Abstract

The influence of chromatic aberration of an objective lens in two-photon fluorescence (TPF) endospectroscopy of scattering media has been systematically investigated through both experiments and numerical simulations. Experiments were carried out on a uniform 3D scattering gelatin phantom embedded with TiO2 granules (to mimic tissue scattering) and fluorescein-tagged polystyrene beads. It was found that fluorescence spectral intensity and lineshape varied as a function of depth when measured with a gradient-index (GRIN) lens which has severe chromatic aberration. The spectral distortion caused by the chromatic aberration became diminishing as the imaging depth increased. Ray tracing analysis and Monte Carlo simulations were carried out to study the interplay of chromatic aberration and scattering in the depth-resolved TPF spectra. The simulation results suggest that the collected fluorescence signals from deeper layers included more out-of-focus photons that experienced a few or multiple scatterings, which diminish the influence of chromatic aberration on the measured TPF spectra. The simulated collection efficiencies of TPF at different wavelengths and depths can be used to properly recover the true depth-resolved TPF spectra of a relatively uniform scattering medium.

© 2010 OSA

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2009 (2)

2007 (1)

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

2006 (2)

2005 (2)

2004 (4)

S. K. Chang, D. Arifler, R. Drezek, M. Follen, and R. Richards-Kortum, “Analytical model to describe fluorescence spectra of normal and preneoplastic epithelial tissue: comparison with Monte Carlo simulations and clinical measurements,” J. Biomed. Opt. 9(3), 511–522 (2004).
[CrossRef] [PubMed]

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[CrossRef] [PubMed]

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[CrossRef] [PubMed]

X. M. Liu, M. J. Cobb, Y. C. Chen, M. B. Kimmey, and X. D. Li, “Rapid-scanning forward-imaging miniature endoscope for real-time optical coherence tomography,” Opt. Lett. 29(15), 1763–1765 (2004).
[CrossRef] [PubMed]

2003 (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]

T. Collier, D. Arifler, A. Malpica, M. Follen, and R. Richards-Kortum, “Determination of epithelial tissue scattering coefficient using confocal microscopy,” IEEE J. Quantum Electron. 9(2), 307–313 (2003).
[CrossRef]

2001 (2)

E. Beaurepaire, M. Oheim, and J. Mertz, “Ultra-deep two-photon fluorescence excitation in turbid media,” Opt. Commun. 188(1-4), 25–29 (2001).
[CrossRef]

R. Drezek, K. Sokolov, U. Utzinger, I. Boiko, A. Malpica, M. Follen, and R. Richards-Kortum, “Understanding the contributions of NADH and collagen to cervical tissue fluorescence spectra: modeling, measurements, and implications,” J. Biomed. Opt. 6(4), 385–396 (2001).
[CrossRef] [PubMed]

2000 (1)

1997 (1)

1996 (2)

1994 (1)

1990 (1)

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248(4951), 73–76 (1990).
[CrossRef] [PubMed]

Aksay, E.

J. C. Jung, A. D. Mehta, E. Aksay, R. Stepnoski, and M. J. Schnitzer, “In vivo mammalian brain imaging using one- and two-photon fluorescence microendoscopy,” J. Neurophysiol. 92(5), 3121–3133 (2004).
[CrossRef] [PubMed]

Alfano, R. R.

Anderson, E. P.

Arifler, D.

S. K. Chang, D. Arifler, R. Drezek, M. Follen, and R. Richards-Kortum, “Analytical model to describe fluorescence spectra of normal and preneoplastic epithelial tissue: comparison with Monte Carlo simulations and clinical measurements,” J. Biomed. Opt. 9(3), 511–522 (2004).
[CrossRef] [PubMed]

T. Collier, D. Arifler, A. Malpica, M. Follen, and R. Richards-Kortum, “Determination of epithelial tissue scattering coefficient using confocal microscopy,” IEEE J. Quantum Electron. 9(2), 307–313 (2003).
[CrossRef]

Beaurepaire, E.

E. Beaurepaire, M. Oheim, and J. Mertz, “Ultra-deep two-photon fluorescence excitation in turbid media,” Opt. Commun. 188(1-4), 25–29 (2001).
[CrossRef]

Ben-Letaief, K.

Berns, M. W.

Boiko, I.

R. Drezek, K. Sokolov, U. Utzinger, I. Boiko, A. Malpica, M. Follen, and R. Richards-Kortum, “Understanding the contributions of NADH and collagen to cervical tissue fluorescence spectra: modeling, measurements, and implications,” J. Biomed. Opt. 6(4), 385–396 (2001).
[CrossRef] [PubMed]

Bückle, R.

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

Cang, H.

Chang, S. K.

S. K. Chang, D. Arifler, R. Drezek, M. Follen, and R. Richards-Kortum, “Analytical model to describe fluorescence spectra of normal and preneoplastic epithelial tissue: comparison with Monte Carlo simulations and clinical measurements,” J. Biomed. Opt. 9(3), 511–522 (2004).
[CrossRef] [PubMed]

Chen, J. Y.

Chen, Y. C.

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]

Cobb, M. J.

Cocker, E. D.

Coleno, M.

Collier, T.

T. Collier, D. Arifler, A. Malpica, M. Follen, and R. Richards-Kortum, “Determination of epithelial tissue scattering coefficient using confocal microscopy,” IEEE J. Quantum Electron. 9(2), 307–313 (2003).
[CrossRef]

Cranfield, C.

Denk, W.

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248(4951), 73–76 (1990).
[CrossRef] [PubMed]

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]

Drezek, R.

S. K. Chang, D. Arifler, R. Drezek, M. Follen, and R. Richards-Kortum, “Analytical model to describe fluorescence spectra of normal and preneoplastic epithelial tissue: comparison with Monte Carlo simulations and clinical measurements,” J. Biomed. Opt. 9(3), 511–522 (2004).
[CrossRef] [PubMed]

R. Drezek, K. Sokolov, U. Utzinger, I. Boiko, A. Malpica, M. Follen, and R. Richards-Kortum, “Understanding the contributions of NADH and collagen to cervical tissue fluorescence spectra: modeling, measurements, and implications,” J. Biomed. Opt. 6(4), 385–396 (2001).
[CrossRef] [PubMed]

Dunn, A. K.

Ehlers, A.

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

Flusberg, B. A.

Follen, M.

S. K. Chang, D. Arifler, R. Drezek, M. Follen, and R. Richards-Kortum, “Analytical model to describe fluorescence spectra of normal and preneoplastic epithelial tissue: comparison with Monte Carlo simulations and clinical measurements,” J. Biomed. Opt. 9(3), 511–522 (2004).
[CrossRef] [PubMed]

T. Collier, D. Arifler, A. Malpica, M. Follen, and R. Richards-Kortum, “Determination of epithelial tissue scattering coefficient using confocal microscopy,” IEEE J. Quantum Electron. 9(2), 307–313 (2003).
[CrossRef]

R. Drezek, K. Sokolov, U. Utzinger, I. Boiko, A. Malpica, M. Follen, and R. Richards-Kortum, “Understanding the contributions of NADH and collagen to cervical tissue fluorescence spectra: modeling, measurements, and implications,” J. Biomed. Opt. 6(4), 385–396 (2001).
[CrossRef] [PubMed]

Fu, L.

Gu, M.

Guo, Y. C.

Harris, D.

Ho, P. P.

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]

Jain, A.

Jung, J. C.

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]

J. C. Jung, A. D. Mehta, E. Aksay, R. Stepnoski, and M. J. Schnitzer, “In vivo mammalian brain imaging using one- and two-photon fluorescence microendoscopy,” J. Neurophysiol. 92(5), 3121–3133 (2004).
[CrossRef] [PubMed]

Kaatz, M.

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

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]

Kimmey, M. B.

König, K.

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

Lam, S.

Leng, Y. X.

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. D.

Li, Z. Y.

Liu, F.

Liu, X. M.

Macaulay, C.

MacDonald, D. J.

Malpica, A.

T. Collier, D. Arifler, A. Malpica, M. Follen, and R. Richards-Kortum, “Determination of epithelial tissue scattering coefficient using confocal microscopy,” IEEE J. Quantum Electron. 9(2), 307–313 (2003).
[CrossRef]

R. Drezek, K. Sokolov, U. Utzinger, I. Boiko, A. Malpica, M. Follen, and R. Richards-Kortum, “Understanding the contributions of NADH and collagen to cervical tissue fluorescence spectra: modeling, measurements, and implications,” J. Biomed. Opt. 6(4), 385–396 (2001).
[CrossRef] [PubMed]

Mehta, A. D.

J. C. Jung, A. D. Mehta, E. Aksay, R. Stepnoski, and M. J. Schnitzer, “In vivo mammalian brain imaging using one- and two-photon fluorescence microendoscopy,” J. Neurophysiol. 92(5), 3121–3133 (2004).
[CrossRef] [PubMed]

Mertz, J.

E. Beaurepaire, M. Oheim, and J. Mertz, “Ultra-deep two-photon fluorescence excitation in turbid media,” Opt. Commun. 188(1-4), 25–29 (2001).
[CrossRef]

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]

Myaing, M. T.

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]

Oheim, M.

E. Beaurepaire, M. Oheim, and J. Mertz, “Ultra-deep two-photon fluorescence excitation in turbid media,” Opt. Commun. 188(1-4), 25–29 (2001).
[CrossRef]

Palcic, B.

Qu, J. N.

Richards-Kortum, R.

S. K. Chang, D. Arifler, R. Drezek, M. Follen, and R. Richards-Kortum, “Analytical model to describe fluorescence spectra of normal and preneoplastic epithelial tissue: comparison with Monte Carlo simulations and clinical measurements,” J. Biomed. Opt. 9(3), 511–522 (2004).
[CrossRef] [PubMed]

T. Collier, D. Arifler, A. Malpica, M. Follen, and R. Richards-Kortum, “Determination of epithelial tissue scattering coefficient using confocal microscopy,” IEEE J. Quantum Electron. 9(2), 307–313 (2003).
[CrossRef]

R. Drezek, K. Sokolov, U. Utzinger, I. Boiko, A. Malpica, M. Follen, and R. Richards-Kortum, “Understanding the contributions of NADH and collagen to cervical tissue fluorescence spectra: modeling, measurements, and implications,” J. Biomed. Opt. 6(4), 385–396 (2001).
[CrossRef] [PubMed]

A. K. Dunn, C. Smithpeter, A. J. Welch, and R. Richards-Kortum, “Sources of contrast in confocal reflectance imaging,” Appl. Opt. 35(19), 3441–3446 (1996).
[CrossRef]

Riemann, I.

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

Sacks, P.

Savage, H.

Schantz, S.

Schenkl, S.

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

Schmitt, J. M.

Schnitzer, M. J.

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]

J. C. Jung, A. D. Mehta, E. Aksay, R. Stepnoski, and M. J. Schnitzer, “In vivo mammalian brain imaging using one- and two-photon fluorescence microendoscopy,” J. Neurophysiol. 92(5), 3121–3133 (2004).
[CrossRef] [PubMed]

Smithpeter, C.

Sokolov, K.

R. Drezek, K. Sokolov, U. Utzinger, I. Boiko, A. Malpica, M. Follen, and R. Richards-Kortum, “Understanding the contributions of NADH and collagen to cervical tissue fluorescence spectra: modeling, measurements, and implications,” J. Biomed. Opt. 6(4), 385–396 (2001).
[CrossRef] [PubMed]

Stepnoski, R.

J. C. Jung, A. D. Mehta, E. Aksay, R. Stepnoski, and M. J. Schnitzer, “In vivo mammalian brain imaging using one- and two-photon fluorescence microendoscopy,” J. Neurophysiol. 92(5), 3121–3133 (2004).
[CrossRef] [PubMed]

Strickler, J. H.

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248(4951), 73–76 (1990).
[CrossRef] [PubMed]

Sun, T.

Tromberg, B. J.

Utzinger, U.

R. Drezek, K. Sokolov, U. Utzinger, I. Boiko, A. Malpica, M. Follen, and R. Richards-Kortum, “Understanding the contributions of NADH and collagen to cervical tissue fluorescence spectra: modeling, measurements, and implications,” J. Biomed. Opt. 6(4), 385–396 (2001).
[CrossRef] [PubMed]

Wallace, V. P.

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]

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. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248(4951), 73–76 (1990).
[CrossRef] [PubMed]

Welch, A. J.

Wiley, B. J.

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]

Wu, Y. C.

Xi, J. F.

Xia, Y. N.

Xie, H. K.

Zhadin, N.

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]

Appl. Opt. (3)

IEEE J. Quantum Electron. (1)

T. Collier, D. Arifler, A. Malpica, M. Follen, and R. Richards-Kortum, “Determination of epithelial tissue scattering coefficient using confocal microscopy,” IEEE J. Quantum Electron. 9(2), 307–313 (2003).
[CrossRef]

J. Biomed. Opt. (2)

S. K. Chang, D. Arifler, R. Drezek, M. Follen, and R. Richards-Kortum, “Analytical model to describe fluorescence spectra of normal and preneoplastic epithelial tissue: comparison with Monte Carlo simulations and clinical measurements,” J. Biomed. Opt. 9(3), 511–522 (2004).
[CrossRef] [PubMed]

R. Drezek, K. Sokolov, U. Utzinger, I. Boiko, A. Malpica, M. Follen, and R. Richards-Kortum, “Understanding the contributions of NADH and collagen to cervical tissue fluorescence spectra: modeling, measurements, and implications,” J. Biomed. Opt. 6(4), 385–396 (2001).
[CrossRef] [PubMed]

J. Neurophysiol. (2)

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]

J. C. Jung, A. D. Mehta, E. Aksay, R. Stepnoski, and M. J. Schnitzer, “In vivo mammalian brain imaging using one- and two-photon fluorescence microendoscopy,” J. Neurophysiol. 92(5), 3121–3133 (2004).
[CrossRef] [PubMed]

J. Opt. Soc. Am. A (1)

Microsc. Res. Tech. (1)

K. König, A. Ehlers, I. Riemann, S. Schenkl, R. Bückle, and M. Kaatz, “Clinical two-photon microendoscopy,” Microsc. Res. Tech. 70(5), 398–402 (2007).
[CrossRef] [PubMed]

Opt. Commun. (1)

E. Beaurepaire, M. Oheim, and J. Mertz, “Ultra-deep two-photon fluorescence excitation in turbid media,” Opt. Commun. 188(1-4), 25–29 (2001).
[CrossRef]

Opt. Express (2)

Opt. Lett. (6)

Proc. Natl. Acad. Sci. U.S.A. (1)

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

Science (1)

W. Denk, J. H. Strickler, and W. W. Webb, “Two-photon laser scanning fluorescence microscopy,” Science 248(4951), 73–76 (1990).
[CrossRef] [PubMed]

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Figures (8)

Fig. 1
Fig. 1

(a) Schematic of the beam paths of double-clad fiber based endospectroscopy probe; (b) Schematic of the endospectroscopy system with chromatic and achromatic lenses. DM: dichroic mirror; FL: focusing lens; CL: coupling lens; DCF: double-clad fiber; PZT: piezoelectric transducer. In the aberrated system, a GRIN lens was used as the focusing unit. In the perfect achromatic system, a 10x/0.2NA Zeiss microscope objective was used to collimate the light from DCF, and a 20x/0.4 NA Zeiss microscope objective was used to focus the light to the sample.

Fig. 2
Fig. 2

Geometry of the two-photon excitation and collection used in the combined ray-tracing simulation and Monte Carlo model.

Fig. 3
Fig. 3

(a) Normalized depth-resolved TPF spectra of the fluorescent beads phantom when measured with the GRIN lens; (b) Normalized depth-dependent TPF intensities at 470 nm and 570 nm when measured with the GRIN lens and achromatic microscope objective lens.

Fig. 4
Fig. 4

Normalized TPF spectra of the beads phantom measured with the GRIN lens and the achromatic microscope objective lens from (a) surface and (b) 240 µm depth.

Fig. 5
Fig. 5

Simulated depth-resolved TPF photons at 400, 500, and 650 nm collected with a GRIN lens and TPF photons at 650 nm collected with an achromatic lens: (a) total detected photons; (b) after normalization.

Fig. 6
Fig. 6

(a & b) Simulated TPF photons with single scattering and multiple scattering at (a) 650 nm and (b) 450 nm; (c & d) Simulated TPF photons at different chromatic focal shifts (0.3 and 1.2 mm) and scattering coefficients (26.8 and 42.6 cm−1) with (c) single scattering event and (d) multiple scattering events.

Fig. 7
Fig. 7

(a) Simulated collection efficiency of the TPF photons from the surface, 100 µm and 240 µm depth. The collection efficiency is defined as the ratio of the chromatic system to the achromatic system at each wavelength and depth. (b) Measured and calibrated depth-resolved TPF spectra acquired with the GRIN lens.

Fig. 8
Fig. 8

(a) Factor of collection efficiency enhancement of TPF spectral signals from the surface, 100 µm and 240 µm depth when using (a) a double-clad fiber with 200 µm inner clad; and (b) a 350 um long multimode fiber collector over a double-clad fiber with 135 µm inner clad.

Tables (1)

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Table 1 Optical properties of the phantom and the chromatic focal shift of the GIRN lens used in the simulations at the excitation and emission wavelengths

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