Abstract

The fundamental limits for detection and characterization of fluorescent (phosphorescent) inhomogeneities embedded in tissuelike highly scattering turbid media are investigated. The absorption and fluorescence contrast introduced by exogenous fluorophores are also compared. Both analyses are based on practical signal-to-noise ratio considerations. For an object with fivefold fluorophore concentration and lifetime contrast with respect to the background tissue, we find the smallest detectable fluorescent object at 3-cm depth in tissuelike turbid media to be ∼0.25 cm in radius, whereas the smallest characterizable object size is ∼0.75 cm in radius, given a model with 1% amplitude and 0.5° phase noise. We also find that, for fluorescence extinction coefficients ∊ ≤ 0.5 × 105 cm-1 M-1, the fluorescence measurement mode is superior to the absorption mode for detecting an inhomogeneity. The optimal choice of modulation frequency for the frequency-domain fluorescence measurements is also discussed.

© 1998 Optical Society of America

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  1. A. Yodh, B. Chance, “Spectroscopy and imaging with diffusing light,” Phys. Today 48(3), 31–36 (1995). and references therein,.
  2. See related studies in B. Chance, R. R. Alfano, A. Katzir, eds., Optical Tomography and Spectroscopy of Tissue: Theory, Instrumentation, Model, and Human Studies II, Proc. SPIE2979 (1997).
  3. D. A. Boas, M. A. O’Leary, B. Chance, A. G. Yodh, “Detection and characterization of optical inhomogeneities with diffuse photon density waves: a signal-to-noise analysis,” Appl. Opt. 36, 75–92 (1997).
    [CrossRef] [PubMed]
  4. R. A. Zangaro, L. Silveira, R. Manoharan, G. Zonios, I. Itzkan, R. R. Dasari, J. VanDam, M. S. Feld, “Rapid multiexcitation fluorescence spectroscopy system for in vivo tissue diagnosis,” Appl. Opt. 35, 5211–5219 (1996).
    [CrossRef] [PubMed]
  5. A. Knüttel, J. M. Schmitt, R. Barnes, J. R. Knutson, “Acousto-optic scanning and interfering photon density waves for precise localization of an absorbing (or fluorescent) body in a turbid medium,” Rev. Sci. Instrum. 64, 638–644 (1993).
    [CrossRef]
  6. D. A. Boas, M. A. O’Leary, B. Chance, A. G. Yodh, “Scattering and wavelength transduction of diffuse photon density waves,” Phys. Rev. E 47, R2999–R3002 (1993).
    [CrossRef]
  7. E. M. Sevick-Muraca, C. L. Burch, “Origin of phosphorescence signals reemitted from tissues,” Opt. Lett. 19, 1928–1930 (1994).
    [CrossRef] [PubMed]
  8. M. S. Patterson, B. W. Pogue, “Mathematical model for time-resolved and frequency-domain fluorescence spectroscopy in biological tissues,” Appl. Opt. 33, 1963–1974 (1994).
    [CrossRef] [PubMed]
  9. M. A. O’Leary, D. A. Boas, B. Chance, A. G. Yodh, “Reradiation and imaging of diffuse photon density waves using fluorescent inhomogeneities,” J. Lumin. 60, 281–286 (1994).
    [CrossRef]
  10. X. D. Li, M. A. O’Leary, D. A. Boas, B. Chance, A. G. Yodh, “Fluorescent diffuse photon density waves in homogeneous and heterogeneous turbid media: analytic solutions and applications,” Appl. Opt. 35, 3746–3758 (1996).
    [CrossRef] [PubMed]
  11. A. E. Cerussi, J. S. Maier, S. Fantini, M. A. Franceschini, W. W. Mantulin, E. Gratton, “Experimental verification of a theory for the time-resolved fluorescence spectroscopy of thick tissues,” Appl. Opt. 36, 116–124 (1997).
    [CrossRef] [PubMed]
  12. E. M. Sevick-Muraca, G. Lopez, J. S. Reynolds, T. L. Troy, C. L. Hutchinson, “Fluorescence and absorption contrast mechanisms for biomedical optical imaging using frequency-domain techniques,” Photochem. Photobiol. 66, 55–64 (1997).
    [CrossRef] [PubMed]
  13. J. Wu, L. Perelman, R. R. Dasari, M. S. Feld, “Fluorescence tomographic imaging in turbid media using early-arriving photons and Laplace transforms,” Proc. Natl. Acad. Sci. USA 94, 8783–8788 (1997).
    [CrossRef] [PubMed]
  14. E. L. Hull, M. G. Nichols, T. H. Foster, “Localization of luminescent inhomogeneities in turbid media with spatially resolved measurements of cw diffuse luminescence emittance,” Appl. Opt. 37, 2755–2765.
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  16. B. C. Wilson, M. S. Patterson, “The physics of photodynamic therapy,” Phys. Med. Biol. 31, 327–360 (1986).
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  17. W. L. Rumsey, J. M. Vanderkooi, D. F. Wilson, “Imaging of phosphorescence: a novel method for measuring oxygen distribution in perfused tissue,” Science 241, 1649–1651 (1988).
    [CrossRef] [PubMed]
  18. J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, M. L. Johnson, “Fluorescence lifetime imaging of calcium using Quin-2,” Cell Calcium 13, 131–147 (1992).
    [CrossRef] [PubMed]
  19. S. A. Vinogradov, L.-W. Lo, W. T. Jenkins, S. M. Evans, C. Koch, D. F. Wilson, “Noninvasive imaging of the distribution of oxygen in tissue in vivo using infrared phosphors,” Biophys. J. 70, 1609–1617 (1996).
    [CrossRef] [PubMed]
  20. J. R. Lakowicz, Principles of Fluorescence Spectroscopy (Plenum, New York, 1983).
    [CrossRef]
  21. P. W. Vaupel, Blood Flow, Oxygenation, Tissue pH Distribution, and Bioenergetic Status of Tumor (Ernst Schering Research Foundation, Berlin, 1994).
  22. M. S. Patterson, B. Chance, B. C. Wilson, “Time resolved reflectance and transmittance for the noninvasive measurement of tissue optical properties,” Appl. Opt. 28, 2331–2335 (1989).
    [CrossRef] [PubMed]
  23. R. C. Haskell, L. O. Svaasand, T. T. Tsay, T. C. Feng, M. S. McAdams, B. J. Tromberg, “Boundary conditions for the diffusion equation in radiative transfer,” J. Opt. Soc. Am. A 11, 2727–2741 (1994).
    [CrossRef]
  24. R. Aronson, “Boundary conditions for diffusion of light,” J. Opt. Soc. Am. A 12, 2532–2539 (1995).
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  26. W. H. Press, S. A. Teukolsky, W. T. Vetterling, B. P. Flannery, Numerical Recipes in C (Cambridge U. Press, New York, 1992).
  27. D. A. Boas, M. A. O’Leary, B. Chance, A. G. Yodh, “Scattering of diffuse photon density waves by spherical inhomogeneities within turbid media: analytic solutions and applications,” Proc. Natl. Acad. Sci. USA 91, 4887–4891 (1994).
    [CrossRef]
  28. J. B. Fishkin, O. Coquoz, E. R. Anderson, M. Brenner, B. J. Tromberg, “Frequency-domain photon migration measurements of normal and malignant tissue optical properties in a human subject,” Appl. Opt. 36, 10–20 (1997).
    [CrossRef] [PubMed]
  29. K. Licha, B. Riefke, W. Semmler, “Synthesis and characterization of cyanine dyes as contrast agents for near-infrared imaging,” in Optical and Imaging Techniques for Biomonitoring II, H. Foth, R. Marchesini, H. Podbielska, eds., Proc. SPIE2927, 192–198 (1996).
    [CrossRef]
  30. K. W. Woodburn, Q. Fan, D. R. Miles, D. Kessel, Y. Luo, S. W. Young, “Localization and efficacy analysis of the phototherapeutic lutetium texaphyrin (PCI-0123) in the murine EMT6 sarcoma model,” Photochem. Photobiol. 65, 410–415 (1997).
    [CrossRef] [PubMed]

1997 (6)

E. M. Sevick-Muraca, G. Lopez, J. S. Reynolds, T. L. Troy, C. L. Hutchinson, “Fluorescence and absorption contrast mechanisms for biomedical optical imaging using frequency-domain techniques,” Photochem. Photobiol. 66, 55–64 (1997).
[CrossRef] [PubMed]

J. Wu, L. Perelman, R. R. Dasari, M. S. Feld, “Fluorescence tomographic imaging in turbid media using early-arriving photons and Laplace transforms,” Proc. Natl. Acad. Sci. USA 94, 8783–8788 (1997).
[CrossRef] [PubMed]

K. W. Woodburn, Q. Fan, D. R. Miles, D. Kessel, Y. Luo, S. W. Young, “Localization and efficacy analysis of the phototherapeutic lutetium texaphyrin (PCI-0123) in the murine EMT6 sarcoma model,” Photochem. Photobiol. 65, 410–415 (1997).
[CrossRef] [PubMed]

J. B. Fishkin, O. Coquoz, E. R. Anderson, M. Brenner, B. J. Tromberg, “Frequency-domain photon migration measurements of normal and malignant tissue optical properties in a human subject,” Appl. Opt. 36, 10–20 (1997).
[CrossRef] [PubMed]

A. E. Cerussi, J. S. Maier, S. Fantini, M. A. Franceschini, W. W. Mantulin, E. Gratton, “Experimental verification of a theory for the time-resolved fluorescence spectroscopy of thick tissues,” Appl. Opt. 36, 116–124 (1997).
[CrossRef] [PubMed]

D. A. Boas, M. A. O’Leary, B. Chance, A. G. Yodh, “Detection and characterization of optical inhomogeneities with diffuse photon density waves: a signal-to-noise analysis,” Appl. Opt. 36, 75–92 (1997).
[CrossRef] [PubMed]

1996 (3)

1995 (3)

P. S. Tofts, B. A. Berkowitz, M. Schnall, “Quantitative analysis of dynamic Gd-DTPA enhancement in breast tumors using a permeability model,” Magn. Res. Med. 33, 564–568 (1995).
[CrossRef]

A. Yodh, B. Chance, “Spectroscopy and imaging with diffusing light,” Phys. Today 48(3), 31–36 (1995). and references therein,.

R. Aronson, “Boundary conditions for diffusion of light,” J. Opt. Soc. Am. A 12, 2532–2539 (1995).
[CrossRef]

1994 (5)

M. S. Patterson, B. W. Pogue, “Mathematical model for time-resolved and frequency-domain fluorescence spectroscopy in biological tissues,” Appl. Opt. 33, 1963–1974 (1994).
[CrossRef] [PubMed]

M. A. O’Leary, D. A. Boas, B. Chance, A. G. Yodh, “Reradiation and imaging of diffuse photon density waves using fluorescent inhomogeneities,” J. Lumin. 60, 281–286 (1994).
[CrossRef]

D. A. Boas, M. A. O’Leary, B. Chance, A. G. Yodh, “Scattering of diffuse photon density waves by spherical inhomogeneities within turbid media: analytic solutions and applications,” Proc. Natl. Acad. Sci. USA 91, 4887–4891 (1994).
[CrossRef]

R. C. Haskell, L. O. Svaasand, T. T. Tsay, T. C. Feng, M. S. McAdams, B. J. Tromberg, “Boundary conditions for the diffusion equation in radiative transfer,” J. Opt. Soc. Am. A 11, 2727–2741 (1994).
[CrossRef]

E. M. Sevick-Muraca, C. L. Burch, “Origin of phosphorescence signals reemitted from tissues,” Opt. Lett. 19, 1928–1930 (1994).
[CrossRef] [PubMed]

1993 (2)

A. Knüttel, J. M. Schmitt, R. Barnes, J. R. Knutson, “Acousto-optic scanning and interfering photon density waves for precise localization of an absorbing (or fluorescent) body in a turbid medium,” Rev. Sci. Instrum. 64, 638–644 (1993).
[CrossRef]

D. A. Boas, M. A. O’Leary, B. Chance, A. G. Yodh, “Scattering and wavelength transduction of diffuse photon density waves,” Phys. Rev. E 47, R2999–R3002 (1993).
[CrossRef]

1992 (1)

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, M. L. Johnson, “Fluorescence lifetime imaging of calcium using Quin-2,” Cell Calcium 13, 131–147 (1992).
[CrossRef] [PubMed]

1989 (1)

1988 (1)

W. L. Rumsey, J. M. Vanderkooi, D. F. Wilson, “Imaging of phosphorescence: a novel method for measuring oxygen distribution in perfused tissue,” Science 241, 1649–1651 (1988).
[CrossRef] [PubMed]

1986 (1)

B. C. Wilson, M. S. Patterson, “The physics of photodynamic therapy,” Phys. Med. Biol. 31, 327–360 (1986).
[CrossRef] [PubMed]

Anderson, E. R.

Aronson, R.

Barnes, R.

A. Knüttel, J. M. Schmitt, R. Barnes, J. R. Knutson, “Acousto-optic scanning and interfering photon density waves for precise localization of an absorbing (or fluorescent) body in a turbid medium,” Rev. Sci. Instrum. 64, 638–644 (1993).
[CrossRef]

Berkowitz, B. A.

P. S. Tofts, B. A. Berkowitz, M. Schnall, “Quantitative analysis of dynamic Gd-DTPA enhancement in breast tumors using a permeability model,” Magn. Res. Med. 33, 564–568 (1995).
[CrossRef]

Boas, D. A.

D. A. Boas, M. A. O’Leary, B. Chance, A. G. Yodh, “Detection and characterization of optical inhomogeneities with diffuse photon density waves: a signal-to-noise analysis,” Appl. Opt. 36, 75–92 (1997).
[CrossRef] [PubMed]

X. D. Li, M. A. O’Leary, D. A. Boas, B. Chance, A. G. Yodh, “Fluorescent diffuse photon density waves in homogeneous and heterogeneous turbid media: analytic solutions and applications,” Appl. Opt. 35, 3746–3758 (1996).
[CrossRef] [PubMed]

D. A. Boas, M. A. O’Leary, B. Chance, A. G. Yodh, “Scattering of diffuse photon density waves by spherical inhomogeneities within turbid media: analytic solutions and applications,” Proc. Natl. Acad. Sci. USA 91, 4887–4891 (1994).
[CrossRef]

M. A. O’Leary, D. A. Boas, B. Chance, A. G. Yodh, “Reradiation and imaging of diffuse photon density waves using fluorescent inhomogeneities,” J. Lumin. 60, 281–286 (1994).
[CrossRef]

D. A. Boas, M. A. O’Leary, B. Chance, A. G. Yodh, “Scattering and wavelength transduction of diffuse photon density waves,” Phys. Rev. E 47, R2999–R3002 (1993).
[CrossRef]

Brenner, M.

Burch, C. L.

Cerussi, A. E.

Chance, B.

D. A. Boas, M. A. O’Leary, B. Chance, A. G. Yodh, “Detection and characterization of optical inhomogeneities with diffuse photon density waves: a signal-to-noise analysis,” Appl. Opt. 36, 75–92 (1997).
[CrossRef] [PubMed]

X. D. Li, M. A. O’Leary, D. A. Boas, B. Chance, A. G. Yodh, “Fluorescent diffuse photon density waves in homogeneous and heterogeneous turbid media: analytic solutions and applications,” Appl. Opt. 35, 3746–3758 (1996).
[CrossRef] [PubMed]

A. Yodh, B. Chance, “Spectroscopy and imaging with diffusing light,” Phys. Today 48(3), 31–36 (1995). and references therein,.

M. A. O’Leary, D. A. Boas, B. Chance, A. G. Yodh, “Reradiation and imaging of diffuse photon density waves using fluorescent inhomogeneities,” J. Lumin. 60, 281–286 (1994).
[CrossRef]

D. A. Boas, M. A. O’Leary, B. Chance, A. G. Yodh, “Scattering of diffuse photon density waves by spherical inhomogeneities within turbid media: analytic solutions and applications,” Proc. Natl. Acad. Sci. USA 91, 4887–4891 (1994).
[CrossRef]

D. A. Boas, M. A. O’Leary, B. Chance, A. G. Yodh, “Scattering and wavelength transduction of diffuse photon density waves,” Phys. Rev. E 47, R2999–R3002 (1993).
[CrossRef]

M. S. Patterson, B. Chance, B. C. Wilson, “Time resolved reflectance and transmittance for the noninvasive measurement of tissue optical properties,” Appl. Opt. 28, 2331–2335 (1989).
[CrossRef] [PubMed]

Coquoz, O.

Dasari, R. R.

J. Wu, L. Perelman, R. R. Dasari, M. S. Feld, “Fluorescence tomographic imaging in turbid media using early-arriving photons and Laplace transforms,” Proc. Natl. Acad. Sci. USA 94, 8783–8788 (1997).
[CrossRef] [PubMed]

R. A. Zangaro, L. Silveira, R. Manoharan, G. Zonios, I. Itzkan, R. R. Dasari, J. VanDam, M. S. Feld, “Rapid multiexcitation fluorescence spectroscopy system for in vivo tissue diagnosis,” Appl. Opt. 35, 5211–5219 (1996).
[CrossRef] [PubMed]

Evans, S. M.

S. A. Vinogradov, L.-W. Lo, W. T. Jenkins, S. M. Evans, C. Koch, D. F. Wilson, “Noninvasive imaging of the distribution of oxygen in tissue in vivo using infrared phosphors,” Biophys. J. 70, 1609–1617 (1996).
[CrossRef] [PubMed]

Fan, Q.

K. W. Woodburn, Q. Fan, D. R. Miles, D. Kessel, Y. Luo, S. W. Young, “Localization and efficacy analysis of the phototherapeutic lutetium texaphyrin (PCI-0123) in the murine EMT6 sarcoma model,” Photochem. Photobiol. 65, 410–415 (1997).
[CrossRef] [PubMed]

Fantini, S.

Feld, M. S.

J. Wu, L. Perelman, R. R. Dasari, M. S. Feld, “Fluorescence tomographic imaging in turbid media using early-arriving photons and Laplace transforms,” Proc. Natl. Acad. Sci. USA 94, 8783–8788 (1997).
[CrossRef] [PubMed]

R. A. Zangaro, L. Silveira, R. Manoharan, G. Zonios, I. Itzkan, R. R. Dasari, J. VanDam, M. S. Feld, “Rapid multiexcitation fluorescence spectroscopy system for in vivo tissue diagnosis,” Appl. Opt. 35, 5211–5219 (1996).
[CrossRef] [PubMed]

Feng, T. C.

Fishkin, J. B.

Flannery, B. P.

W. H. Press, S. A. Teukolsky, W. T. Vetterling, B. P. Flannery, Numerical Recipes in C (Cambridge U. Press, New York, 1992).

Foster, T. H.

Franceschini, M. A.

Gratton, E.

Haskell, R. C.

Hull, E. L.

Hutchinson, C. L.

E. M. Sevick-Muraca, G. Lopez, J. S. Reynolds, T. L. Troy, C. L. Hutchinson, “Fluorescence and absorption contrast mechanisms for biomedical optical imaging using frequency-domain techniques,” Photochem. Photobiol. 66, 55–64 (1997).
[CrossRef] [PubMed]

Itzkan, I.

Jenkins, W. T.

S. A. Vinogradov, L.-W. Lo, W. T. Jenkins, S. M. Evans, C. Koch, D. F. Wilson, “Noninvasive imaging of the distribution of oxygen in tissue in vivo using infrared phosphors,” Biophys. J. 70, 1609–1617 (1996).
[CrossRef] [PubMed]

Johnson, M. L.

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, M. L. Johnson, “Fluorescence lifetime imaging of calcium using Quin-2,” Cell Calcium 13, 131–147 (1992).
[CrossRef] [PubMed]

Kessel, D.

K. W. Woodburn, Q. Fan, D. R. Miles, D. Kessel, Y. Luo, S. W. Young, “Localization and efficacy analysis of the phototherapeutic lutetium texaphyrin (PCI-0123) in the murine EMT6 sarcoma model,” Photochem. Photobiol. 65, 410–415 (1997).
[CrossRef] [PubMed]

Knutson, J. R.

A. Knüttel, J. M. Schmitt, R. Barnes, J. R. Knutson, “Acousto-optic scanning and interfering photon density waves for precise localization of an absorbing (or fluorescent) body in a turbid medium,” Rev. Sci. Instrum. 64, 638–644 (1993).
[CrossRef]

Knüttel, A.

A. Knüttel, J. M. Schmitt, R. Barnes, J. R. Knutson, “Acousto-optic scanning and interfering photon density waves for precise localization of an absorbing (or fluorescent) body in a turbid medium,” Rev. Sci. Instrum. 64, 638–644 (1993).
[CrossRef]

Koch, C.

S. A. Vinogradov, L.-W. Lo, W. T. Jenkins, S. M. Evans, C. Koch, D. F. Wilson, “Noninvasive imaging of the distribution of oxygen in tissue in vivo using infrared phosphors,” Biophys. J. 70, 1609–1617 (1996).
[CrossRef] [PubMed]

Lakowicz, J. R.

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, M. L. Johnson, “Fluorescence lifetime imaging of calcium using Quin-2,” Cell Calcium 13, 131–147 (1992).
[CrossRef] [PubMed]

J. R. Lakowicz, Principles of Fluorescence Spectroscopy (Plenum, New York, 1983).
[CrossRef]

Li, X. D.

Licha, K.

K. Licha, B. Riefke, W. Semmler, “Synthesis and characterization of cyanine dyes as contrast agents for near-infrared imaging,” in Optical and Imaging Techniques for Biomonitoring II, H. Foth, R. Marchesini, H. Podbielska, eds., Proc. SPIE2927, 192–198 (1996).
[CrossRef]

Lo, L.-W.

S. A. Vinogradov, L.-W. Lo, W. T. Jenkins, S. M. Evans, C. Koch, D. F. Wilson, “Noninvasive imaging of the distribution of oxygen in tissue in vivo using infrared phosphors,” Biophys. J. 70, 1609–1617 (1996).
[CrossRef] [PubMed]

Lopez, G.

E. M. Sevick-Muraca, G. Lopez, J. S. Reynolds, T. L. Troy, C. L. Hutchinson, “Fluorescence and absorption contrast mechanisms for biomedical optical imaging using frequency-domain techniques,” Photochem. Photobiol. 66, 55–64 (1997).
[CrossRef] [PubMed]

Luo, Y.

K. W. Woodburn, Q. Fan, D. R. Miles, D. Kessel, Y. Luo, S. W. Young, “Localization and efficacy analysis of the phototherapeutic lutetium texaphyrin (PCI-0123) in the murine EMT6 sarcoma model,” Photochem. Photobiol. 65, 410–415 (1997).
[CrossRef] [PubMed]

Maier, J. S.

Manoharan, R.

Mantulin, W. W.

McAdams, M. S.

Miles, D. R.

K. W. Woodburn, Q. Fan, D. R. Miles, D. Kessel, Y. Luo, S. W. Young, “Localization and efficacy analysis of the phototherapeutic lutetium texaphyrin (PCI-0123) in the murine EMT6 sarcoma model,” Photochem. Photobiol. 65, 410–415 (1997).
[CrossRef] [PubMed]

Nichols, M. G.

Nowaczyk, K.

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, M. L. Johnson, “Fluorescence lifetime imaging of calcium using Quin-2,” Cell Calcium 13, 131–147 (1992).
[CrossRef] [PubMed]

O’Leary, M. A.

D. A. Boas, M. A. O’Leary, B. Chance, A. G. Yodh, “Detection and characterization of optical inhomogeneities with diffuse photon density waves: a signal-to-noise analysis,” Appl. Opt. 36, 75–92 (1997).
[CrossRef] [PubMed]

X. D. Li, M. A. O’Leary, D. A. Boas, B. Chance, A. G. Yodh, “Fluorescent diffuse photon density waves in homogeneous and heterogeneous turbid media: analytic solutions and applications,” Appl. Opt. 35, 3746–3758 (1996).
[CrossRef] [PubMed]

D. A. Boas, M. A. O’Leary, B. Chance, A. G. Yodh, “Scattering of diffuse photon density waves by spherical inhomogeneities within turbid media: analytic solutions and applications,” Proc. Natl. Acad. Sci. USA 91, 4887–4891 (1994).
[CrossRef]

M. A. O’Leary, D. A. Boas, B. Chance, A. G. Yodh, “Reradiation and imaging of diffuse photon density waves using fluorescent inhomogeneities,” J. Lumin. 60, 281–286 (1994).
[CrossRef]

D. A. Boas, M. A. O’Leary, B. Chance, A. G. Yodh, “Scattering and wavelength transduction of diffuse photon density waves,” Phys. Rev. E 47, R2999–R3002 (1993).
[CrossRef]

Patterson, M. S.

Perelman, L.

J. Wu, L. Perelman, R. R. Dasari, M. S. Feld, “Fluorescence tomographic imaging in turbid media using early-arriving photons and Laplace transforms,” Proc. Natl. Acad. Sci. USA 94, 8783–8788 (1997).
[CrossRef] [PubMed]

Pogue, B. W.

Press, W. H.

W. H. Press, S. A. Teukolsky, W. T. Vetterling, B. P. Flannery, Numerical Recipes in C (Cambridge U. Press, New York, 1992).

Reynolds, J. S.

E. M. Sevick-Muraca, G. Lopez, J. S. Reynolds, T. L. Troy, C. L. Hutchinson, “Fluorescence and absorption contrast mechanisms for biomedical optical imaging using frequency-domain techniques,” Photochem. Photobiol. 66, 55–64 (1997).
[CrossRef] [PubMed]

Riefke, B.

K. Licha, B. Riefke, W. Semmler, “Synthesis and characterization of cyanine dyes as contrast agents for near-infrared imaging,” in Optical and Imaging Techniques for Biomonitoring II, H. Foth, R. Marchesini, H. Podbielska, eds., Proc. SPIE2927, 192–198 (1996).
[CrossRef]

Rumsey, W. L.

W. L. Rumsey, J. M. Vanderkooi, D. F. Wilson, “Imaging of phosphorescence: a novel method for measuring oxygen distribution in perfused tissue,” Science 241, 1649–1651 (1988).
[CrossRef] [PubMed]

Schmitt, J. M.

A. Knüttel, J. M. Schmitt, R. Barnes, J. R. Knutson, “Acousto-optic scanning and interfering photon density waves for precise localization of an absorbing (or fluorescent) body in a turbid medium,” Rev. Sci. Instrum. 64, 638–644 (1993).
[CrossRef]

Schnall, M.

P. S. Tofts, B. A. Berkowitz, M. Schnall, “Quantitative analysis of dynamic Gd-DTPA enhancement in breast tumors using a permeability model,” Magn. Res. Med. 33, 564–568 (1995).
[CrossRef]

Semmler, W.

K. Licha, B. Riefke, W. Semmler, “Synthesis and characterization of cyanine dyes as contrast agents for near-infrared imaging,” in Optical and Imaging Techniques for Biomonitoring II, H. Foth, R. Marchesini, H. Podbielska, eds., Proc. SPIE2927, 192–198 (1996).
[CrossRef]

Sevick-Muraca, E. M.

E. M. Sevick-Muraca, G. Lopez, J. S. Reynolds, T. L. Troy, C. L. Hutchinson, “Fluorescence and absorption contrast mechanisms for biomedical optical imaging using frequency-domain techniques,” Photochem. Photobiol. 66, 55–64 (1997).
[CrossRef] [PubMed]

E. M. Sevick-Muraca, C. L. Burch, “Origin of phosphorescence signals reemitted from tissues,” Opt. Lett. 19, 1928–1930 (1994).
[CrossRef] [PubMed]

Silveira, L.

Svaasand, L. O.

Szmacinski, H.

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, M. L. Johnson, “Fluorescence lifetime imaging of calcium using Quin-2,” Cell Calcium 13, 131–147 (1992).
[CrossRef] [PubMed]

Teukolsky, S. A.

W. H. Press, S. A. Teukolsky, W. T. Vetterling, B. P. Flannery, Numerical Recipes in C (Cambridge U. Press, New York, 1992).

Tofts, P. S.

P. S. Tofts, B. A. Berkowitz, M. Schnall, “Quantitative analysis of dynamic Gd-DTPA enhancement in breast tumors using a permeability model,” Magn. Res. Med. 33, 564–568 (1995).
[CrossRef]

Tromberg, B. J.

Troy, T. L.

E. M. Sevick-Muraca, G. Lopez, J. S. Reynolds, T. L. Troy, C. L. Hutchinson, “Fluorescence and absorption contrast mechanisms for biomedical optical imaging using frequency-domain techniques,” Photochem. Photobiol. 66, 55–64 (1997).
[CrossRef] [PubMed]

Tsay, T. T.

VanDam, J.

Vanderkooi, J. M.

W. L. Rumsey, J. M. Vanderkooi, D. F. Wilson, “Imaging of phosphorescence: a novel method for measuring oxygen distribution in perfused tissue,” Science 241, 1649–1651 (1988).
[CrossRef] [PubMed]

Vaupel, P. W.

P. W. Vaupel, Blood Flow, Oxygenation, Tissue pH Distribution, and Bioenergetic Status of Tumor (Ernst Schering Research Foundation, Berlin, 1994).

Vetterling, W. T.

W. H. Press, S. A. Teukolsky, W. T. Vetterling, B. P. Flannery, Numerical Recipes in C (Cambridge U. Press, New York, 1992).

Vinogradov, S. A.

S. A. Vinogradov, L.-W. Lo, W. T. Jenkins, S. M. Evans, C. Koch, D. F. Wilson, “Noninvasive imaging of the distribution of oxygen in tissue in vivo using infrared phosphors,” Biophys. J. 70, 1609–1617 (1996).
[CrossRef] [PubMed]

Wilson, B. C.

Wilson, D. F.

S. A. Vinogradov, L.-W. Lo, W. T. Jenkins, S. M. Evans, C. Koch, D. F. Wilson, “Noninvasive imaging of the distribution of oxygen in tissue in vivo using infrared phosphors,” Biophys. J. 70, 1609–1617 (1996).
[CrossRef] [PubMed]

W. L. Rumsey, J. M. Vanderkooi, D. F. Wilson, “Imaging of phosphorescence: a novel method for measuring oxygen distribution in perfused tissue,” Science 241, 1649–1651 (1988).
[CrossRef] [PubMed]

Woodburn, K. W.

K. W. Woodburn, Q. Fan, D. R. Miles, D. Kessel, Y. Luo, S. W. Young, “Localization and efficacy analysis of the phototherapeutic lutetium texaphyrin (PCI-0123) in the murine EMT6 sarcoma model,” Photochem. Photobiol. 65, 410–415 (1997).
[CrossRef] [PubMed]

Wu, J.

J. Wu, L. Perelman, R. R. Dasari, M. S. Feld, “Fluorescence tomographic imaging in turbid media using early-arriving photons and Laplace transforms,” Proc. Natl. Acad. Sci. USA 94, 8783–8788 (1997).
[CrossRef] [PubMed]

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A. Yodh, B. Chance, “Spectroscopy and imaging with diffusing light,” Phys. Today 48(3), 31–36 (1995). and references therein,.

Yodh, A. G.

D. A. Boas, M. A. O’Leary, B. Chance, A. G. Yodh, “Detection and characterization of optical inhomogeneities with diffuse photon density waves: a signal-to-noise analysis,” Appl. Opt. 36, 75–92 (1997).
[CrossRef] [PubMed]

X. D. Li, M. A. O’Leary, D. A. Boas, B. Chance, A. G. Yodh, “Fluorescent diffuse photon density waves in homogeneous and heterogeneous turbid media: analytic solutions and applications,” Appl. Opt. 35, 3746–3758 (1996).
[CrossRef] [PubMed]

M. A. O’Leary, D. A. Boas, B. Chance, A. G. Yodh, “Reradiation and imaging of diffuse photon density waves using fluorescent inhomogeneities,” J. Lumin. 60, 281–286 (1994).
[CrossRef]

D. A. Boas, M. A. O’Leary, B. Chance, A. G. Yodh, “Scattering of diffuse photon density waves by spherical inhomogeneities within turbid media: analytic solutions and applications,” Proc. Natl. Acad. Sci. USA 91, 4887–4891 (1994).
[CrossRef]

D. A. Boas, M. A. O’Leary, B. Chance, A. G. Yodh, “Scattering and wavelength transduction of diffuse photon density waves,” Phys. Rev. E 47, R2999–R3002 (1993).
[CrossRef]

Young, S. W.

K. W. Woodburn, Q. Fan, D. R. Miles, D. Kessel, Y. Luo, S. W. Young, “Localization and efficacy analysis of the phototherapeutic lutetium texaphyrin (PCI-0123) in the murine EMT6 sarcoma model,” Photochem. Photobiol. 65, 410–415 (1997).
[CrossRef] [PubMed]

Zangaro, R. A.

Zonios, G.

Appl. Opt. (8)

M. S. Patterson, B. Chance, B. C. Wilson, “Time resolved reflectance and transmittance for the noninvasive measurement of tissue optical properties,” Appl. Opt. 28, 2331–2335 (1989).
[CrossRef] [PubMed]

M. S. Patterson, B. W. Pogue, “Mathematical model for time-resolved and frequency-domain fluorescence spectroscopy in biological tissues,” Appl. Opt. 33, 1963–1974 (1994).
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J. B. Fishkin, O. Coquoz, E. R. Anderson, M. Brenner, B. J. Tromberg, “Frequency-domain photon migration measurements of normal and malignant tissue optical properties in a human subject,” Appl. Opt. 36, 10–20 (1997).
[CrossRef] [PubMed]

A. E. Cerussi, J. S. Maier, S. Fantini, M. A. Franceschini, W. W. Mantulin, E. Gratton, “Experimental verification of a theory for the time-resolved fluorescence spectroscopy of thick tissues,” Appl. Opt. 36, 116–124 (1997).
[CrossRef] [PubMed]

X. D. Li, M. A. O’Leary, D. A. Boas, B. Chance, A. G. Yodh, “Fluorescent diffuse photon density waves in homogeneous and heterogeneous turbid media: analytic solutions and applications,” Appl. Opt. 35, 3746–3758 (1996).
[CrossRef] [PubMed]

R. A. Zangaro, L. Silveira, R. Manoharan, G. Zonios, I. Itzkan, R. R. Dasari, J. VanDam, M. S. Feld, “Rapid multiexcitation fluorescence spectroscopy system for in vivo tissue diagnosis,” Appl. Opt. 35, 5211–5219 (1996).
[CrossRef] [PubMed]

D. A. Boas, M. A. O’Leary, B. Chance, A. G. Yodh, “Detection and characterization of optical inhomogeneities with diffuse photon density waves: a signal-to-noise analysis,” Appl. Opt. 36, 75–92 (1997).
[CrossRef] [PubMed]

E. L. Hull, M. G. Nichols, T. H. Foster, “Localization of luminescent inhomogeneities in turbid media with spatially resolved measurements of cw diffuse luminescence emittance,” Appl. Opt. 37, 2755–2765.

Biophys. J. (1)

S. A. Vinogradov, L.-W. Lo, W. T. Jenkins, S. M. Evans, C. Koch, D. F. Wilson, “Noninvasive imaging of the distribution of oxygen in tissue in vivo using infrared phosphors,” Biophys. J. 70, 1609–1617 (1996).
[CrossRef] [PubMed]

Cell Calcium (1)

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, M. L. Johnson, “Fluorescence lifetime imaging of calcium using Quin-2,” Cell Calcium 13, 131–147 (1992).
[CrossRef] [PubMed]

J. Lumin. (1)

M. A. O’Leary, D. A. Boas, B. Chance, A. G. Yodh, “Reradiation and imaging of diffuse photon density waves using fluorescent inhomogeneities,” J. Lumin. 60, 281–286 (1994).
[CrossRef]

J. Opt. Soc. Am. A (2)

Magn. Res. Med. (1)

P. S. Tofts, B. A. Berkowitz, M. Schnall, “Quantitative analysis of dynamic Gd-DTPA enhancement in breast tumors using a permeability model,” Magn. Res. Med. 33, 564–568 (1995).
[CrossRef]

Opt. Lett. (1)

Photochem. Photobiol. (2)

K. W. Woodburn, Q. Fan, D. R. Miles, D. Kessel, Y. Luo, S. W. Young, “Localization and efficacy analysis of the phototherapeutic lutetium texaphyrin (PCI-0123) in the murine EMT6 sarcoma model,” Photochem. Photobiol. 65, 410–415 (1997).
[CrossRef] [PubMed]

E. M. Sevick-Muraca, G. Lopez, J. S. Reynolds, T. L. Troy, C. L. Hutchinson, “Fluorescence and absorption contrast mechanisms for biomedical optical imaging using frequency-domain techniques,” Photochem. Photobiol. 66, 55–64 (1997).
[CrossRef] [PubMed]

Phys. Med. Biol. (1)

B. C. Wilson, M. S. Patterson, “The physics of photodynamic therapy,” Phys. Med. Biol. 31, 327–360 (1986).
[CrossRef] [PubMed]

Phys. Rev. E (1)

D. A. Boas, M. A. O’Leary, B. Chance, A. G. Yodh, “Scattering and wavelength transduction of diffuse photon density waves,” Phys. Rev. E 47, R2999–R3002 (1993).
[CrossRef]

Phys. Today (1)

A. Yodh, B. Chance, “Spectroscopy and imaging with diffusing light,” Phys. Today 48(3), 31–36 (1995). and references therein,.

Proc. Natl. Acad. Sci. USA (2)

J. Wu, L. Perelman, R. R. Dasari, M. S. Feld, “Fluorescence tomographic imaging in turbid media using early-arriving photons and Laplace transforms,” Proc. Natl. Acad. Sci. USA 94, 8783–8788 (1997).
[CrossRef] [PubMed]

D. A. Boas, M. A. O’Leary, B. Chance, A. G. Yodh, “Scattering of diffuse photon density waves by spherical inhomogeneities within turbid media: analytic solutions and applications,” Proc. Natl. Acad. Sci. USA 91, 4887–4891 (1994).
[CrossRef]

Rev. Sci. Instrum. (1)

A. Knüttel, J. M. Schmitt, R. Barnes, J. R. Knutson, “Acousto-optic scanning and interfering photon density waves for precise localization of an absorbing (or fluorescent) body in a turbid medium,” Rev. Sci. Instrum. 64, 638–644 (1993).
[CrossRef]

Science (1)

W. L. Rumsey, J. M. Vanderkooi, D. F. Wilson, “Imaging of phosphorescence: a novel method for measuring oxygen distribution in perfused tissue,” Science 241, 1649–1651 (1988).
[CrossRef] [PubMed]

Other (6)

See related studies in B. Chance, R. R. Alfano, A. Katzir, eds., Optical Tomography and Spectroscopy of Tissue: Theory, Instrumentation, Model, and Human Studies II, Proc. SPIE2979 (1997).

K. Licha, B. Riefke, W. Semmler, “Synthesis and characterization of cyanine dyes as contrast agents for near-infrared imaging,” in Optical and Imaging Techniques for Biomonitoring II, H. Foth, R. Marchesini, H. Podbielska, eds., Proc. SPIE2927, 192–198 (1996).
[CrossRef]

J. R. Lakowicz, Principles of Fluorescence Spectroscopy (Plenum, New York, 1983).
[CrossRef]

P. W. Vaupel, Blood Flow, Oxygenation, Tissue pH Distribution, and Bioenergetic Status of Tumor (Ernst Schering Research Foundation, Berlin, 1994).

T. R. Carski, “Indocynanine green: history, chemistry, pharmacology, indication, adverse reactions, investigations and prognosis,” in An Investigator’s Brochure, 24June1994.

W. H. Press, S. A. Teukolsky, W. T. Vetterling, B. P. Flannery, Numerical Recipes in C (Cambridge U. Press, New York, 1992).

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Figures (11)

Fig. 1
Fig. 1

Infinite slab with one side at z = 0 cm and the other side at z = 5 cm. (a) Single source–detector geometry. The source and the detector are fixed as shown. A single object is centered between the source and the detector at (0, 2.5) cm. The FDPDW is calculated under this single source–detector configuration for the detection limits analysis. (b) Source position fixed as shown. The detector scans along one side of the slab (x axis) in steps of 0.2 cm. The fluorescence amplitudes and phases at 21 detector positions are calculated for characterization limits analysis.

Fig. 2
Fig. 2

Extrapolated zero boundary conditions are incorporated into the forward FDPDW calculations by introduction of a series of image source–object pairs. Planes B 1 and B 2 are the two physical surfaces of the slab turbid medium. Planes P 1 and P 2 are the extrapolated boundaries a distance z b = 0.704/ μ s from the corresponding physical surfaces B 1 and B 2. The fluorescence photon fluence is approximated to be zero on the extrapolated boundaries P 1 and P 2. The thickness of the slab is denoted w. The source (S) is at z = 0, the object (O) is at z = -d, and the detector (D) can be anywhere on the physical surfaces or within the slab. S 1O 1 is the image source–object pair of the real source–object pair SO with respect to plane P 1; S 1O 1 and SO are mirror symmetric about plane P 1. S 2O 2 is the image source–object pair of the real source–object pair SO with respect to plane P 2; S 2O 2 and SO are symmetric about plane P 2. S 3O 3 is the image source–object pair of the image source–object pair S 2O 2 with respect to plane P1; S 3O 3 and S 2O 2 are symmetric about plane P 1. Series of image source–object pairs can go on following a simple observation. The signs of the image sources are also indicated here. The total FDPDW is the superposition of the FDPDW’s generated by the real source–object pair SO and all the image source–object pairs S i O i with appropriate signs for the image sources. The series converges fast because the fluorescence photon fluence decays exponentially with respect to the (image) source–detector separation.

Fig. 3
Fig. 3

Contour plots of fractional amplitude and relative phase change versus fluorophore concentration (N 2/N 1) and lifetime variation (τ21) for different-sized objects. The radii are indicated in units inverse centimeters. (a) Curves, 1% fraction amplitude perturbation contours. Hatched areas, fractional amplitude change greater than 1% (or less -1%). (b) Curves, 0.5° relative phase change contours. Hatched areas, relative phase change greater than 0.5° (or less than -0.5°).

Fig. 4
Fig. 4

Characterization limits for an object of a known size (radius a = 0.5 cm). (a) characterization uncertainties in fluorophore concentration N 2. For a given lifetime the uncertainty is smaller for a higher concentration; for a given fluorophore concentration the uncertainty is smaller for a longer lifetime. (b) Characterization uncertainties in lifetime τ2. For a given lifetime the uncertainty is smaller for a higher concentration; for a given concentration the uncertainty is smaller for a greater lifetime variation. See Subsection 5.A for explanations.

Fig. 5
Fig. 5

Example of χ2 distribution versus fitting parameters in characterization of an object with a known size. Fluorophore concentration N 2 and lifetime τ2 are the two fitting parameters, which we characterize simultaneously. (a) χ2 versus concentration for a long and a short lifetime (τ2). A longer lifetime (τ21 = 1.7) corresponds to a narrower valley. (b) χ2 versus lifetime for a high and a low concentration (N 2). A higher concentration (N 2/N 1 = 6) corresponds to a narrower valley.

Fig. 6
Fig. 6

Characterization limits for an object of an unknown size. (a) Characterization uncertainties in fluorophore concentration N 2. (b) Characterization uncertainties in radius a. In both (a) and (b), for a given object size the uncertainties are smaller for a higher concentration; for a given fluorophore concentration the uncertainties are smaller for a bigger size. The smallest characterizable object size is ∼0.75 cm in radius, considering a fivefold concentration contrast and a 20% characterization uncertainty.

Fig. 7
Fig. 7

Example of χ2 distribution versus fitting parameters in characterization of an object with an unknown size: (a) χ2 versus concentration and (b) χ2 versus radius.

Fig. 8
Fig. 8

(a) Fractional amplitude and (b) relative phase changes for different moments versus object size. The concentration contrast is assumed to be fivefold. Horizontal dashed lines indicate 1% amplitude and 0.5° phase noise level. The geometry is given in Fig. 1(a).

Fig. 9
Fig. 9

Contours of fractional amplitude and relative phase changes versus concentration and radius. The lifetime contrast is set to 1 for the fluorescence detection. (a) and (b) show the absorption contrast; (c) and (d) show the fluorescence contrast introduced by exogenous fluorophores.

Fig. 10
Fig. 10

Contours of fractional amplitude and relative phase changes for (a), (b) absorption and (c), (d) fluorescence contrast versus concentration and extinction coefficient. The object size is 0.5 cm in radius, and the source–detector geometry is shown in Fig. 1(a). For fluorophores with an extinction coefficient near 1.0 × 105 cm-1 M-1, we see that the fluorescence contrast is in general greater than the absorption contrast.

Fig. 11
Fig. 11

(a) Fractional amplitude perturbation versus modulation frequency for different lifetime contrasts; (b) relative phase perturbation versus modulation frequency for different lifetime contrasts. Given a lifetime contrast τ21, we find that the amplitude and the phase perturbation that are due to the lifetime contrast will be optimally elevated when the source modulation frequency is appropriately chosen, e.g., ωτ2 ≈ 1.

Tables (2)

Tables Icon

Table 1 Chromophore Optical Properties at λex and λem and Source Modulation Frequencya

Tables Icon

Table 2 Quantum Yield η, Background Fluorophore Concentration N1, Lifetime τ1, and Extinction Coefficients ∊ and ∊ f a

Equations (5)

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Φ hetero flr r s ,   r d ,   ω ,   a = Φ homo flr r s ,   r d ,   ω + Φ sc flr r s ,   r d ,   ω ,   a = q 1 η 1 N 1 1 - i ω τ 1   F 1 r s ,   r d ,   ω + q 2 η 2 N 2 1 - i ω τ 2   F 2 r s ,   r d ,   ω ,   a .
χ 2 N 2 ,   τ 2 = i = 1 21 A i ,   M N 2 ,   τ 2 - A i ,   Th N 2 ,   τ 2 2 δ A 2 + θ i ,   M N 2 ,   τ 2 - θ i ,   Th N 2 ,   τ 2 2 δ θ 2 ,
Φ hetero flr r s ,   r d ,   ω ,   a = Φ homo flr r s ,   r d ,   ω + Φ sc flr r s ,   r d ,   ω ,   a .
Φ homo flr r d ,   r s ,   ω = A 1 q 1 η 1 N 1 1 - i ω τ 1 exp ik 1 | r d - r s | 4 π | r d - r s | - exp ik 1 f | r d - r s | 4 π | r d - r s | .
Φ sc flr r d ,   r s ,   ω ,   a = A 2 q 2 η 2 N 2 1 - i ω τ 2 × lm B lm h l 1 k 1 f r + C lm h l 1 k 1 r × Y lm Ω .

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