Abstract

We present a miniature endomicroscope that combines large field-of-view (FOV) (1.15 mm) reflectance imaging with high-resolution (~0.5 μm) multiphoton intrinsic fluorescence imaging. We acquired in vivo and ex vivo images of unstained normal and tumor-laden tissues by using the large-FOV mode to navigate to the site of interest and then switching to the high-resolution modality to resolve cellular details.

© 2013 OSA

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  27. I. Pavlova, K. R. Hume, S. A. Yazinski, J. Flanders, T. L. Southard, R. S. Weiss, and W. W. Webb, “Multiphoton microscopy and microspectroscopy for diagnostics of inflammatory and neoplastic lung,” J. Biomed. Opt.17(3), 036014 (2012).
    [CrossRef] [PubMed]
  28. 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(12), 7075–7080 (2003).
    [CrossRef] [PubMed]
  29. E. L. Jackson, N. Willis, K. Mercer, R. T. Bronson, D. Crowley, R. Montoya, T. Jacks, and D. A. Tuveson, “Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras,” Genes Dev.15(24), 3243–3248 (2001).
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    [CrossRef] [PubMed]

2012 (2)

I. Pavlova, K. R. Hume, S. A. Yazinski, J. Flanders, T. L. Southard, R. S. Weiss, and W. W. Webb, “Multiphoton microscopy and microspectroscopy for diagnostics of inflammatory and neoplastic lung,” J. Biomed. Opt.17(3), 036014 (2012).
[CrossRef] [PubMed]

J. F. Xi, Y. Chen, Y. Zhang, K. Murari, M. J. Li, and X. Li, “Integrated multimodal endomicroscopy platform for simultaneous en face optical coherence and two-photon fluorescence imaging,” Opt. Lett.37(3), 362–364 (2012).
[CrossRef] [PubMed]

2011 (1)

D. R. Rivera, C. M. Brown, D. G. Ouzounov, I. Pavlova, D. Kobat, W. W. Webb, and C. Xu, “Compact and flexible raster scanning multiphoton endoscope capable of imaging unstained tissue,” Proc. Natl. Acad. Sci. U.S.A.108(43), 17598–17603 (2011).
[CrossRef] [PubMed]

2010 (2)

P. Kim, E. Chung, H. Yamashita, K. E. Hung, A. Mizoguchi, R. Kucherlapati, D. Fukumura, R. K. Jain, and S. H. Yun, “In vivo wide-area cellular imaging by side-view endomicroscopy,” Nat. Methods7(4), 303–305 (2010).
[CrossRef] [PubMed]

S. M. Landau, C. Liang, R. T. Kester, T. S. Tkaczyk, and M. R. Descour, “Design and evaluation of an ultra-slim objective for in-vivo deep optical biopsy,” Opt. Express18(5), 4758–4775 (2010).
[CrossRef] [PubMed]

2009 (4)

Y. C. Wu, J. F. Xi, M. J. Cobb, and X. D. Li, “Scanning fiber-optic nonlinear endomicroscopy with miniature aspherical compound lens and multimode fiber collector,” Opt. Lett.34(7), 953–955 (2009).
[CrossRef] [PubMed]

G. J. Liu, T. Xie, I. V. Tomov, J. Su, L. Yu, J. Zhang, B. J. Tromberg, and Z. Chen, “Rotational multiphoton endoscopy with a 1 μm fiber laser system,” Opt. Lett.34(15), 2249–2251 (2009).
[CrossRef] [PubMed]

R. P. Barretto, B. Messerschmidt, and M. J. Schnitzer, “In vivo fluorescence imaging with high-resolution microlenses,” Nat. Methods6(7), 511–512 (2009).
[CrossRef] [PubMed]

S. S. Mukherjee, J. S. Wysock, C. K. Ng, M. Akhtar, S. Perner, M. Lee, M. Rubin, F. Maxfield, W. Webb, and S. Scherr, “Human bladder cancer diagnosis using Multiphoton microscopy,” Proc. SPIE7161, 96839 (2009).

2008 (3)

2007 (3)

R. T. Kester, T. S. Tkaczyk, M. R. Descour, T. Christenson, and R. Richards-Kortum, “High numerical aperture microendoscope objective for a fiber confocal reflectance microscope,” Opt. Express15(5), 2409–2420 (2007).
[CrossRef] [PubMed]

R. Kiesslich and M. F. Neurath, “Endomicroscopy is born--do we still need the pathologist?” Gastrointest. Endosc.66(1), 150–153 (2007).
[CrossRef] [PubMed]

L. Fu, A. Jain, C. Cranfield, H. K. Xie, and M. Gu, “Three-dimensional nonlinear optical endoscopy,” J. Biomed. Opt.12(4), 040501 (2007).
[CrossRef] [PubMed]

2006 (1)

2005 (4)

2003 (3)

D. Bird and M. Gu, “Two-photon fluorescence endoscopy with a micro-optic scanning head,” Opt. Lett.28(17), 1552–1554 (2003).
[CrossRef] [PubMed]

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A.100(12), 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(11), 1369–1377 (2003).
[CrossRef] [PubMed]

2002 (3)

2001 (1)

E. L. Jackson, N. Willis, K. Mercer, R. T. Bronson, D. Crowley, R. Montoya, T. Jacks, and D. A. Tuveson, “Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras,” Genes Dev.15(24), 3243–3248 (2001).
[CrossRef] [PubMed]

1993 (1)

M. Gu, J. R. Sheppard, and H. Zhou, “Optimization of axial resolution in confocal imaging using annular pupils,” Optik (Stuttg.)93, 87–90 (1993).

1991 (1)

D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and J. Fujimoto, “Optical coherence tomography,” Science254(5035), 1178–1181 (1991).
[CrossRef] [PubMed]

1990 (1)

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science248(4951), 73–76 (1990).
[CrossRef] [PubMed]

1988 (1)

M. Minsky, “Memoir on inventing the confocal scanning microscope,” Scanning10(4), 128–138 (1988).
[CrossRef]

1977 (1)

J. R. Sheppard, “The use of lenses with annular aperture in scanning optical microscopy,” Optik (Stuttg.)48, 329–334 (1977).

Akhtar, M.

S. S. Mukherjee, J. S. Wysock, C. K. Ng, M. Akhtar, S. Perner, M. Lee, M. Rubin, F. Maxfield, W. Webb, and S. Scherr, “Human bladder cancer diagnosis using Multiphoton microscopy,” Proc. SPIE7161, 96839 (2009).

Allen, J.

Anderson, E. P.

Bao, H. C.

Barretto, R. P.

R. P. Barretto, B. Messerschmidt, and M. J. Schnitzer, “In vivo fluorescence imaging with high-resolution microlenses,” Nat. Methods6(7), 511–512 (2009).
[CrossRef] [PubMed]

Beaurepaire, E.

Bentley, J.

D. G. Ouzounov, D. R. Rivera, W. W. Webb, J. Bentley, and C. Xu, “Miniature varifocal objective lens for endomicroscopy,” Opt. Lett. (to be published).

Bird, D.

Bronson, R. T.

E. L. Jackson, N. Willis, K. Mercer, R. T. Bronson, D. Crowley, R. Montoya, T. Jacks, and D. A. Tuveson, “Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras,” Genes Dev.15(24), 3243–3248 (2001).
[CrossRef] [PubMed]

Brown, C. M.

D. R. Rivera, C. M. Brown, D. G. Ouzounov, I. Pavlova, D. Kobat, W. W. Webb, and C. Xu, “Compact and flexible raster scanning multiphoton endoscope capable of imaging unstained tissue,” Proc. Natl. Acad. Sci. U.S.A.108(43), 17598–17603 (2011).
[CrossRef] [PubMed]

Carlson, K.

Chang, W.

D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and J. Fujimoto, “Optical coherence tomography,” Science254(5035), 1178–1181 (1991).
[CrossRef] [PubMed]

Chen, Y.

Chen, Z.

Chidley, M.

Christenson, T.

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(12), 7075–7080 (2003).
[CrossRef] [PubMed]

Chung, E.

P. Kim, E. Chung, H. Yamashita, K. E. Hung, A. Mizoguchi, R. Kucherlapati, D. Fukumura, R. K. Jain, and S. H. Yun, “In vivo wide-area cellular imaging by side-view endomicroscopy,” Nat. Methods7(4), 303–305 (2010).
[CrossRef] [PubMed]

Cobb, M. J.

Cocker, E. D.

Cranfield, C.

L. Fu, A. Jain, C. Cranfield, H. K. Xie, and M. Gu, “Three-dimensional nonlinear optical endoscopy,” J. Biomed. Opt.12(4), 040501 (2007).
[CrossRef] [PubMed]

Crowley, D.

E. L. Jackson, N. Willis, K. Mercer, R. T. Bronson, D. Crowley, R. Montoya, T. Jacks, and D. A. Tuveson, “Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras,” Genes Dev.15(24), 3243–3248 (2001).
[CrossRef] [PubMed]

Denk, W.

F. Helmchen and W. Denk, “Deep tissue two-photon microscopy,” Nat. Methods2(12), 932–940 (2005).
[CrossRef] [PubMed]

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science248(4951), 73–76 (1990).
[CrossRef] [PubMed]

Descour, M.

Descour, M. R.

Engelbrecht, C. J.

Flanders, J.

I. Pavlova, K. R. Hume, S. A. Yazinski, J. Flanders, T. L. Southard, R. S. Weiss, and W. W. Webb, “Multiphoton microscopy and microspectroscopy for diagnostics of inflammatory and neoplastic lung,” J. Biomed. Opt.17(3), 036014 (2012).
[CrossRef] [PubMed]

Flotte, T.

D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and J. Fujimoto, “Optical coherence tomography,” Science254(5035), 1178–1181 (1991).
[CrossRef] [PubMed]

Flusberg, B. A.

Follen, M.

Fu, L.

L. Fu, A. Jain, C. Cranfield, H. K. Xie, and M. Gu, “Three-dimensional nonlinear optical endoscopy,” J. Biomed. Opt.12(4), 040501 (2007).
[CrossRef] [PubMed]

Fujimoto, J.

D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and J. Fujimoto, “Optical coherence tomography,” Science254(5035), 1178–1181 (1991).
[CrossRef] [PubMed]

Fukumura, D.

P. Kim, E. Chung, H. Yamashita, K. E. Hung, A. Mizoguchi, R. Kucherlapati, D. Fukumura, R. K. Jain, and S. H. Yun, “In vivo wide-area cellular imaging by side-view endomicroscopy,” Nat. Methods7(4), 303–305 (2010).
[CrossRef] [PubMed]

Galle, P. R.

R. Kiesslich, M. Goetz, M. Vieth, P. R. Galle, and M. F. Neurath, “Confocal laser endomicroscopy,” Gastrointest. Endosc. Clin. N. Am.15(4), 715–731 (2005).
[CrossRef] [PubMed]

Gillenwater, A.

Goetz, M.

R. Kiesslich, M. Goetz, M. Vieth, P. R. Galle, and M. F. Neurath, “Confocal laser endomicroscopy,” Gastrointest. Endosc. Clin. N. Am.15(4), 715–731 (2005).
[CrossRef] [PubMed]

Gregory, K.

D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and J. Fujimoto, “Optical coherence tomography,” Science254(5035), 1178–1181 (1991).
[CrossRef] [PubMed]

Gu, M.

H. C. Bao, J. Allen, R. Pattie, R. Vance, and M. Gu, “Fast handheld two-photon fluorescence microendoscope with a 475 μm x 475 μm field of view for in vivo imaging,” Opt. Lett.33(12), 1333–1335 (2008).
[CrossRef] [PubMed]

L. Fu, A. Jain, C. Cranfield, H. K. Xie, and M. Gu, “Three-dimensional nonlinear optical endoscopy,” J. Biomed. Opt.12(4), 040501 (2007).
[CrossRef] [PubMed]

D. Bird and M. Gu, “Two-photon fluorescence endoscopy with a micro-optic scanning head,” Opt. Lett.28(17), 1552–1554 (2003).
[CrossRef] [PubMed]

M. Gu, J. R. Sheppard, and H. Zhou, “Optimization of axial resolution in confocal imaging using annular pupils,” Optik (Stuttg.)93, 87–90 (1993).

Hee, M. R.

D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and J. Fujimoto, “Optical coherence tomography,” Science254(5035), 1178–1181 (1991).
[CrossRef] [PubMed]

Helmchen, F.

Huang, D.

D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and J. Fujimoto, “Optical coherence tomography,” Science254(5035), 1178–1181 (1991).
[CrossRef] [PubMed]

Hume, K. R.

I. Pavlova, K. R. Hume, S. A. Yazinski, J. Flanders, T. L. Southard, R. S. Weiss, and W. W. Webb, “Multiphoton microscopy and microspectroscopy for diagnostics of inflammatory and neoplastic lung,” J. Biomed. Opt.17(3), 036014 (2012).
[CrossRef] [PubMed]

Hung, K. E.

P. Kim, E. Chung, H. Yamashita, K. E. Hung, A. Mizoguchi, R. Kucherlapati, D. Fukumura, R. K. Jain, and S. H. Yun, “In vivo wide-area cellular imaging by side-view endomicroscopy,” Nat. Methods7(4), 303–305 (2010).
[CrossRef] [PubMed]

Hyman, B. T.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A.100(12), 7075–7080 (2003).
[CrossRef] [PubMed]

Jacks, T.

E. L. Jackson, N. Willis, K. Mercer, R. T. Bronson, D. Crowley, R. Montoya, T. Jacks, and D. A. Tuveson, “Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras,” Genes Dev.15(24), 3243–3248 (2001).
[CrossRef] [PubMed]

Jackson, E. L.

E. L. Jackson, N. Willis, K. Mercer, R. T. Bronson, D. Crowley, R. Montoya, T. Jacks, and D. A. Tuveson, “Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras,” Genes Dev.15(24), 3243–3248 (2001).
[CrossRef] [PubMed]

Jain, A.

L. Fu, A. Jain, C. Cranfield, H. K. Xie, and M. Gu, “Three-dimensional nonlinear optical endoscopy,” J. Biomed. Opt.12(4), 040501 (2007).
[CrossRef] [PubMed]

Jain, R. K.

P. Kim, E. Chung, H. Yamashita, K. E. Hung, A. Mizoguchi, R. Kucherlapati, D. Fukumura, R. K. Jain, and S. H. Yun, “In vivo wide-area cellular imaging by side-view endomicroscopy,” Nat. Methods7(4), 303–305 (2010).
[CrossRef] [PubMed]

Johnston, R. S.

Jung, J. C.

Kester, R. T.

Kiesslich, R.

R. Kiesslich and M. F. Neurath, “Endomicroscopy is born--do we still need the pathologist?” Gastrointest. Endosc.66(1), 150–153 (2007).
[CrossRef] [PubMed]

R. Kiesslich, M. Goetz, M. Vieth, P. R. Galle, and M. F. Neurath, “Confocal laser endomicroscopy,” Gastrointest. Endosc. Clin. N. Am.15(4), 715–731 (2005).
[CrossRef] [PubMed]

Kim, P.

P. Kim, E. Chung, H. Yamashita, K. E. Hung, A. Mizoguchi, R. Kucherlapati, D. Fukumura, R. K. Jain, and S. H. Yun, “In vivo wide-area cellular imaging by side-view endomicroscopy,” Nat. Methods7(4), 303–305 (2010).
[CrossRef] [PubMed]

Kobat, D.

D. R. Rivera, C. M. Brown, D. G. Ouzounov, I. Pavlova, D. Kobat, W. W. Webb, and C. Xu, “Compact and flexible raster scanning multiphoton endoscope capable of imaging unstained tissue,” Proc. Natl. Acad. Sci. U.S.A.108(43), 17598–17603 (2011).
[CrossRef] [PubMed]

König, K.

Kucherlapati, R.

P. Kim, E. Chung, H. Yamashita, K. E. Hung, A. Mizoguchi, R. Kucherlapati, D. Fukumura, R. K. Jain, and S. H. Yun, “In vivo wide-area cellular imaging by side-view endomicroscopy,” Nat. Methods7(4), 303–305 (2010).
[CrossRef] [PubMed]

Landau, S. M.

Le Harzic, R.

Lee, M.

S. S. Mukherjee, J. S. Wysock, C. K. Ng, M. Akhtar, S. Perner, M. Lee, M. Rubin, F. Maxfield, W. Webb, and S. Scherr, “Human bladder cancer diagnosis using Multiphoton microscopy,” Proc. SPIE7161, 96839 (2009).

Li, M. J.

Li, X.

Li, X. D.

Liang, C.

Lin, C. P.

D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and J. Fujimoto, “Optical coherence tomography,” Science254(5035), 1178–1181 (1991).
[CrossRef] [PubMed]

Liu, G. J.

MacDonald, D. J.

Maxfield, F.

S. S. Mukherjee, J. S. Wysock, C. K. Ng, M. Akhtar, S. Perner, M. Lee, M. Rubin, F. Maxfield, W. Webb, and S. Scherr, “Human bladder cancer diagnosis using Multiphoton microscopy,” Proc. SPIE7161, 96839 (2009).

Mercer, K.

E. L. Jackson, N. Willis, K. Mercer, R. T. Bronson, D. Crowley, R. Montoya, T. Jacks, and D. A. Tuveson, “Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras,” Genes Dev.15(24), 3243–3248 (2001).
[CrossRef] [PubMed]

Mertz, J.

Messerschmidt, B.

Minsky, M.

M. Minsky, “Memoir on inventing the confocal scanning microscope,” Scanning10(4), 128–138 (1988).
[CrossRef]

Mizoguchi, A.

P. Kim, E. Chung, H. Yamashita, K. E. Hung, A. Mizoguchi, R. Kucherlapati, D. Fukumura, R. K. Jain, and S. H. Yun, “In vivo wide-area cellular imaging by side-view endomicroscopy,” Nat. Methods7(4), 303–305 (2010).
[CrossRef] [PubMed]

Montoya, R.

E. L. Jackson, N. Willis, K. Mercer, R. T. Bronson, D. Crowley, R. Montoya, T. Jacks, and D. A. Tuveson, “Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras,” Genes Dev.15(24), 3243–3248 (2001).
[CrossRef] [PubMed]

Mukherjee, S. S.

S. S. Mukherjee, J. S. Wysock, C. K. Ng, M. Akhtar, S. Perner, M. Lee, M. Rubin, F. Maxfield, W. Webb, and S. Scherr, “Human bladder cancer diagnosis using Multiphoton microscopy,” Proc. SPIE7161, 96839 (2009).

Murari, K.

Myaing, M. T.

Neurath, M. F.

R. Kiesslich and M. F. Neurath, “Endomicroscopy is born--do we still need the pathologist?” Gastrointest. Endosc.66(1), 150–153 (2007).
[CrossRef] [PubMed]

R. Kiesslich, M. Goetz, M. Vieth, P. R. Galle, and M. F. Neurath, “Confocal laser endomicroscopy,” Gastrointest. Endosc. Clin. N. Am.15(4), 715–731 (2005).
[CrossRef] [PubMed]

Ng, C. K.

S. S. Mukherjee, J. S. Wysock, C. K. Ng, M. Akhtar, S. Perner, M. Lee, M. Rubin, F. Maxfield, W. Webb, and S. Scherr, “Human bladder cancer diagnosis using Multiphoton microscopy,” Proc. SPIE7161, 96839 (2009).

Nikitin, A. Y.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A.100(12), 7075–7080 (2003).
[CrossRef] [PubMed]

Ouzounov, D. G.

D. R. Rivera, C. M. Brown, D. G. Ouzounov, I. Pavlova, D. Kobat, W. W. Webb, and C. Xu, “Compact and flexible raster scanning multiphoton endoscope capable of imaging unstained tissue,” Proc. Natl. Acad. Sci. U.S.A.108(43), 17598–17603 (2011).
[CrossRef] [PubMed]

D. G. Ouzounov, D. R. Rivera, W. W. Webb, J. Bentley, and C. Xu, “Miniature varifocal objective lens for endomicroscopy,” Opt. Lett. (to be published).

Pattie, R.

Pavlova, I.

I. Pavlova, K. R. Hume, S. A. Yazinski, J. Flanders, T. L. Southard, R. S. Weiss, and W. W. Webb, “Multiphoton microscopy and microspectroscopy for diagnostics of inflammatory and neoplastic lung,” J. Biomed. Opt.17(3), 036014 (2012).
[CrossRef] [PubMed]

D. R. Rivera, C. M. Brown, D. G. Ouzounov, I. Pavlova, D. Kobat, W. W. Webb, and C. Xu, “Compact and flexible raster scanning multiphoton endoscope capable of imaging unstained tissue,” Proc. Natl. Acad. Sci. U.S.A.108(43), 17598–17603 (2011).
[CrossRef] [PubMed]

Perner, S.

S. S. Mukherjee, J. S. Wysock, C. K. Ng, M. Akhtar, S. Perner, M. Lee, M. Rubin, F. Maxfield, W. Webb, and S. Scherr, “Human bladder cancer diagnosis using Multiphoton microscopy,” Proc. SPIE7161, 96839 (2009).

Puliafito, C. A.

D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and J. Fujimoto, “Optical coherence tomography,” Science254(5035), 1178–1181 (1991).
[CrossRef] [PubMed]

Richards-Kortum, R.

Richards-Kortum, R. R.

Riemann, I.

Rivera, D. R.

D. R. Rivera, C. M. Brown, D. G. Ouzounov, I. Pavlova, D. Kobat, W. W. Webb, and C. Xu, “Compact and flexible raster scanning multiphoton endoscope capable of imaging unstained tissue,” Proc. Natl. Acad. Sci. U.S.A.108(43), 17598–17603 (2011).
[CrossRef] [PubMed]

D. G. Ouzounov, D. R. Rivera, W. W. Webb, J. Bentley, and C. Xu, “Miniature varifocal objective lens for endomicroscopy,” Opt. Lett. (to be published).

Rubin, M.

S. S. Mukherjee, J. S. Wysock, C. K. Ng, M. Akhtar, S. Perner, M. Lee, M. Rubin, F. Maxfield, W. Webb, and S. Scherr, “Human bladder cancer diagnosis using Multiphoton microscopy,” Proc. SPIE7161, 96839 (2009).

Scherr, S.

S. S. Mukherjee, J. S. Wysock, C. K. Ng, M. Akhtar, S. Perner, M. Lee, M. Rubin, F. Maxfield, W. Webb, and S. Scherr, “Human bladder cancer diagnosis using Multiphoton microscopy,” Proc. SPIE7161, 96839 (2009).

Schnitzer, M. J.

Schuman, J. S.

D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and J. Fujimoto, “Optical coherence tomography,” Science254(5035), 1178–1181 (1991).
[CrossRef] [PubMed]

Seibel, E. J.

Sheppard, J. R.

M. Gu, J. R. Sheppard, and H. Zhou, “Optimization of axial resolution in confocal imaging using annular pupils,” Optik (Stuttg.)93, 87–90 (1993).

J. R. Sheppard, “The use of lenses with annular aperture in scanning optical microscopy,” Optik (Stuttg.)48, 329–334 (1977).

Smithwick, Q. Y.

E. J. Seibel and Q. Y. Smithwick, “Unique features of optical scanning, single fiber endoscopy,” Lasers Surg. Med.30(3), 177–183 (2002).
[CrossRef] [PubMed]

Southard, T. L.

I. Pavlova, K. R. Hume, S. A. Yazinski, J. Flanders, T. L. Southard, R. S. Weiss, and W. W. Webb, “Multiphoton microscopy and microspectroscopy for diagnostics of inflammatory and neoplastic lung,” J. Biomed. Opt.17(3), 036014 (2012).
[CrossRef] [PubMed]

Stinson, W. G.

D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and J. Fujimoto, “Optical coherence tomography,” Science254(5035), 1178–1181 (1991).
[CrossRef] [PubMed]

Strickler, J. H.

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science248(4951), 73–76 (1990).
[CrossRef] [PubMed]

Su, J.

Sung, K. B.

Swanson, E. A.

D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and J. Fujimoto, “Optical coherence tomography,” Science254(5035), 1178–1181 (1991).
[CrossRef] [PubMed]

Tkaczyk, T. S.

Tomov, I. V.

Tromberg, B. J.

Tuveson, D. A.

E. L. Jackson, N. Willis, K. Mercer, R. T. Bronson, D. Crowley, R. Montoya, T. Jacks, and D. A. Tuveson, “Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras,” Genes Dev.15(24), 3243–3248 (2001).
[CrossRef] [PubMed]

Vance, R.

Vieth, M.

R. Kiesslich, M. Goetz, M. Vieth, P. R. Galle, and M. F. Neurath, “Confocal laser endomicroscopy,” Gastrointest. Endosc. Clin. N. Am.15(4), 715–731 (2005).
[CrossRef] [PubMed]

Webb, W.

S. S. Mukherjee, J. S. Wysock, C. K. Ng, M. Akhtar, S. Perner, M. Lee, M. Rubin, F. Maxfield, W. Webb, and S. Scherr, “Human bladder cancer diagnosis using Multiphoton microscopy,” Proc. SPIE7161, 96839 (2009).

Webb, W. W.

I. Pavlova, K. R. Hume, S. A. Yazinski, J. Flanders, T. L. Southard, R. S. Weiss, and W. W. Webb, “Multiphoton microscopy and microspectroscopy for diagnostics of inflammatory and neoplastic lung,” J. Biomed. Opt.17(3), 036014 (2012).
[CrossRef] [PubMed]

D. R. Rivera, C. M. Brown, D. G. Ouzounov, I. Pavlova, D. Kobat, W. W. Webb, and C. Xu, “Compact and flexible raster scanning multiphoton endoscope capable of imaging unstained tissue,” Proc. Natl. Acad. Sci. U.S.A.108(43), 17598–17603 (2011).
[CrossRef] [PubMed]

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. U.S.A.100(12), 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(11), 1369–1377 (2003).
[CrossRef] [PubMed]

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science248(4951), 73–76 (1990).
[CrossRef] [PubMed]

D. G. Ouzounov, D. R. Rivera, W. W. Webb, J. Bentley, and C. Xu, “Miniature varifocal objective lens for endomicroscopy,” Opt. Lett. (to be published).

Weinigel, M.

Weiss, R. S.

I. Pavlova, K. R. Hume, S. A. Yazinski, J. Flanders, T. L. Southard, R. S. Weiss, and W. W. Webb, “Multiphoton microscopy and microspectroscopy for diagnostics of inflammatory and neoplastic lung,” J. Biomed. Opt.17(3), 036014 (2012).
[CrossRef] [PubMed]

Williams, R. M.

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(12), 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(11), 1369–1377 (2003).
[CrossRef] [PubMed]

Willis, N.

E. L. Jackson, N. Willis, K. Mercer, R. T. Bronson, D. Crowley, R. Montoya, T. Jacks, and D. A. Tuveson, “Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras,” Genes Dev.15(24), 3243–3248 (2001).
[CrossRef] [PubMed]

Wu, Y. C.

Wysock, J. S.

S. S. Mukherjee, J. S. Wysock, C. K. Ng, M. Akhtar, S. Perner, M. Lee, M. Rubin, F. Maxfield, W. Webb, and S. Scherr, “Human bladder cancer diagnosis using Multiphoton microscopy,” Proc. SPIE7161, 96839 (2009).

Xi, J. F.

Xie, H. K.

L. Fu, A. Jain, C. Cranfield, H. K. Xie, and M. Gu, “Three-dimensional nonlinear optical endoscopy,” J. Biomed. Opt.12(4), 040501 (2007).
[CrossRef] [PubMed]

Xie, T.

Xu, C.

D. R. Rivera, C. M. Brown, D. G. Ouzounov, I. Pavlova, D. Kobat, W. W. Webb, and C. Xu, “Compact and flexible raster scanning multiphoton endoscope capable of imaging unstained tissue,” Proc. Natl. Acad. Sci. U.S.A.108(43), 17598–17603 (2011).
[CrossRef] [PubMed]

D. G. Ouzounov, D. R. Rivera, W. W. Webb, J. Bentley, and C. Xu, “Miniature varifocal objective lens for endomicroscopy,” Opt. Lett. (to be published).

Yamashita, H.

P. Kim, E. Chung, H. Yamashita, K. E. Hung, A. Mizoguchi, R. Kucherlapati, D. Fukumura, R. K. Jain, and S. H. Yun, “In vivo wide-area cellular imaging by side-view endomicroscopy,” Nat. Methods7(4), 303–305 (2010).
[CrossRef] [PubMed]

Yazinski, S. A.

I. Pavlova, K. R. Hume, S. A. Yazinski, J. Flanders, T. L. Southard, R. S. Weiss, and W. W. Webb, “Multiphoton microscopy and microspectroscopy for diagnostics of inflammatory and neoplastic lung,” J. Biomed. Opt.17(3), 036014 (2012).
[CrossRef] [PubMed]

Yu, L.

Yun, S. H.

P. Kim, E. Chung, H. Yamashita, K. E. Hung, A. Mizoguchi, R. Kucherlapati, D. Fukumura, R. K. Jain, and S. H. Yun, “In vivo wide-area cellular imaging by side-view endomicroscopy,” Nat. Methods7(4), 303–305 (2010).
[CrossRef] [PubMed]

Zhang, J.

Zhang, Y.

Zhou, H.

M. Gu, J. R. Sheppard, and H. Zhou, “Optimization of axial resolution in confocal imaging using annular pupils,” Optik (Stuttg.)93, 87–90 (1993).

Zipfel, W. 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(12), 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(11), 1369–1377 (2003).
[CrossRef] [PubMed]

Appl. Opt. (3)

Gastrointest. Endosc. (1)

R. Kiesslich and M. F. Neurath, “Endomicroscopy is born--do we still need the pathologist?” Gastrointest. Endosc.66(1), 150–153 (2007).
[CrossRef] [PubMed]

Gastrointest. Endosc. Clin. N. Am. (1)

R. Kiesslich, M. Goetz, M. Vieth, P. R. Galle, and M. F. Neurath, “Confocal laser endomicroscopy,” Gastrointest. Endosc. Clin. N. Am.15(4), 715–731 (2005).
[CrossRef] [PubMed]

Genes Dev. (1)

E. L. Jackson, N. Willis, K. Mercer, R. T. Bronson, D. Crowley, R. Montoya, T. Jacks, and D. A. Tuveson, “Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras,” Genes Dev.15(24), 3243–3248 (2001).
[CrossRef] [PubMed]

J. Biomed. Opt. (2)

I. Pavlova, K. R. Hume, S. A. Yazinski, J. Flanders, T. L. Southard, R. S. Weiss, and W. W. Webb, “Multiphoton microscopy and microspectroscopy for diagnostics of inflammatory and neoplastic lung,” J. Biomed. Opt.17(3), 036014 (2012).
[CrossRef] [PubMed]

L. Fu, A. Jain, C. Cranfield, H. K. Xie, and M. Gu, “Three-dimensional nonlinear optical endoscopy,” J. Biomed. Opt.12(4), 040501 (2007).
[CrossRef] [PubMed]

Lasers Surg. Med. (1)

E. J. Seibel and Q. Y. Smithwick, “Unique features of optical scanning, single fiber endoscopy,” Lasers Surg. Med.30(3), 177–183 (2002).
[CrossRef] [PubMed]

Nat. Biotechnol. (1)

W. R. Zipfel, R. M. Williams, and W. W. Webb, “Nonlinear magic: multiphoton microscopy in the biosciences,” Nat. Biotechnol.21(11), 1369–1377 (2003).
[CrossRef] [PubMed]

Nat. Methods (3)

R. P. Barretto, B. Messerschmidt, and M. J. Schnitzer, “In vivo fluorescence imaging with high-resolution microlenses,” Nat. Methods6(7), 511–512 (2009).
[CrossRef] [PubMed]

P. Kim, E. Chung, H. Yamashita, K. E. Hung, A. Mizoguchi, R. Kucherlapati, D. Fukumura, R. K. Jain, and S. H. Yun, “In vivo wide-area cellular imaging by side-view endomicroscopy,” Nat. Methods7(4), 303–305 (2010).
[CrossRef] [PubMed]

F. Helmchen and W. Denk, “Deep tissue two-photon microscopy,” Nat. Methods2(12), 932–940 (2005).
[CrossRef] [PubMed]

Opt. Express (4)

Opt. Lett. (8)

D. Bird and M. Gu, “Two-photon fluorescence endoscopy with a micro-optic scanning head,” Opt. Lett.28(17), 1552–1554 (2003).
[CrossRef] [PubMed]

G. J. Liu, T. Xie, I. V. Tomov, J. Su, L. Yu, J. Zhang, B. J. Tromberg, and Z. Chen, “Rotational multiphoton endoscopy with a 1 μm fiber laser system,” Opt. Lett.34(15), 2249–2251 (2009).
[CrossRef] [PubMed]

M. T. Myaing, D. J. MacDonald, and X. D. Li, “Fiber-optic scanning two-photon fluorescence endoscope,” Opt. Lett.31(8), 1076–1078 (2006).
[CrossRef] [PubMed]

J. F. Xi, Y. Chen, Y. Zhang, K. Murari, M. J. Li, and X. Li, “Integrated multimodal endomicroscopy platform for simultaneous en face optical coherence and two-photon fluorescence imaging,” Opt. Lett.37(3), 362–364 (2012).
[CrossRef] [PubMed]

B. A. Flusberg, J. C. Jung, E. D. Cocker, E. P. Anderson, and M. J. Schnitzer, “In vivo brain imaging using a portable 3.9 gram two-photon fluorescence microendoscope,” Opt. Lett.30(17), 2272–2274 (2005).
[CrossRef] [PubMed]

H. C. Bao, J. Allen, R. Pattie, R. Vance, and M. Gu, “Fast handheld two-photon fluorescence microendoscope with a 475 μm x 475 μm field of view for in vivo imaging,” Opt. Lett.33(12), 1333–1335 (2008).
[CrossRef] [PubMed]

Y. C. Wu, J. F. Xi, M. J. Cobb, and X. D. Li, “Scanning fiber-optic nonlinear endomicroscopy with miniature aspherical compound lens and multimode fiber collector,” Opt. Lett.34(7), 953–955 (2009).
[CrossRef] [PubMed]

D. G. Ouzounov, D. R. Rivera, W. W. Webb, J. Bentley, and C. Xu, “Miniature varifocal objective lens for endomicroscopy,” Opt. Lett. (to be published).

Optik (Stuttg.) (2)

M. Gu, J. R. Sheppard, and H. Zhou, “Optimization of axial resolution in confocal imaging using annular pupils,” Optik (Stuttg.)93, 87–90 (1993).

J. R. Sheppard, “The use of lenses with annular aperture in scanning optical microscopy,” Optik (Stuttg.)48, 329–334 (1977).

Proc. Natl. Acad. Sci. U.S.A. (2)

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(12), 7075–7080 (2003).
[CrossRef] [PubMed]

D. R. Rivera, C. M. Brown, D. G. Ouzounov, I. Pavlova, D. Kobat, W. W. Webb, and C. Xu, “Compact and flexible raster scanning multiphoton endoscope capable of imaging unstained tissue,” Proc. Natl. Acad. Sci. U.S.A.108(43), 17598–17603 (2011).
[CrossRef] [PubMed]

Proc. SPIE (1)

S. S. Mukherjee, J. S. Wysock, C. K. Ng, M. Akhtar, S. Perner, M. Lee, M. Rubin, F. Maxfield, W. Webb, and S. Scherr, “Human bladder cancer diagnosis using Multiphoton microscopy,” Proc. SPIE7161, 96839 (2009).

Scanning (1)

M. Minsky, “Memoir on inventing the confocal scanning microscope,” Scanning10(4), 128–138 (1988).
[CrossRef]

Science (2)

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science248(4951), 73–76 (1990).
[CrossRef] [PubMed]

D. Huang, E. A. Swanson, C. P. Lin, J. S. Schuman, W. G. Stinson, W. Chang, M. R. Hee, T. Flotte, K. Gregory, C. A. Puliafito, and J. Fujimoto, “Optical coherence tomography,” Science254(5035), 1178–1181 (1991).
[CrossRef] [PubMed]

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Figures (5)

Fig. 1
Fig. 1

Dual modality endomicroscope. (a) Photograph of the endomicroscope with optical zoom. (b) Schematic illustration of the optical and mechanical configurations of the endomicroscope.

Fig. 2
Fig. 2

Endoscope characterization and imaging setup.

Fig. 3
Fig. 3

Dual modality endomicroscope characterization. (a) Calculated (red solid line) and measured (blue dashed line) lateral point spread function for the high-resolution imaging mode. Inset: Group 9 of USAF high-resolution target imaged in transmission using the high-resolution imaging mode at 800 nm. (b) USAF resolution target imaged in transmission using the high-magnification mode (λi = 800 nm). (c) USAF resolution target imaged in transmission using the low-magnification mode (λi = 406 nm). (d) Axial scan of a thin Rhodamine B film showing the two-photon axial resolution (FWHM) of 10.5 micron.

Fig. 4
Fig. 4

Ex vivo images of unstained tumor-laden mouse lung tissue. (a) Low magnification image of an H&E-stained section from the periphery of the entire lung lob. The locations of the sites imaged are indicated. (b)-(e) A site that contains mildly affected lung tissue. (b) High Magnification H&E image shows mildly expanded alveolar septa surrounding lumens containing increased numbers of alveolar macrophages containing brightly eosinophilic crystals (M). (c) Low magnification H&E of the same site. (d) Low-magnification reflection/scattering image of this region within the mouse lung, in which the alveolar tissue is distinguishable. (e) High-magnification two-photon intrinsic fluorescence image of unstained ex vivo mouse lung tissue from the area displayed in (b). Alveolar lumens (A) and walls (W) are distinguishable as well as most likely a few macrophages within the lumens. (f)-(i) A site with moderate infiltrates of macrophages. (f) High magnification H&E image confirms that alveolar lumens are filled with large numbers of macrophages containing abundant intracytoplasmic eosinophilic crystals. (g) Low magnification H&E image of this site. (h) Low-magnification reflection/scattering image of this inflammatory site, in which the alveolar structure is not well distinguishable. (i) High-magnification two-photon intrinsic fluorescence image of unstained ex vivo mouse lung tissue from the area displayed in (h). A large number of cells, most likely macrophages, have migrated into the alveolar lumens, which is characteristic of inflammation. (j)-(m) A site with neoplasia proliferation of alveolar epithelial cells. (j) High magnification H&E image confirms that alveolar architecture is effaced by atypical epithelial cells forming glandular and papillary structures. (k) Low magnification H&E image of this site. (l) Low-magnification reflection/scattering image of this abnormal site, the alveolar structure is not well distinguishable. (m) High-magnification two-photon intrinsic fluorescence image of unstained ex vivo mouse lung tissue from the area displayed in (l). Compact mass of cells covers the whole area and the alveolar structure is not seen. The indicated area in (c), (g) and (k) correlates to the corresponding reflectance image in (d), (h) and (l). The red circle in (d), (h) and (l) indicates the approximate location of the site from which the multiphoton image shown in (e), (i) and (m) is obtained. Scale bars in (a), 1 mm. Scale bars in (c), (g), (k), (d), (h) and (l) are 100 um. Scale bars in (b), (f), (j), (e), (i) and (m) are 10 um.

Fig. 5
Fig. 5

In vivo Images of unstained rat kidney tissues. (A), Low magnification reflection/scattering images of unstained in vivo rat kidney. The fibrous structure of the kidney capsule and outermost features of the kidney cortex are visible. (B)-(E), High-magnification two-photon intrinsic fluorescence image of unstained in vivo rat kidney 20 um below the surface (B), at ~60 um below the surface (C), at ~100 um below the surface (D) and at ~140 um below the surface (E). (F) High magnification H&E image shows similar features and information as two-photon intrinsic fluorescence images. (B)-(F) show cross sections of proximal convoluted tubules, each tubule contains a central lumen (CL) lined with cuboidal epithelium (CE) and separated by the poorly fluorescent renal interstitium (RI) containing sparse connective tissue components. Scale bars in (A), 100 um. Scale bars in (B)-(F), 10 um.

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