Abstract

In this paper we report the design, testing and use of a scannerless probe specifically for minimally invasive imaging of deep tissue in vivo with an epi-fluorescence modality. The probe images a 500 μm diameter field of view through a 710 μm outer diameter probe with a maximum tissue penetration depth of 15 mm specifically configured for eGFP imaging. Example results are given from imaging the pituitary gland of rats and zebrafish hearts with lateral resolution of 2.5 μm.

© 2012 OSA

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2011

K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. E. Gamal, and M. J. Schnitzer, “Miniaturized integration of a fluorescence microscope,” Nat. Methods8(10), 871–878 (2011).
[CrossRef] [PubMed]

2010

C. V. Harper, K. Featherstone, S. Semprini, S. Friedrichsen, J. McNeilly, P. Paszek, D. G. Spiller, A. S. McNeilly, J. J. Mullins, J. R. Davis, and M. R. White, “Dynamic organisation of prolactin gene expression in living pituitary tissue,” J. Cell Sci.123(3), 424–430 (2010).
[CrossRef] [PubMed]

J. Sun, S. Guo, L. Wu, L. Liu, S. W. Choe, B. S. Sorg, and H. Xie, “3D in vivo optical coherence tomography based on a low-voltage, large-scan-range 2D MEMS mirror,” Opt. Express18(12), 12065–12075 (2010).
[CrossRef] [PubMed]

2009

S. S. Semprini, S. Friedrichsen, C. V. Harper, J. R. McNeilly, A. D. Adamson, D. G. Spiller, N. Kotelevtseva, G. Brooker, D. G. Brownstein, A. S. McNeilly, M. R. White, J. R. Davis, and J. J. Mullins, “Real-time visualization of human prolactin alternate promoter usage in vivo using a double-transgenic rat model,” Mol. Endocrinol.23(4), 529–538 (2009).
[CrossRef] [PubMed]

2008

2007

2005

C. G. Burns, D. J. Milan, E. J. Grande, W. Rottbauer, C. A. MacRae, and M. C. Fishman, “High-throughput assay for small molecules that modulate zebrafish embryonic heart rate,” Nat. Chem. Biol.1(5), 263–264 (2005).
[CrossRef] [PubMed]

2004

M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol.91(4), 1908–1912 (2004).
[CrossRef] [PubMed]

2003

2001

J. Knittel, L. Schnieder, G. Buess, B. Messerschmidt, and T. Possner, “Endoscope-compatible confocal microscope using a gradient index-lens system,” Opt. Commun.188(5–6), 267–273 (2001).
[CrossRef]

R. M. Zucker and O. Price, “Evaluation of confocal microscopy system performance,” Cytometry44(4), 273–294 (2001).
[CrossRef] [PubMed]

1999

T. W. Gardiner and L. A. Toth, “Stereotactic surgery and long-term maintenance of cranial implants in research animals,” Contemp. Top. Lab. Anim. Sci.38(1), 56–63 (1999).
[PubMed]

Adamson, A. D.

S. S. Semprini, S. Friedrichsen, C. V. Harper, J. R. McNeilly, A. D. Adamson, D. G. Spiller, N. Kotelevtseva, G. Brooker, D. G. Brownstein, A. S. McNeilly, M. R. White, J. R. Davis, and J. J. Mullins, “Real-time visualization of human prolactin alternate promoter usage in vivo using a double-transgenic rat model,” Mol. Endocrinol.23(4), 529–538 (2009).
[CrossRef] [PubMed]

Allen, J.

Bao, H.

Brooker, G.

S. S. Semprini, S. Friedrichsen, C. V. Harper, J. R. McNeilly, A. D. Adamson, D. G. Spiller, N. Kotelevtseva, G. Brooker, D. G. Brownstein, A. S. McNeilly, M. R. White, J. R. Davis, and J. J. Mullins, “Real-time visualization of human prolactin alternate promoter usage in vivo using a double-transgenic rat model,” Mol. Endocrinol.23(4), 529–538 (2009).
[CrossRef] [PubMed]

Brownstein, D. G.

S. S. Semprini, S. Friedrichsen, C. V. Harper, J. R. McNeilly, A. D. Adamson, D. G. Spiller, N. Kotelevtseva, G. Brooker, D. G. Brownstein, A. S. McNeilly, M. R. White, J. R. Davis, and J. J. Mullins, “Real-time visualization of human prolactin alternate promoter usage in vivo using a double-transgenic rat model,” Mol. Endocrinol.23(4), 529–538 (2009).
[CrossRef] [PubMed]

Buess, G.

J. Knittel, L. Schnieder, G. Buess, B. Messerschmidt, and T. Possner, “Endoscope-compatible confocal microscope using a gradient index-lens system,” Opt. Commun.188(5–6), 267–273 (2001).
[CrossRef]

Burns, C. G.

C. G. Burns, D. J. Milan, E. J. Grande, W. Rottbauer, C. A. MacRae, and M. C. Fishman, “High-throughput assay for small molecules that modulate zebrafish embryonic heart rate,” Nat. Chem. Biol.1(5), 263–264 (2005).
[CrossRef] [PubMed]

Burns, L. D.

K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. E. Gamal, and M. J. Schnitzer, “Miniaturized integration of a fluorescence microscope,” Nat. Methods8(10), 871–878 (2011).
[CrossRef] [PubMed]

Choe, S. W.

Cocker, E. D.

K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. E. Gamal, and M. J. Schnitzer, “Miniaturized integration of a fluorescence microscope,” Nat. Methods8(10), 871–878 (2011).
[CrossRef] [PubMed]

Davis, J. R.

C. V. Harper, K. Featherstone, S. Semprini, S. Friedrichsen, J. McNeilly, P. Paszek, D. G. Spiller, A. S. McNeilly, J. J. Mullins, J. R. Davis, and M. R. White, “Dynamic organisation of prolactin gene expression in living pituitary tissue,” J. Cell Sci.123(3), 424–430 (2010).
[CrossRef] [PubMed]

S. S. Semprini, S. Friedrichsen, C. V. Harper, J. R. McNeilly, A. D. Adamson, D. G. Spiller, N. Kotelevtseva, G. Brooker, D. G. Brownstein, A. S. McNeilly, M. R. White, J. R. Davis, and J. J. Mullins, “Real-time visualization of human prolactin alternate promoter usage in vivo using a double-transgenic rat model,” Mol. Endocrinol.23(4), 529–538 (2009).
[CrossRef] [PubMed]

Dawson, M. D.

Dombeck, D. A.

M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol.91(4), 1908–1912 (2004).
[CrossRef] [PubMed]

Elson, D. S.

Engelbrecht, C. J.

Featherstone, K.

C. V. Harper, K. Featherstone, S. Semprini, S. Friedrichsen, J. McNeilly, P. Paszek, D. G. Spiller, A. S. McNeilly, J. J. Mullins, J. R. Davis, and M. R. White, “Dynamic organisation of prolactin gene expression in living pituitary tissue,” J. Cell Sci.123(3), 424–430 (2010).
[CrossRef] [PubMed]

Fishman, M. C.

C. G. Burns, D. J. Milan, E. J. Grande, W. Rottbauer, C. A. MacRae, and M. C. Fishman, “High-throughput assay for small molecules that modulate zebrafish embryonic heart rate,” Nat. Chem. Biol.1(5), 263–264 (2005).
[CrossRef] [PubMed]

French, P. M. W.

Friedrichsen, S.

C. V. Harper, K. Featherstone, S. Semprini, S. Friedrichsen, J. McNeilly, P. Paszek, D. G. Spiller, A. S. McNeilly, J. J. Mullins, J. R. Davis, and M. R. White, “Dynamic organisation of prolactin gene expression in living pituitary tissue,” J. Cell Sci.123(3), 424–430 (2010).
[CrossRef] [PubMed]

S. S. Semprini, S. Friedrichsen, C. V. Harper, J. R. McNeilly, A. D. Adamson, D. G. Spiller, N. Kotelevtseva, G. Brooker, D. G. Brownstein, A. S. McNeilly, M. R. White, J. R. Davis, and J. J. Mullins, “Real-time visualization of human prolactin alternate promoter usage in vivo using a double-transgenic rat model,” Mol. Endocrinol.23(4), 529–538 (2009).
[CrossRef] [PubMed]

Gamal, A. E.

K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. E. Gamal, and M. J. Schnitzer, “Miniaturized integration of a fluorescence microscope,” Nat. Methods8(10), 871–878 (2011).
[CrossRef] [PubMed]

Gardiner, T. W.

T. W. Gardiner and L. A. Toth, “Stereotactic surgery and long-term maintenance of cranial implants in research animals,” Contemp. Top. Lab. Anim. Sci.38(1), 56–63 (1999).
[PubMed]

Ghosh, K. K.

K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. E. Gamal, and M. J. Schnitzer, “Miniaturized integration of a fluorescence microscope,” Nat. Methods8(10), 871–878 (2011).
[CrossRef] [PubMed]

Girkin, M.

Grande, E. J.

C. G. Burns, D. J. Milan, E. J. Grande, W. Rottbauer, C. A. MacRae, and M. C. Fishman, “High-throughput assay for small molecules that modulate zebrafish embryonic heart rate,” Nat. Chem. Biol.1(5), 263–264 (2005).
[CrossRef] [PubMed]

Griffin, C.

Gu, E.

Gu, M.

Guo, S.

Harper, C. V.

C. V. Harper, K. Featherstone, S. Semprini, S. Friedrichsen, J. McNeilly, P. Paszek, D. G. Spiller, A. S. McNeilly, J. J. Mullins, J. R. Davis, and M. R. White, “Dynamic organisation of prolactin gene expression in living pituitary tissue,” J. Cell Sci.123(3), 424–430 (2010).
[CrossRef] [PubMed]

S. S. Semprini, S. Friedrichsen, C. V. Harper, J. R. McNeilly, A. D. Adamson, D. G. Spiller, N. Kotelevtseva, G. Brooker, D. G. Brownstein, A. S. McNeilly, M. R. White, J. R. Davis, and J. J. Mullins, “Real-time visualization of human prolactin alternate promoter usage in vivo using a double-transgenic rat model,” Mol. Endocrinol.23(4), 529–538 (2009).
[CrossRef] [PubMed]

Helmchen, F.

Johnston, R. S.

Jung, J. C.

Kasischke, K. A.

M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol.91(4), 1908–1912 (2004).
[CrossRef] [PubMed]

Kennedy, G. T.

Knittel, J.

J. Knittel, L. Schnieder, G. Buess, B. Messerschmidt, and T. Possner, “Endoscope-compatible confocal microscope using a gradient index-lens system,” Opt. Commun.188(5–6), 267–273 (2001).
[CrossRef]

Kotelevtseva, N.

S. S. Semprini, S. Friedrichsen, C. V. Harper, J. R. McNeilly, A. D. Adamson, D. G. Spiller, N. Kotelevtseva, G. Brooker, D. G. Brownstein, A. S. McNeilly, M. R. White, J. R. Davis, and J. J. Mullins, “Real-time visualization of human prolactin alternate promoter usage in vivo using a double-transgenic rat model,” Mol. Endocrinol.23(4), 529–538 (2009).
[CrossRef] [PubMed]

Levene, M. J.

M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol.91(4), 1908–1912 (2004).
[CrossRef] [PubMed]

Li, X.

X. Li and W. Yu, “Deep tissue microscopic imaging of the kidney with a gradient-index lens system,” Opt. Commun.281(7), 1833–1840 (2008).
[CrossRef] [PubMed]

Liu, L.

MacRae, C. A.

C. G. Burns, D. J. Milan, E. J. Grande, W. Rottbauer, C. A. MacRae, and M. C. Fishman, “High-throughput assay for small molecules that modulate zebrafish embryonic heart rate,” Nat. Chem. Biol.1(5), 263–264 (2005).
[CrossRef] [PubMed]

McNeilly, A. S.

C. V. Harper, K. Featherstone, S. Semprini, S. Friedrichsen, J. McNeilly, P. Paszek, D. G. Spiller, A. S. McNeilly, J. J. Mullins, J. R. Davis, and M. R. White, “Dynamic organisation of prolactin gene expression in living pituitary tissue,” J. Cell Sci.123(3), 424–430 (2010).
[CrossRef] [PubMed]

S. S. Semprini, S. Friedrichsen, C. V. Harper, J. R. McNeilly, A. D. Adamson, D. G. Spiller, N. Kotelevtseva, G. Brooker, D. G. Brownstein, A. S. McNeilly, M. R. White, J. R. Davis, and J. J. Mullins, “Real-time visualization of human prolactin alternate promoter usage in vivo using a double-transgenic rat model,” Mol. Endocrinol.23(4), 529–538 (2009).
[CrossRef] [PubMed]

McNeilly, J.

C. V. Harper, K. Featherstone, S. Semprini, S. Friedrichsen, J. McNeilly, P. Paszek, D. G. Spiller, A. S. McNeilly, J. J. Mullins, J. R. Davis, and M. R. White, “Dynamic organisation of prolactin gene expression in living pituitary tissue,” J. Cell Sci.123(3), 424–430 (2010).
[CrossRef] [PubMed]

McNeilly, J. R.

S. S. Semprini, S. Friedrichsen, C. V. Harper, J. R. McNeilly, A. D. Adamson, D. G. Spiller, N. Kotelevtseva, G. Brooker, D. G. Brownstein, A. S. McNeilly, M. R. White, J. R. Davis, and J. J. Mullins, “Real-time visualization of human prolactin alternate promoter usage in vivo using a double-transgenic rat model,” Mol. Endocrinol.23(4), 529–538 (2009).
[CrossRef] [PubMed]

Messerschmidt, B.

J. Knittel, L. Schnieder, G. Buess, B. Messerschmidt, and T. Possner, “Endoscope-compatible confocal microscope using a gradient index-lens system,” Opt. Commun.188(5–6), 267–273 (2001).
[CrossRef]

Milan, D. J.

C. G. Burns, D. J. Milan, E. J. Grande, W. Rottbauer, C. A. MacRae, and M. C. Fishman, “High-throughput assay for small molecules that modulate zebrafish embryonic heart rate,” Nat. Chem. Biol.1(5), 263–264 (2005).
[CrossRef] [PubMed]

Molloy, R. P.

M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol.91(4), 1908–1912 (2004).
[CrossRef] [PubMed]

Mullins, J. J.

C. V. Harper, K. Featherstone, S. Semprini, S. Friedrichsen, J. McNeilly, P. Paszek, D. G. Spiller, A. S. McNeilly, J. J. Mullins, J. R. Davis, and M. R. White, “Dynamic organisation of prolactin gene expression in living pituitary tissue,” J. Cell Sci.123(3), 424–430 (2010).
[CrossRef] [PubMed]

S. S. Semprini, S. Friedrichsen, C. V. Harper, J. R. McNeilly, A. D. Adamson, D. G. Spiller, N. Kotelevtseva, G. Brooker, D. G. Brownstein, A. S. McNeilly, M. R. White, J. R. Davis, and J. J. Mullins, “Real-time visualization of human prolactin alternate promoter usage in vivo using a double-transgenic rat model,” Mol. Endocrinol.23(4), 529–538 (2009).
[CrossRef] [PubMed]

Neil, M. A. A.

Nimmerjahn, A.

K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. E. Gamal, and M. J. Schnitzer, “Miniaturized integration of a fluorescence microscope,” Nat. Methods8(10), 871–878 (2011).
[CrossRef] [PubMed]

Oddos, S.

Paszek, P.

C. V. Harper, K. Featherstone, S. Semprini, S. Friedrichsen, J. McNeilly, P. Paszek, D. G. Spiller, A. S. McNeilly, J. J. Mullins, J. R. Davis, and M. R. White, “Dynamic organisation of prolactin gene expression in living pituitary tissue,” J. Cell Sci.123(3), 424–430 (2010).
[CrossRef] [PubMed]

Pattie, R.

Poher, V.

Possner, T.

J. Knittel, L. Schnieder, G. Buess, B. Messerschmidt, and T. Possner, “Endoscope-compatible confocal microscope using a gradient index-lens system,” Opt. Commun.188(5–6), 267–273 (2001).
[CrossRef]

Price, O.

R. M. Zucker and O. Price, “Evaluation of confocal microscopy system performance,” Cytometry44(4), 273–294 (2001).
[CrossRef] [PubMed]

Rottbauer, W.

C. G. Burns, D. J. Milan, E. J. Grande, W. Rottbauer, C. A. MacRae, and M. C. Fishman, “High-throughput assay for small molecules that modulate zebrafish embryonic heart rate,” Nat. Chem. Biol.1(5), 263–264 (2005).
[CrossRef] [PubMed]

Schnieder, L.

J. Knittel, L. Schnieder, G. Buess, B. Messerschmidt, and T. Possner, “Endoscope-compatible confocal microscope using a gradient index-lens system,” Opt. Commun.188(5–6), 267–273 (2001).
[CrossRef]

Schnitzer, M. J.

K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. E. Gamal, and M. J. Schnitzer, “Miniaturized integration of a fluorescence microscope,” Nat. Methods8(10), 871–878 (2011).
[CrossRef] [PubMed]

J. C. Jung and M. J. Schnitzer, “Multiphoton endoscopy,” Opt. Lett.28(11), 902–904 (2003).
[CrossRef] [PubMed]

Seibel, E. J.

Semprini, S.

C. V. Harper, K. Featherstone, S. Semprini, S. Friedrichsen, J. McNeilly, P. Paszek, D. G. Spiller, A. S. McNeilly, J. J. Mullins, J. R. Davis, and M. R. White, “Dynamic organisation of prolactin gene expression in living pituitary tissue,” J. Cell Sci.123(3), 424–430 (2010).
[CrossRef] [PubMed]

Semprini, S. S.

S. S. Semprini, S. Friedrichsen, C. V. Harper, J. R. McNeilly, A. D. Adamson, D. G. Spiller, N. Kotelevtseva, G. Brooker, D. G. Brownstein, A. S. McNeilly, M. R. White, J. R. Davis, and J. J. Mullins, “Real-time visualization of human prolactin alternate promoter usage in vivo using a double-transgenic rat model,” Mol. Endocrinol.23(4), 529–538 (2009).
[CrossRef] [PubMed]

Sorg, B. S.

Spiller, D. G.

C. V. Harper, K. Featherstone, S. Semprini, S. Friedrichsen, J. McNeilly, P. Paszek, D. G. Spiller, A. S. McNeilly, J. J. Mullins, J. R. Davis, and M. R. White, “Dynamic organisation of prolactin gene expression in living pituitary tissue,” J. Cell Sci.123(3), 424–430 (2010).
[CrossRef] [PubMed]

S. S. Semprini, S. Friedrichsen, C. V. Harper, J. R. McNeilly, A. D. Adamson, D. G. Spiller, N. Kotelevtseva, G. Brooker, D. G. Brownstein, A. S. McNeilly, M. R. White, J. R. Davis, and J. J. Mullins, “Real-time visualization of human prolactin alternate promoter usage in vivo using a double-transgenic rat model,” Mol. Endocrinol.23(4), 529–538 (2009).
[CrossRef] [PubMed]

Sun, J.

Toth, L. A.

T. W. Gardiner and L. A. Toth, “Stereotactic surgery and long-term maintenance of cranial implants in research animals,” Contemp. Top. Lab. Anim. Sci.38(1), 56–63 (1999).
[PubMed]

Vance, R.

Webb, W. W.

M. J. Levene, D. A. Dombeck, K. A. Kasischke, R. P. Molloy, and W. W. Webb, “In vivo multiphoton microscopy of deep brain tissue,” J. Neurophysiol.91(4), 1908–1912 (2004).
[CrossRef] [PubMed]

White, M. R.

C. V. Harper, K. Featherstone, S. Semprini, S. Friedrichsen, J. McNeilly, P. Paszek, D. G. Spiller, A. S. McNeilly, J. J. Mullins, J. R. Davis, and M. R. White, “Dynamic organisation of prolactin gene expression in living pituitary tissue,” J. Cell Sci.123(3), 424–430 (2010).
[CrossRef] [PubMed]

S. S. Semprini, S. Friedrichsen, C. V. Harper, J. R. McNeilly, A. D. Adamson, D. G. Spiller, N. Kotelevtseva, G. Brooker, D. G. Brownstein, A. S. McNeilly, M. R. White, J. R. Davis, and J. J. Mullins, “Real-time visualization of human prolactin alternate promoter usage in vivo using a double-transgenic rat model,” Mol. Endocrinol.23(4), 529–538 (2009).
[CrossRef] [PubMed]

Wu, L.

Xie, H.

Yu, W.

X. Li and W. Yu, “Deep tissue microscopic imaging of the kidney with a gradient-index lens system,” Opt. Commun.281(7), 1833–1840 (2008).
[CrossRef] [PubMed]

Zhang, H. X.

Ziv, Y.

K. K. Ghosh, L. D. Burns, E. D. Cocker, A. Nimmerjahn, Y. Ziv, A. E. Gamal, and M. J. Schnitzer, “Miniaturized integration of a fluorescence microscope,” Nat. Methods8(10), 871–878 (2011).
[CrossRef] [PubMed]

Zucker, R. M.

R. M. Zucker and O. Price, “Evaluation of confocal microscopy system performance,” Cytometry44(4), 273–294 (2001).
[CrossRef] [PubMed]

Contemp. Top. Lab. Anim. Sci.

T. W. Gardiner and L. A. Toth, “Stereotactic surgery and long-term maintenance of cranial implants in research animals,” Contemp. Top. Lab. Anim. Sci.38(1), 56–63 (1999).
[PubMed]

Cytometry

R. M. Zucker and O. Price, “Evaluation of confocal microscopy system performance,” Cytometry44(4), 273–294 (2001).
[CrossRef] [PubMed]

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Figures (3)

Fig. 1
Fig. 1

Optical path of the instrument. 405 nm light is delivered to the probe by a single mode fiber. This light is expanded into a collimated beam by a fiber coupler. The central 0.5 mm of this beam is incident upon the proximal end of the GRIN rod. This light emerges as a collimated beam at the distal end (not shown), where it causes fluorescence of biomarkers. The GRIN rod reimages this fluorescent light to its proximal end. The proximal end of the rod is reimaged onto a detector by lens L1. A dichroic beamsplitter separates excitation and emission light.

Fig. 2
Fig. 2

Measured efficiency of the widefield probe as a function of radius from the center of the field of view. This is the combined effect of vignetting of the GRIN rod on the pupil-plane relay of illumination light and image-plane relay of collected fluorescence light.

Fig. 3
Fig. 3

Example images taken with the epi-fluorescence GRIN probe. (a) Pollen grains on a test sample visible through auto-fluorescence (b) Ex vivo image showing GFP expression in the myocardium of an adult Tg(cmlc2:GFP) transgenic zebrafish heart. (c) In vivo image of individual cells expressing EGFP as a reporter gene for prolactin on the surface of the pituitary gland in a rat model. It appears that the probe has been placed towards the edge of the gland, covering approximately one quadrant of the field of view.

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