 22, 969-976 (2004).
[CrossRef] [PubMed]

Li, C.

S. Ke, W. Xiaoxia, M. Gurfinkel, C. Charnsangavej, S. Wallace, E. M. Sevick-Muraca, and C. Li, "Near-infrared optical imaging of epidermal growth factor receptor in breast cancer xenografts," Cancer Res. 63, 7870-7875 (2003).
[PubMed]

Liang, C.

K.-B. Sung, R. Richards-Kortum, M. Follen, A. Malpica, C. Liang, and M. Descour, "Fiber optic confocal reflectance microscopy: a new real-time technique to view nuclear morphology in cervical squamous epithelium in vivo," Opt. Express 11, 3171-3181 (2003).
[CrossRef] [PubMed]

C. Liang, M. Descour, K.-B. Sung, and R. Richards-Kortum, "Fiber confocal reflectance microscope (FCRM) for in-vivo imaging," Opt. Express 9, 821-830 (2001).
[CrossRef] [PubMed]

Licha, K.

A. Becker, C. Hessenius, K. Licha, B. Ebert, U. Sukowski, W. Semmler, B. Wiedenmann, and C. Grötzinger, "Receptor-targeted optical imaging of tumors with near-infrared fluorescent ligands," Nat. Biotechnol. 19, 327-331 (2001).
[CrossRef] [PubMed]

Liu, J. T. C.

Mahmood, U.

R. Weissleder, C. H. Tung, U. Mahmood, and A. Bogdanov, Jr, "In vivo imaging of tumors with protease-activated near-infrared fluorescent probes," Nat. Biotechnol 17, 375-378 (1999).
[CrossRef] [PubMed]

Malpica, A.

T. Collier, M. Guillaud, M. Follen, A. Malpica, and R. Richards-Kortum, "Real-time reflectance confocal microscopy: comparison of two-dimensional images and three-dimensional image stacks for detection of cervical precancer," J. Biomed. Opt. 12, 024021 (2007).
[CrossRef] [PubMed]

K.-B. Sung, R. Richards-Kortum, M. Follen, A. Malpica, C. Liang, and M. Descour, "Fiber optic confocal reflectance microscopy: a new real-time technique to view nuclear morphology in cervical squamous epithelium in vivo," Opt. Express 11, 3171-3181 (2003).
[CrossRef] [PubMed]

Mandella, M. J.

Massoud, T. F.

T. F. Massoud and S. S. Gambhir, "Integrating noninvasive molecular imaging into molecular medicine: an evolving paradigm," Trends Mol. Med. 13, 183-191 (2007).
[CrossRef] [PubMed]

Mazzolini, A.

V. Dubaj, A. Mazzolini, A. Wood, and M. Harris, "Optic fibre bundle contact imaging probe employing a laser scanning confocal microscope," J. Microsc. 207, 108-117 (2002).
[CrossRef] [PubMed]

McLaren, W. J.

A. L. Polglase, W. J. McLaren, S. A. Skinner, R. Kiesslich, M. F. Neurath, and P. M. Delaney, "Fluorescence confocal endomicroscope for in vivo microscopy of the upper and lower gastrointestinal tract," Gastrointest. Endosc. 62, 686-695 (2005).
[CrossRef] [PubMed]

Miyakawa, A.

M. Hirano, Y. Yamashita, and A. Miyakawa, "In vivo visualization of hippocampal cells and dynamics of Ca2+ concentration during anoxia: feasibility of a fiber-optic plate microscope system for in vivo experiments," Brain. Res. 732, 61-68 (1996).
[CrossRef] [PubMed]

Motz, J. T.

D. Yelin, I. Rizvi, W. M. White, J. T. Motz, T. Hasan, B. E. Bouma, and G. J. Tearney, "Three-dimensional miniature endoscopy" Nature 443, 765 (2006).
[CrossRef] [PubMed]

Neurath, M. F.

R. Kiesslich, M. Goetz, M. Vieth, P. R. Galle, and M. F. Neurath, "Technology insight: confocal laser endoscopy for in vivo diagnosis of colorectal cancer," Nat. Clin. Pract. Oncol. 4, 480-490 (2007).
[CrossRef] [PubMed]

A. L. Polglase, W. J. McLaren, S. A. Skinner, R. Kiesslich, M. F. Neurath, and P. M. Delaney, "Fluorescence confocal endomicroscope for in vivo microscopy of the upper and lower gastrointestinal tract," Gastrointest. Endosc. 62, 686-695 (2005).
[CrossRef] [PubMed]

Nie, S.

X. Gao, Y. Cui, R. M. Levenson, L. W. K. Chung, and S. Nie, "In vivo cancer targeting and imaging with semiconductor quantum dots," Nat. Biotechnol. 22, 969-976 (2004).
[CrossRef] [PubMed]

Perchant, A.

E. Laemmel, M. Genet, G. Le Goualher, A. Perchant, J.-F. Le Gargasson, and E. Vicaut, "Fibered confocal fluorescence microscopy (Cell-viZio) facilitates extended imaging in the field of microcirculation. A comparison with intravital microscopy," J. Vasc. Res. 41, 400-411 (2004).
[CrossRef] [PubMed]

Pierce, M. C.

Piyawattanametha, W.

Poe, G. R.

G. R. Poe, D. M. Rector, and R. M. Harper, "Hippocampal reflected optical patterns during sleep and waking states in the freely behaving cat," J. Neurosci. 14, 2933-2942 (1994).
[PubMed]

Polglase, A. L.

A. L. Polglase, W. J. McLaren, S. A. Skinner, R. Kiesslich, M. F. Neurath, and P. M. Delaney, "Fluorescence confocal endomicroscope for in vivo microscopy of the upper and lower gastrointestinal tract," Gastrointest. Endosc. 62, 686-695 (2005).
[CrossRef] [PubMed]

Ra, H.

Rector, D. M.

G. R. Poe, D. M. Rector, and R. M. Harper, "Hippocampal reflected optical patterns during sleep and waking states in the freely behaving cat," J. Neurosci. 14, 2933-2942 (1994).
[PubMed]

Richards-Kortum, R.

T. Collier, M. Guillaud, M. Follen, A. Malpica, and R. Richards-Kortum, "Real-time reflectance confocal microscopy: comparison of two-dimensional images and three-dimensional image stacks for detection of cervical precancer," J. Biomed. Opt. 12, 024021 (2007).
[CrossRef] [PubMed]

H.-J. Shin, M. C. Pierce, D. Lee, H. Ra, O. Solgaard, and R. Richards-Kortum, "Fiber-optic confocal microscope using a MEMS scanner and miniature objective lens" Opt. Express 15, 9113-9122 (2007).
[CrossRef] [PubMed]

K.-B. Sung, R. Richards-Kortum, M. Follen, A. Malpica, C. Liang, and M. Descour, "Fiber optic confocal reflectance microscopy: a new real-time technique to view nuclear morphology in cervical squamous epithelium in vivo," Opt. Express 11, 3171-3181 (2003).
[CrossRef] [PubMed]

C. Liang, M. Descour, K.-B. Sung, and R. Richards-Kortum, "Fiber confocal reflectance microscope (FCRM) for in-vivo imaging," Opt. Express 9, 821-830 (2001).
[CrossRef] [PubMed]

Rizvi, I.

D. Yelin, I. Rizvi, W. M. White, J. T. Motz, T. Hasan, B. E. Bouma, and G. J. Tearney, "Three-dimensional miniature endoscopy" Nature 443, 765 (2006).
[CrossRef] [PubMed]

Rouse, A. R.

Sabharwal, Y. S.

Schnitzer, M. J.

B. A. Flusberg, E. D. Cocker, W. Piyawattanametha, J. C. Jung, E. L. Cheung, and M. J. Schnitzer, "Fiber-optic fluorescence imaging," Nat. Methods 2, 941-950 (2005).
[CrossRef] [PubMed]

Seibel, E. J.

E. J. Seibel and Q. Y. J. Smithwick, "Unique features of optical scanning, single fiber Endoscopy," Lasers Surg. Med. 30, 177-183 (2002).
[CrossRef] [PubMed]

Semmler, W.

A. Becker, C. Hessenius, K. Licha, B. Ebert, U. Sukowski, W. Semmler, B. Wiedenmann, and C. Grötzinger, "Receptor-targeted optical imaging of tumors with near-infrared fluorescent ligands," Nat. Biotechnol. 19, 327-331 (2001).
[CrossRef] [PubMed]

Sevick-Muraca, E. M.

S. Ke, W. Xiaoxia, M. Gurfinkel, C. Charnsangavej, S. Wallace, E. M. Sevick-Muraca, and C. Li, "Near-infrared optical imaging of epidermal growth factor receptor in breast cancer xenografts," Cancer Res. 63, 7870-7875 (2003).
[PubMed]

Shatalin, S. V.

L. Giniunas, R. Juškaitis, and S. V. Shatalin, "Scanning fiber-optic microscope" Electron Lett. 27, 724-726 (1991).
[CrossRef]

Shin, H.-J.

Skinner, S. A.

A. L. Polglase, W. J. McLaren, S. A. Skinner, R. Kiesslich, M. F. Neurath, and P. M. Delaney, "Fluorescence confocal endomicroscope for in vivo microscopy of the upper and lower gastrointestinal tract," Gastrointest. Endosc. 62, 686-695 (2005).
[CrossRef] [PubMed]

Smithwick, Q. Y. J.

E. J. Seibel and Q. Y. J. Smithwick, "Unique features of optical scanning, single fiber Endoscopy," Lasers Surg. Med. 30, 177-183 (2002).
[CrossRef] [PubMed]

Solgaard, O.

Steinman, R. R.

R. R. Steinman, "Pharmacologic control of dentinal fluid movement and dental caries in rats," J. Dent. Res. 47, 720-724 (1968).
[CrossRef] [PubMed]

Sukowski, U.

A. Becker, C. Hessenius, K. Licha, B. Ebert, U. Sukowski, W. Semmler, B. Wiedenmann, and C. Grötzinger, "Receptor-targeted optical imaging of tumors with near-infrared fluorescent ligands," Nat. Biotechnol. 19, 327-331 (2001).
[CrossRef] [PubMed]

Sung, K.-B.

K.-B. Sung, R. Richards-Kortum, M. Follen, A. Malpica, C. Liang, and M. Descour, "Fiber optic confocal reflectance microscopy: a new real-time technique to view nuclear morphology in cervical squamous epithelium in vivo," Opt. Express 11, 3171-3181 (2003).
[CrossRef] [PubMed]

C. Liang, M. Descour, K.-B. Sung, and R. Richards-Kortum, "Fiber confocal reflectance microscope (FCRM) for in-vivo imaging," Opt. Express 9, 821-830 (2001).
[CrossRef] [PubMed]

Tearney, G. J.

D. Yelin, I. Rizvi, W. M. White, J. T. Motz, T. Hasan, B. E. Bouma, and G. J. Tearney, "Three-dimensional miniature endoscopy" Nature 443, 765 (2006).
[CrossRef] [PubMed]

Tung, C. H.

R. Weissleder, C. H. Tung, U. Mahmood, and A. Bogdanov, Jr, "In vivo imaging of tumors with protease-activated near-infrared fluorescent probes," Nat. Biotechnol 17, 375-378 (1999).
[CrossRef] [PubMed]

Udovich, J. A.

Vicaut, E.

E. Laemmel, M. Genet, G. Le Goualher, A. Perchant, J.-F. Le Gargasson, and E. Vicaut, "Fibered confocal fluorescence microscopy (Cell-viZio) facilitates extended imaging in the field of microcirculation. A comparison with intravital microscopy," J. Vasc. Res. 41, 400-411 (2004).
[CrossRef] [PubMed]

Viellerobe, B.

Vieth, M.

R. Kiesslich, M. Goetz, M. Vieth, P. R. Galle, and M. F. Neurath, "Technology insight: confocal laser endoscopy for in vivo diagnosis of colorectal cancer," Nat. Clin. Pract. Oncol. 4, 480-490 (2007).
[CrossRef] [PubMed]

Wallace, S.

S. Ke, W. Xiaoxia, M. Gurfinkel, C. Charnsangavej, S. Wallace, E. M. Sevick-Muraca, and C. Li, "Near-infrared optical imaging of epidermal growth factor receptor in breast cancer xenografts," Cancer Res. 63, 7870-7875 (2003).
[PubMed]

Wang, T. D.

Watson, T. F.

R. Juškaitis, T. Wilson, and T. F. Watson, "Real-time white light reflection confocal microscopy using a fibre-optic bundle," Scanning 19, 15-19 (1997).

Weissleder, R.

F. A. Jaffer and R. Weissleder, "Molecular imaging in the clinical arena," JAMA 293, 855-862 (2005).
[CrossRef] [PubMed]

R. Weissleder, C. H. Tung, U. Mahmood, and A. Bogdanov, Jr, "In vivo imaging of tumors with protease-activated near-infrared fluorescent probes," Nat. Biotechnol 17, 375-378 (1999).
[CrossRef] [PubMed]

White, W. M.

D. Yelin, I. Rizvi, W. M. White, J. T. Motz, T. Hasan, B. E. Bouma, and G. J. Tearney, "Three-dimensional miniature endoscopy" Nature 443, 765 (2006).
[CrossRef] [PubMed]

Wiedenmann, B.

A. Becker, C. Hessenius, K. Licha, B. Ebert, U. Sukowski, W. Semmler, B. Wiedenmann, and C. Grötzinger, "Receptor-targeted optical imaging of tumors with near-infrared fluorescent ligands," Nat. Biotechnol. 19, 327-331 (2001).
[CrossRef] [PubMed]

Wilson, T.

R. Juškaitis, T. Wilson, and T. F. Watson, "Real-time white light reflection confocal microscopy using a fibre-optic bundle," Scanning 19, 15-19 (1997).

S. Kimura and T. Wilson, "Confocal scanning optical microscope using single-mode fiber for signal detection," Appl. Opt. 30, 2143-2150 (1991).
[CrossRef] [PubMed]

Wong, L. K.

Wood, A.

V. Dubaj, A. Mazzolini, A. Wood, and M. Harris, "Optic fibre bundle contact imaging probe employing a laser scanning confocal microscope," J. Microsc. 207, 108-117 (2002).
[CrossRef] [PubMed]

Xiaoxia, W.

S. Ke, W. Xiaoxia, M. Gurfinkel, C. Charnsangavej, S. Wallace, E. M. Sevick-Muraca, and C. Li, "Near-infrared optical imaging of epidermal growth factor receptor in breast cancer xenografts," Cancer Res. 63, 7870-7875 (2003).
[PubMed]

Yamashita, Y.

M. Hirano, Y. Yamashita, and A. Miyakawa, "In vivo visualization of hippocampal cells and dynamics of Ca2+ concentration during anoxia: feasibility of a fiber-optic plate microscope system for in vivo experiments," Brain. Res. 732, 61-68 (1996).
[CrossRef] [PubMed]

Yelin, D.

D. Yelin, I. Rizvi, W. M. White, J. T. Motz, T. Hasan, B. E. Bouma, and G. J. Tearney, "Three-dimensional miniature endoscopy" Nature 443, 765 (2006).
[CrossRef] [PubMed]

Appl. Opt. (4)

Brain. Res. (1)

M. Hirano, Y. Yamashita, and A. Miyakawa, "In vivo visualization of hippocampal cells and dynamics of Ca2+ concentration during anoxia: feasibility of a fiber-optic plate microscope system for in vivo experiments," Brain. Res. 732, 61-68 (1996).
[CrossRef] [PubMed]

Cancer Res. (1)

S. Ke, W. Xiaoxia, M. Gurfinkel, C. Charnsangavej, S. Wallace, E. M. Sevick-Muraca, and C. Li, "Near-infrared optical imaging of epidermal growth factor receptor in breast cancer xenografts," Cancer Res. 63, 7870-7875 (2003).
[PubMed]

Electron Lett. (1)

L. Giniunas, R. Juškaitis, and S. V. Shatalin, "Scanning fiber-optic microscope" Electron Lett. 27, 724-726 (1991).
[CrossRef]

Gastrointest. Endosc. (1)

A. L. Polglase, W. J. McLaren, S. A. Skinner, R. Kiesslich, M. F. Neurath, and P. M. Delaney, "Fluorescence confocal endomicroscope for in vivo microscopy of the upper and lower gastrointestinal tract," Gastrointest. Endosc. 62, 686-695 (2005).
[CrossRef] [PubMed]

J. Biomed. Opt. (1)

T. Collier, M. Guillaud, M. Follen, A. Malpica, and R. Richards-Kortum, "Real-time reflectance confocal microscopy: comparison of two-dimensional images and three-dimensional image stacks for detection of cervical precancer," J. Biomed. Opt. 12, 024021 (2007).
[CrossRef] [PubMed]

J. Dent. Res. (1)

R. R. Steinman, "Pharmacologic control of dentinal fluid movement and dental caries in rats," J. Dent. Res. 47, 720-724 (1968).
[CrossRef] [PubMed]

J. Microsc. (1)

V. Dubaj, A. Mazzolini, A. Wood, and M. Harris, "Optic fibre bundle contact imaging probe employing a laser scanning confocal microscope," J. Microsc. 207, 108-117 (2002).
[CrossRef] [PubMed]

J. Neurosci. (1)

G. R. Poe, D. M. Rector, and R. M. Harper, "Hippocampal reflected optical patterns during sleep and waking states in the freely behaving cat," J. Neurosci. 14, 2933-2942 (1994).
[PubMed]

J. Vasc. Res. (1)

E. Laemmel, M. Genet, G. Le Goualher, A. Perchant, J.-F. Le Gargasson, and E. Vicaut, "Fibered confocal fluorescence microscopy (Cell-viZio) facilitates extended imaging in the field of microcirculation. A comparison with intravital microscopy," J. Vasc. Res. 41, 400-411 (2004).
[CrossRef] [PubMed]

JAMA (1)

F. A. Jaffer and R. Weissleder, "Molecular imaging in the clinical arena," JAMA 293, 855-862 (2005).
[CrossRef] [PubMed]

Lasers Surg. Med. (1)

E. J. Seibel and Q. Y. J. Smithwick, "Unique features of optical scanning, single fiber Endoscopy," Lasers Surg. Med. 30, 177-183 (2002).
[CrossRef] [PubMed]

Nat. Biotechnol (1)

R. Weissleder, C. H. Tung, U. Mahmood, and A. Bogdanov, Jr, "In vivo imaging of tumors with protease-activated near-infrared fluorescent probes," Nat. Biotechnol 17, 375-378 (1999).
[CrossRef] [PubMed]

Nat. Biotechnol. (2)

X. Gao, Y. Cui, R. M. Levenson, L. W. K. Chung, and S. Nie, "In vivo cancer targeting and imaging with semiconductor quantum dots," Nat. Biotechnol. 22, 969-976 (2004).
[CrossRef] [PubMed]

A. Becker, C. Hessenius, K. Licha, B. Ebert, U. Sukowski, W. Semmler, B. Wiedenmann, and C. Grötzinger, "Receptor-targeted optical imaging of tumors with near-infrared fluorescent ligands," Nat. Biotechnol. 19, 327-331 (2001).
[CrossRef] [PubMed]

Nat. Clin. Pract. Oncol. (1)

R. Kiesslich, M. Goetz, M. Vieth, P. R. Galle, and M. F. Neurath, "Technology insight: confocal laser endoscopy for in vivo diagnosis of colorectal cancer," Nat. Clin. Pract. Oncol. 4, 480-490 (2007).
[CrossRef] [PubMed]

Nat. Methods (1)

B. A. Flusberg, E. D. Cocker, W. Piyawattanametha, J. C. Jung, E. L. Cheung, and M. J. Schnitzer, "Fiber-optic fluorescence imaging," Nat. Methods 2, 941-950 (2005).
[CrossRef] [PubMed]

Nature (1)

D. Yelin, I. Rizvi, W. M. White, J. T. Motz, T. Hasan, B. E. Bouma, and G. J. Tearney, "Three-dimensional miniature endoscopy" Nature 443, 765 (2006).
[CrossRef] [PubMed]

Opt. Express (3)

Opt. Lett. (4)

Opt. Express (1)

K.-B. Sung, R. Richards-Kortum, M. Follen, A. Malpica, C. Liang, and M. Descour, "Fiber optic confocal reflectance microscopy: a new real-time technique to view nuclear morphology in cervical squamous epithelium in vivo," Opt. Express 11, 3171-3181 (2003).
[CrossRef] [PubMed]

Scanning (1)

R. Juškaitis, T. Wilson, and T. F. Watson, "Real-time white light reflection confocal microscopy using a fibre-optic bundle," Scanning 19, 15-19 (1997).

Trends Mol. Med. (1)

T. F. Massoud and S. S. Gambhir, "Integrating noninvasive molecular imaging into molecular medicine: an evolving paradigm," Trends Mol. Med. 13, 183-191 (2007).
[CrossRef] [PubMed]

Other (2)

M. R. Harris, UK patent: GB 2,340 332 B (2001).

P. Delaney and M. Harris, Handbook of Biological Confocal Microscopy, 3rd edition, (Springer, New York, 2007), Chap. 26.

Supplementary Material (2)

» Media 1: MOV (2948 KB)     
» Media 2: MOV (3179 KB)     

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Figures (5)

Fig. 1.
Fig. 1.

Fiber-optic microendoscopy system. (a) Schematic diagram. (b) Photograph of fiber-optic bundles on a US penny. Bundles 1 and 2 have outer diameters of 1.0 mm and 0.5 mm respectively.

Fig. 2.
Fig. 2.

System resolution and multiplexed cell culture imaging. (a) Image of a standard US Air Force resolution target, demonstrating resolution of the 4.4 µm-wide bars in group 6, element 6 (circled). (b) False-color composite image of a 3-D collagen construct containing 1483 oral squamous cell carcinoma cells (red), SK-BR-3 breast cancer cells (green), and SiHa cervical cancer cells (blue), with each cell type stained with a spectrally-distinct fluorophore. (c) Single frame image of the same tissue construct acquired in real-time with a single long-pass emission filter. 1483 cells appear red, SK-BR-3 cells yellow, and SiHa cells appear light green. All scale bars represent 50 µm.

Fig. 3.
Fig. 3.

Murine tumor model imaging. (a) Photograph of an athymic nude mouse showing the fiber microendoscope and subcutaneous tumor. (b) Macroscopic fluorescence image (CRI Maestro) acquired following direct injection of fluorescent contrast agent at the tumor site. (c) Image acquired by the fiber microendoscope in the living mouse, as the fiber is advanced through the tumor within the lumen of a 16-gauge needle (frame from Video 1, 2.87 MB movie). Tumor cell nuclei appear as bright green dots, with connective tissue within the tumor mass. (d) Corresponding histology section following tumor excision. Scale bars represent 100 µm. [Media 1]

Fig. 4.
Fig. 4.

Surgical specimen imaging. (a) Normal epithelium. Left; photograph of fiber probe in contact with excised tumor tissue. Yellow border represents the clinically-abnormal region identified by the surgeon (AG). Center; microendoscopy image of tissue with probe at location indicated in photograph. Right; corresponding transverse histopathology section from the imaged region. (b) Tumor region. Microendoscopy image (center) and histology (right) demonstrate squamous carcinoma throughout the entire epithelium. Scale bars represent 100 µm. (c) Graph of calculated nuclear to cytoplasmic ratio for microendoscopy images in (a,b). The dashed line represents an N/C ratio of 0.08.

Fig.5. .
Fig.5. .

In vivo human tissue imaging. (a) Fiber microendoscopy imaging of normal human oral mucosa in vivo, following topical application of fluorescent acriflavine neutral (0.05% in saline). This image was acquired with a scientific-grade CCD camera. (b) Image of the same tissue acquired with a standard CCD camera (frame from Video 2, 3.10 MB movie). In both images, cell nuclei appear bright surrounded by dark cytoplasm. Scale bars represent 100 µm. [Media 2]

Tables (1)

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Table 1. Experimental Parameters For Each CCD Camera

Equations (1)

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FOV max = w CCD w p ϕ c n

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