Abstract

We report a new time-resolved optical measurement method which combines single photon counting and the spread spectrum time-resolved optical measurement method. A laser diode modulated with pseudo-random bit sequences replaces the short pulse laser used in conventional time-resolved optical systems, while a single photon detector records the pulse sequence in response to the modulated excitation. Periodic cross-correlation is used to retrieve the impulse response. Feasibility of our approach is validated experimentally. A rise time around 150 picoseconds has been achieved with our prototype. Besides high temporal resolution, the new method also affords other benefits such as high photon counting rate, fast data acquisition, portability, and low cost.

© 2008 Optical Society of America

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  1. M. S. Patterson, B. Chance, and B. C. Wilson, "Time resolved reflectance and transmittance for the noninvasive measurement of tissue optical properties," Appl. Opt. 28, 2331-2336 (1989).
    [CrossRef] [PubMed]
  2. J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, K.W. Berndt, and M. Johnson, "Fluorescence lifetime imaging," Anal. Biochem. 202, 316-330 (1992).
    [CrossRef] [PubMed]
  3. P. I. H. Bastiaens and A. Squire, "Fluorescence lifetime imaging microscopy: spatial resolution of biochemical processes in the cell," Trends Cell Biol. 9, 48-52 (1999).
    [CrossRef] [PubMed]
  4. F. Gao, H. J. Zhao, and Y. Yamada, "Improvement of Image Quality in Diffuse Optical Tomography by use of Full Time-Resolved Data," Appl. Opt. 41, 778-791 (2002).
    [CrossRef] [PubMed]
  5. M. Essenpreis, C. E. Elwell, M. Cope, P. van der Zee, S. R. Arridge, and D. T. Delpy, "Spectral dependence of temporal point spread functions in human tissues," Appl. Opt. 32, 418-425 (1993).
    [CrossRef] [PubMed]
  6. W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, "Fluorescence lifetime imaging by time-correlated single-photon counting," Microsc. Res. Tech. 63, 58-66 (2004).
    [CrossRef]
  7. D. V. O'Connor and D. Phillips, "Basic Principle of the Single Photon Counting Lifetime Measurement," in Time-correlated single photon counting, (Academic, 1984), pp. 36-54.
  8. Becker & Hickl GmbH, "The bh TCSPC handbook,"http://www.becker-hickl.com/literature.htm.
  9. D. Grosenick, H. Wabnitz, H. H. Rinneberg, K. T. Moesta, and P. M. Schlag, "Development of a Time-Domain Optical Mammograph and First in vivo Applications," Appl. Opt. 38, 2927-2943 (1999).
    [CrossRef]
  10. R. Cubeddu, A. Pifferi, P. Taroni, A. Torricelli, and G. Valentini, "Compact Tissue Oximeter Based on Dual-Wavelength Multichannel Time-Resolved Reflectance," Appl. Opt. 38, 3670-3680 (1999).
    [CrossRef]
  11. M. Prummer, C. G. Hübner, B. Sick, B. Hecht, A. Renn, and U. P. Wild, "Single-Molecule Identification by Spectrally and Time-Resolved Fluorescence Detection," Anal. Chem. 72, 443 - 447 (2000).
    [CrossRef] [PubMed]
  12. P. Schwille, S. Kummer, A. A. Heikal, W. E. Moerner, and W. W. Webb, "Fluorescence correlation spectroscopy reveals fast optical excitation-driven intramolecular dynamics of yellow fluorescent proteins," PNAS,  97, 151-156 (2000)
    [CrossRef] [PubMed]
  13. H. Eda, I. Oda, Y. Ito, Y. Wada, Y. Oikawa, Y. Tsunazawa, and M. Takada, "Multichannel time-resolved optical tomographic imaging system," Rev. Sci. Instrum. 70, 3595-3602 (1999).
    [CrossRef]
  14. F. E. W. Schmidt, M. E. Fry, E. M. C. Hillman, J. C. Hebden, and D. T. Delpy, "A 32-channel time-resolved instrument for medical optical tomography," Rev. Sci. Instrum. 71, 256-265 (2000).
    [CrossRef]
  15. N. G. Chen and Q. Zhu, "Time-resolved diffusive optical tomography using pseudo-random sequences," Opt. Express. 11, 3445-3454 (2003).
    [CrossRef] [PubMed]
  16. N. G. Chen and Q. Zhu, "Time-resolved optical measurements with spread spectrum excitations," Opt. Lett. 27, 1806-1808 (2002).
    [CrossRef]
  17. N. G. Chen and Q. Zhu, "Spread spectrum time-resolved photon migration imaging system: the principle and simulation results," Proc. SPIE 4955, 474-479 (2003).
    [CrossRef]

2004 (1)

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, "Fluorescence lifetime imaging by time-correlated single-photon counting," Microsc. Res. Tech. 63, 58-66 (2004).
[CrossRef]

2003 (2)

N. G. Chen and Q. Zhu, "Spread spectrum time-resolved photon migration imaging system: the principle and simulation results," Proc. SPIE 4955, 474-479 (2003).
[CrossRef]

N. G. Chen and Q. Zhu, "Time-resolved diffusive optical tomography using pseudo-random sequences," Opt. Express. 11, 3445-3454 (2003).
[CrossRef] [PubMed]

2002 (2)

2000 (3)

F. E. W. Schmidt, M. E. Fry, E. M. C. Hillman, J. C. Hebden, and D. T. Delpy, "A 32-channel time-resolved instrument for medical optical tomography," Rev. Sci. Instrum. 71, 256-265 (2000).
[CrossRef]

M. Prummer, C. G. Hübner, B. Sick, B. Hecht, A. Renn, and U. P. Wild, "Single-Molecule Identification by Spectrally and Time-Resolved Fluorescence Detection," Anal. Chem. 72, 443 - 447 (2000).
[CrossRef] [PubMed]

P. Schwille, S. Kummer, A. A. Heikal, W. E. Moerner, and W. W. Webb, "Fluorescence correlation spectroscopy reveals fast optical excitation-driven intramolecular dynamics of yellow fluorescent proteins," PNAS,  97, 151-156 (2000)
[CrossRef] [PubMed]

1999 (4)

H. Eda, I. Oda, Y. Ito, Y. Wada, Y. Oikawa, Y. Tsunazawa, and M. Takada, "Multichannel time-resolved optical tomographic imaging system," Rev. Sci. Instrum. 70, 3595-3602 (1999).
[CrossRef]

P. I. H. Bastiaens and A. Squire, "Fluorescence lifetime imaging microscopy: spatial resolution of biochemical processes in the cell," Trends Cell Biol. 9, 48-52 (1999).
[CrossRef] [PubMed]

D. Grosenick, H. Wabnitz, H. H. Rinneberg, K. T. Moesta, and P. M. Schlag, "Development of a Time-Domain Optical Mammograph and First in vivo Applications," Appl. Opt. 38, 2927-2943 (1999).
[CrossRef]

R. Cubeddu, A. Pifferi, P. Taroni, A. Torricelli, and G. Valentini, "Compact Tissue Oximeter Based on Dual-Wavelength Multichannel Time-Resolved Reflectance," Appl. Opt. 38, 3670-3680 (1999).
[CrossRef]

1993 (1)

1992 (1)

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, K.W. Berndt, and M. Johnson, "Fluorescence lifetime imaging," Anal. Biochem. 202, 316-330 (1992).
[CrossRef] [PubMed]

1989 (1)

Arridge, S. R.

Bastiaens, P. I. H.

P. I. H. Bastiaens and A. Squire, "Fluorescence lifetime imaging microscopy: spatial resolution of biochemical processes in the cell," Trends Cell Biol. 9, 48-52 (1999).
[CrossRef] [PubMed]

Becker, W.

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, "Fluorescence lifetime imaging by time-correlated single-photon counting," Microsc. Res. Tech. 63, 58-66 (2004).
[CrossRef]

Benndorf, K.

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, "Fluorescence lifetime imaging by time-correlated single-photon counting," Microsc. Res. Tech. 63, 58-66 (2004).
[CrossRef]

Bergmann, A.

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, "Fluorescence lifetime imaging by time-correlated single-photon counting," Microsc. Res. Tech. 63, 58-66 (2004).
[CrossRef]

Berndt, K.W.

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, K.W. Berndt, and M. Johnson, "Fluorescence lifetime imaging," Anal. Biochem. 202, 316-330 (1992).
[CrossRef] [PubMed]

Biskup, C.

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, "Fluorescence lifetime imaging by time-correlated single-photon counting," Microsc. Res. Tech. 63, 58-66 (2004).
[CrossRef]

Chance, B.

Chen, N. G.

N. G. Chen and Q. Zhu, "Time-resolved diffusive optical tomography using pseudo-random sequences," Opt. Express. 11, 3445-3454 (2003).
[CrossRef] [PubMed]

N. G. Chen and Q. Zhu, "Spread spectrum time-resolved photon migration imaging system: the principle and simulation results," Proc. SPIE 4955, 474-479 (2003).
[CrossRef]

N. G. Chen and Q. Zhu, "Time-resolved optical measurements with spread spectrum excitations," Opt. Lett. 27, 1806-1808 (2002).
[CrossRef]

Cope, M.

Cubeddu, R.

Delpy, D. T.

F. E. W. Schmidt, M. E. Fry, E. M. C. Hillman, J. C. Hebden, and D. T. Delpy, "A 32-channel time-resolved instrument for medical optical tomography," Rev. Sci. Instrum. 71, 256-265 (2000).
[CrossRef]

M. Essenpreis, C. E. Elwell, M. Cope, P. van der Zee, S. R. Arridge, and D. T. Delpy, "Spectral dependence of temporal point spread functions in human tissues," Appl. Opt. 32, 418-425 (1993).
[CrossRef] [PubMed]

Eda, H.

H. Eda, I. Oda, Y. Ito, Y. Wada, Y. Oikawa, Y. Tsunazawa, and M. Takada, "Multichannel time-resolved optical tomographic imaging system," Rev. Sci. Instrum. 70, 3595-3602 (1999).
[CrossRef]

Elwell, C. E.

Essenpreis, M.

Fry, M. E.

F. E. W. Schmidt, M. E. Fry, E. M. C. Hillman, J. C. Hebden, and D. T. Delpy, "A 32-channel time-resolved instrument for medical optical tomography," Rev. Sci. Instrum. 71, 256-265 (2000).
[CrossRef]

Gao, F.

Grosenick, D.

Hebden, J. C.

F. E. W. Schmidt, M. E. Fry, E. M. C. Hillman, J. C. Hebden, and D. T. Delpy, "A 32-channel time-resolved instrument for medical optical tomography," Rev. Sci. Instrum. 71, 256-265 (2000).
[CrossRef]

Hecht, B.

M. Prummer, C. G. Hübner, B. Sick, B. Hecht, A. Renn, and U. P. Wild, "Single-Molecule Identification by Spectrally and Time-Resolved Fluorescence Detection," Anal. Chem. 72, 443 - 447 (2000).
[CrossRef] [PubMed]

Heikal, A. A.

P. Schwille, S. Kummer, A. A. Heikal, W. E. Moerner, and W. W. Webb, "Fluorescence correlation spectroscopy reveals fast optical excitation-driven intramolecular dynamics of yellow fluorescent proteins," PNAS,  97, 151-156 (2000)
[CrossRef] [PubMed]

Hillman, E. M. C.

F. E. W. Schmidt, M. E. Fry, E. M. C. Hillman, J. C. Hebden, and D. T. Delpy, "A 32-channel time-resolved instrument for medical optical tomography," Rev. Sci. Instrum. 71, 256-265 (2000).
[CrossRef]

Hink, M. A.

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, "Fluorescence lifetime imaging by time-correlated single-photon counting," Microsc. Res. Tech. 63, 58-66 (2004).
[CrossRef]

Hübner, C. G.

M. Prummer, C. G. Hübner, B. Sick, B. Hecht, A. Renn, and U. P. Wild, "Single-Molecule Identification by Spectrally and Time-Resolved Fluorescence Detection," Anal. Chem. 72, 443 - 447 (2000).
[CrossRef] [PubMed]

Ito, Y.

H. Eda, I. Oda, Y. Ito, Y. Wada, Y. Oikawa, Y. Tsunazawa, and M. Takada, "Multichannel time-resolved optical tomographic imaging system," Rev. Sci. Instrum. 70, 3595-3602 (1999).
[CrossRef]

Johnson, M.

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, K.W. Berndt, and M. Johnson, "Fluorescence lifetime imaging," Anal. Biochem. 202, 316-330 (1992).
[CrossRef] [PubMed]

König, K.

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, "Fluorescence lifetime imaging by time-correlated single-photon counting," Microsc. Res. Tech. 63, 58-66 (2004).
[CrossRef]

Kummer, S.

P. Schwille, S. Kummer, A. A. Heikal, W. E. Moerner, and W. W. Webb, "Fluorescence correlation spectroscopy reveals fast optical excitation-driven intramolecular dynamics of yellow fluorescent proteins," PNAS,  97, 151-156 (2000)
[CrossRef] [PubMed]

Lakowicz, J. R.

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, K.W. Berndt, and M. Johnson, "Fluorescence lifetime imaging," Anal. Biochem. 202, 316-330 (1992).
[CrossRef] [PubMed]

Moerner, W. E.

P. Schwille, S. Kummer, A. A. Heikal, W. E. Moerner, and W. W. Webb, "Fluorescence correlation spectroscopy reveals fast optical excitation-driven intramolecular dynamics of yellow fluorescent proteins," PNAS,  97, 151-156 (2000)
[CrossRef] [PubMed]

Moesta, K. T.

Nowaczyk, K.

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, K.W. Berndt, and M. Johnson, "Fluorescence lifetime imaging," Anal. Biochem. 202, 316-330 (1992).
[CrossRef] [PubMed]

Oda, I.

H. Eda, I. Oda, Y. Ito, Y. Wada, Y. Oikawa, Y. Tsunazawa, and M. Takada, "Multichannel time-resolved optical tomographic imaging system," Rev. Sci. Instrum. 70, 3595-3602 (1999).
[CrossRef]

Oikawa, Y.

H. Eda, I. Oda, Y. Ito, Y. Wada, Y. Oikawa, Y. Tsunazawa, and M. Takada, "Multichannel time-resolved optical tomographic imaging system," Rev. Sci. Instrum. 70, 3595-3602 (1999).
[CrossRef]

Patterson, M. S.

Pifferi, A.

Prummer, M.

M. Prummer, C. G. Hübner, B. Sick, B. Hecht, A. Renn, and U. P. Wild, "Single-Molecule Identification by Spectrally and Time-Resolved Fluorescence Detection," Anal. Chem. 72, 443 - 447 (2000).
[CrossRef] [PubMed]

Renn, A.

M. Prummer, C. G. Hübner, B. Sick, B. Hecht, A. Renn, and U. P. Wild, "Single-Molecule Identification by Spectrally and Time-Resolved Fluorescence Detection," Anal. Chem. 72, 443 - 447 (2000).
[CrossRef] [PubMed]

Rinneberg, H. H.

Schlag, P. M.

Schmidt, F. E. W.

F. E. W. Schmidt, M. E. Fry, E. M. C. Hillman, J. C. Hebden, and D. T. Delpy, "A 32-channel time-resolved instrument for medical optical tomography," Rev. Sci. Instrum. 71, 256-265 (2000).
[CrossRef]

Schwille, P.

P. Schwille, S. Kummer, A. A. Heikal, W. E. Moerner, and W. W. Webb, "Fluorescence correlation spectroscopy reveals fast optical excitation-driven intramolecular dynamics of yellow fluorescent proteins," PNAS,  97, 151-156 (2000)
[CrossRef] [PubMed]

Sick, B.

M. Prummer, C. G. Hübner, B. Sick, B. Hecht, A. Renn, and U. P. Wild, "Single-Molecule Identification by Spectrally and Time-Resolved Fluorescence Detection," Anal. Chem. 72, 443 - 447 (2000).
[CrossRef] [PubMed]

Squire, A.

P. I. H. Bastiaens and A. Squire, "Fluorescence lifetime imaging microscopy: spatial resolution of biochemical processes in the cell," Trends Cell Biol. 9, 48-52 (1999).
[CrossRef] [PubMed]

Szmacinski, H.

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, K.W. Berndt, and M. Johnson, "Fluorescence lifetime imaging," Anal. Biochem. 202, 316-330 (1992).
[CrossRef] [PubMed]

Takada, M.

H. Eda, I. Oda, Y. Ito, Y. Wada, Y. Oikawa, Y. Tsunazawa, and M. Takada, "Multichannel time-resolved optical tomographic imaging system," Rev. Sci. Instrum. 70, 3595-3602 (1999).
[CrossRef]

Taroni, P.

Torricelli, A.

Tsunazawa, Y.

H. Eda, I. Oda, Y. Ito, Y. Wada, Y. Oikawa, Y. Tsunazawa, and M. Takada, "Multichannel time-resolved optical tomographic imaging system," Rev. Sci. Instrum. 70, 3595-3602 (1999).
[CrossRef]

Valentini, G.

van der Zee, P.

Wabnitz, H.

Wada, Y.

H. Eda, I. Oda, Y. Ito, Y. Wada, Y. Oikawa, Y. Tsunazawa, and M. Takada, "Multichannel time-resolved optical tomographic imaging system," Rev. Sci. Instrum. 70, 3595-3602 (1999).
[CrossRef]

Webb, W. W.

P. Schwille, S. Kummer, A. A. Heikal, W. E. Moerner, and W. W. Webb, "Fluorescence correlation spectroscopy reveals fast optical excitation-driven intramolecular dynamics of yellow fluorescent proteins," PNAS,  97, 151-156 (2000)
[CrossRef] [PubMed]

Wild, U. P.

M. Prummer, C. G. Hübner, B. Sick, B. Hecht, A. Renn, and U. P. Wild, "Single-Molecule Identification by Spectrally and Time-Resolved Fluorescence Detection," Anal. Chem. 72, 443 - 447 (2000).
[CrossRef] [PubMed]

Wilson, B. C.

Yamada, Y.

Zhao, H. J.

Zhu, Q.

N. G. Chen and Q. Zhu, "Time-resolved diffusive optical tomography using pseudo-random sequences," Opt. Express. 11, 3445-3454 (2003).
[CrossRef] [PubMed]

N. G. Chen and Q. Zhu, "Spread spectrum time-resolved photon migration imaging system: the principle and simulation results," Proc. SPIE 4955, 474-479 (2003).
[CrossRef]

N. G. Chen and Q. Zhu, "Time-resolved optical measurements with spread spectrum excitations," Opt. Lett. 27, 1806-1808 (2002).
[CrossRef]

Anal. Biochem. (1)

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, K.W. Berndt, and M. Johnson, "Fluorescence lifetime imaging," Anal. Biochem. 202, 316-330 (1992).
[CrossRef] [PubMed]

Anal. Chem. (1)

M. Prummer, C. G. Hübner, B. Sick, B. Hecht, A. Renn, and U. P. Wild, "Single-Molecule Identification by Spectrally and Time-Resolved Fluorescence Detection," Anal. Chem. 72, 443 - 447 (2000).
[CrossRef] [PubMed]

Appl. Opt. (5)

Microsc. Res. Tech. (1)

W. Becker, A. Bergmann, M. A. Hink, K. König, K. Benndorf, and C. Biskup, "Fluorescence lifetime imaging by time-correlated single-photon counting," Microsc. Res. Tech. 63, 58-66 (2004).
[CrossRef]

Opt. Express. (1)

N. G. Chen and Q. Zhu, "Time-resolved diffusive optical tomography using pseudo-random sequences," Opt. Express. 11, 3445-3454 (2003).
[CrossRef] [PubMed]

Opt. Lett. (1)

PNAS (1)

P. Schwille, S. Kummer, A. A. Heikal, W. E. Moerner, and W. W. Webb, "Fluorescence correlation spectroscopy reveals fast optical excitation-driven intramolecular dynamics of yellow fluorescent proteins," PNAS,  97, 151-156 (2000)
[CrossRef] [PubMed]

Proc. SPIE (1)

N. G. Chen and Q. Zhu, "Spread spectrum time-resolved photon migration imaging system: the principle and simulation results," Proc. SPIE 4955, 474-479 (2003).
[CrossRef]

Rev. Sci. Instrum. (2)

H. Eda, I. Oda, Y. Ito, Y. Wada, Y. Oikawa, Y. Tsunazawa, and M. Takada, "Multichannel time-resolved optical tomographic imaging system," Rev. Sci. Instrum. 70, 3595-3602 (1999).
[CrossRef]

F. E. W. Schmidt, M. E. Fry, E. M. C. Hillman, J. C. Hebden, and D. T. Delpy, "A 32-channel time-resolved instrument for medical optical tomography," Rev. Sci. Instrum. 71, 256-265 (2000).
[CrossRef]

Trends Cell Biol. (1)

P. I. H. Bastiaens and A. Squire, "Fluorescence lifetime imaging microscopy: spatial resolution of biochemical processes in the cell," Trends Cell Biol. 9, 48-52 (1999).
[CrossRef] [PubMed]

Other (2)

D. V. O'Connor and D. Phillips, "Basic Principle of the Single Photon Counting Lifetime Measurement," in Time-correlated single photon counting, (Academic, 1984), pp. 36-54.

Becker & Hickl GmbH, "The bh TCSPC handbook,"http://www.becker-hickl.com/literature.htm.

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Figures (4)

Fig. 1.
Fig. 1.

Principle of PRSPC measurement.

Fig. 2.
Fig. 2.

Impulse response representing the TPSF of a diffusive photon density wave. Blue curve, theoretical prediction; red dots, reconstruction using PRSPC approach.

Fig. 3
Fig. 3

Calibration result. (b) is partial magnification of (a).

Fig. 4.
Fig. 4.

TPSFs of light diffusing through solid breast tissue phantom. The thicknesses of the phantom are 1 cm (blue) and 2 cm (red), respectively.

Equations (4)

Equations on this page are rendered with MathJax. Learn more.

R ( t ) = A I ( t ) * ( P ( t ) + 1 ) ,
g ( τ ) = P ( t ) P ( t τ )
= { 1 , τ T 0 = 0 1 N , τ T 0 = ± 1 , ± 2 , ,
f ( t ) = ( R ( t ) R ( t ) ) P ( t t ) = A I ( t ) * g ( t ) ,

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