Abstract

We present a fiber optic probe that combines polarized illumination and detection with an angled distal probe geometry to detect the size-dependent scattering at a specific depth within epithelium. Analysis of the scattering signal by use of Mie theory allows the extraction of scatterer size and size distribution—key parameters for precancer detection. The probe was evaluated in two tissue phantoms: polystyrene beads atop collagen gel and multiple layers of cancer cells atop collagen. We also present in vivo measurements in the oral cavity of normal volunteers. The sizes of scatterers extracted from the scattering spectra corresponded to independently measured values.

© 2004 Optical Society of America

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    [CrossRef]
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    [CrossRef]
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  4. J. R. Mourant, T. Fuselier, J. Boyer, T. M. Johnson, I. J. Bigio, “Predictions and measurements of scattering and absorption over broad wavelength ranges in tissue phantoms,” Appl. Opt. 36, 949–957 (1997).
    [CrossRef] [PubMed]
  5. A. H. Hielscher, J. R. Mourant, I. J. Bigio, “Influence of particle size and concentration on the diffuse backscattering of polarized light from tissue phantoms and biological cell suspensions,” Appl. Opt. 36, 125–135 (1997).
    [CrossRef] [PubMed]
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  17. R. Drezek, M. Guillaud, T. Collier, I. Boiko, A. Malpica, C. Macaulay, M. Follen, R. Richards-Kortum, “Light scattering from cervical cells throughout neoplastic progression: influence of nuclear morphology, DNA content, and chromatin texture,” J. Biomed. Opt. 8, 7–16 (2001).
    [CrossRef]
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    [PubMed]
  19. R. R. Anderson, “Polarized light examination and photography of the skin,” Arch. Dermatol. 127, 1000–1005 (1991).
    [CrossRef] [PubMed]
  20. V. Backman, R. Gurjar, K. Badizadegan, I. Itzkan, R. Dasari, L. T. Perelman, M. S. Feld, “Polarized light scattering spectroscopy for quantitative measurements of epithelial cellular structures in situ,” IEEE J. Sel. Top. Quantum Electron. 5, 1019–1026 (1999).
    [CrossRef]
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    [CrossRef] [PubMed]
  23. L. Quan, N. Ramanujam, “Relationship between depth of target in a turbid medium and fluorescence measured by a variable-aperture method,” Opt. Lett. 27, 104–106 (2002).
    [CrossRef]
  24. T. J. Pfefer, K. T. Schomacker, M. N. Ediger, N. S. Nishioka, “Multiple-fiber probe design for fluorescence spectroscopy in tissue,” Appl. Opt. 41, 4712–4721 (2002).
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  25. U. Utzinger, R. Richards-Kortum, “Fiber optic probes for biomedical optical spectroscopy,” J. Biomed. Opt. 8, 121–147 (2003).
    [CrossRef] [PubMed]
  26. W. M. White, M. Rajadhyaksha, S. Gonzalez, R. L. Fabian, R. R. Anderson, “Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy,” Laryngoscope 109, 1709–1717 (1999).
    [CrossRef] [PubMed]
  27. K. Sokolov, J. Galvan, A. Myakov, A. Lacy, R. Lotan, R. Richards-Kortum, “Realistic three-dimensional epithelial tissue phantoms for biomedical optics,” J. Biomed. Opt. 7, 1–9 (2002).
    [CrossRef]
  28. T. Collier, D. Arifler, A. Malpica, M. Follen, R. Richards-Kortum, “Determination of epithelial tissue scattering coefficient using confocal microscopy,” IEEE J. Sel. Top. Quantum Electron. 9, 307–313 (2003).
    [CrossRef]
  29. A. Dunn, C. Smithpeter, A. J. Welch, R. Richards-Kortum, “FDTD simulations of light scattering from single cells,” J. Biomed. Opt. 2, 262–266 (1997).
    [CrossRef] [PubMed]
  30. R. Drezek, A. Dunn, R. Richards-Kortum, “Light scattering from cells: finite-difference time-domain simulations and goniometric measurements,” Appl. Opt. 38, 3651–3661 (1999).
    [CrossRef]
  31. J. R. Mourant, J. P. Freyer, A. H. Hielscher, A. A. Eick, D. Shen, T. M. Johnson, “Mechanism of light scattering from biological cells relevant to noninvasive optical-tissue diagnostics,” Appl. Opt. 37, 3586–3593 (1998).
    [CrossRef]
  32. A. Brunsting, P. F. Mullaney, “Differential light scattering from spherical mammalian cells,” Biophys. J. 14, 439–453 (1974).
    [CrossRef] [PubMed]
  33. J. R. Mourant, T. M. Johnson, J. P. Freyer, “Characterizing mammalian cells and cell phantoms by polarized backscattering fiber-optic measurements,” Appl. Opt. 40, 5114–5123 (2001).
    [CrossRef]
  34. J. M. Schmitt, G. Kumar, “Optical scattering properties of soft tissue: a discrete particle model,” Appl. Opt. 37, 2788–2797 (1998).
    [CrossRef]
  35. N. Takaha, A. L. Hawkins, C. A. Griffin, W. B. Isaacs, D. S. Coffey, “High mobility group protein I (Y): a candidate architectural protein for chromosomal rearrangements in prostate cancer cells,” Cancer Res. 62, 647–651 (2002).
    [PubMed]
  36. G. Zonios, J. Bykowski, N. Kollias, “Skin melanin, hemoglobin, and light scattering properties can be quantitatively assessed in vivo using diffuse reflectance spectroscopy,” J. Investigat. Dermatol. 117, 1452–1457 (2001).
    [CrossRef]

2003

I. Pavlova, K. Sokolov, R. Drezek, A. Malpica, M. Follen, R. Richards-Kortum, “Microanatomical and biochemical origins of normal and precancerous cervical autofluorescence using laser scanning fluorescence confocal microscopy,” Photochem. Photobiol. 77, 550–555 (2003).
[CrossRef] [PubMed]

U. Utzinger, R. Richards-Kortum, “Fiber optic probes for biomedical optical spectroscopy,” J. Biomed. Opt. 8, 121–147 (2003).
[CrossRef] [PubMed]

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

2002

A. Myakov, L. Nieman, L. Wicky, U. Utzinger, R. Richards-Kortum, K. Sokolov, “Fiber optic probe for polarized reflectance spectroscopy in vivo: design and performance,” J. Biomed. Opt. 7, 388–397 (2002).
[CrossRef] [PubMed]

N. Takaha, A. L. Hawkins, C. A. Griffin, W. B. Isaacs, D. S. Coffey, “High mobility group protein I (Y): a candidate architectural protein for chromosomal rearrangements in prostate cancer cells,” Cancer Res. 62, 647–651 (2002).
[PubMed]

K. Sokolov, J. Galvan, A. Myakov, A. Lacy, R. Lotan, R. Richards-Kortum, “Realistic three-dimensional epithelial tissue phantoms for biomedical optics,” J. Biomed. Opt. 7, 1–9 (2002).
[CrossRef]

L. Quan, N. Ramanujam, “Relationship between depth of target in a turbid medium and fluorescence measured by a variable-aperture method,” Opt. Lett. 27, 104–106 (2002).
[CrossRef]

T. J. Pfefer, K. T. Schomacker, M. N. Ediger, N. S. Nishioka, “Multiple-fiber probe design for fluorescence spectroscopy in tissue,” Appl. Opt. 41, 4712–4721 (2002).
[CrossRef] [PubMed]

K. Sokolov, M. Follen, R. Richards-Kortum, “Optical spectroscopy for detection of neoplasia,” Curr. Opin. Chem. Biol. 6, 651–658 (2002).
[CrossRef] [PubMed]

S. L. Jacques, J. C. Ramella-Roman, K. Lee, “Imaging skin pathology with polarized light,” J. Biomed. Opt. 7, 329–340 (2002).
[CrossRef] [PubMed]

I. Georgakoudi, E. Sheets, M. G. Muller, V. Backman, C. P. Crum, K. Badizadegan, R. R. Dasari, M. S. Feld, G. R. Harrison, “Trimodal spectroscopy for the detection and characterization of cervical precancers in vivo,” Am. J. Obstet. Gynecol. 166, 374–362 (2002).
[CrossRef]

I. Georgakoudi, B. C. Jacobson, M. G. Muller, E. E. Sheets, K. Badizadegan, D. L. Carr-Locke, C. P. Crum, C. W. Boone, R. R. Dasari, J. Van Dam, M. S. Feld, “NAD(P)H and collagen as in vivo quantitative fluorescent biomarkers of epithelial precancerous changes,” Cancer Res. 62, 682–687 (2002).
[PubMed]

2001

R. Drezek, M. Guillaud, T. Collier, I. Boiko, A. Malpica, C. Macaulay, M. Follen, R. Richards-Kortum, “Light scattering from cervical cells throughout neoplastic progression: influence of nuclear morphology, DNA content, and chromatin texture,” J. Biomed. Opt. 8, 7–16 (2001).
[CrossRef]

R. Drezek, C. Brookner, I. Pavlova, I. Boiko, A. Malpica, R. Lotan, M. Follen, R. Richards-Kortum, “Autofluorescence microscopy of fresh cervical-tissue sections reveals alterations in tissue biochemistry with dysplasia,” Photochem. Photobiol. 73, 636–641 (2001).
[CrossRef] [PubMed]

G. Zonios, J. Bykowski, N. Kollias, “Skin melanin, hemoglobin, and light scattering properties can be quantitatively assessed in vivo using diffuse reflectance spectroscopy,” J. Investigat. Dermatol. 117, 1452–1457 (2001).
[CrossRef]

J. R. Mourant, T. M. Johnson, J. P. Freyer, “Characterizing mammalian cells and cell phantoms by polarized backscattering fiber-optic measurements,” Appl. Opt. 40, 5114–5123 (2001).
[CrossRef]

2000

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

S. L. Jacques, J. Roman, K. Lee, “Imaging superficial tissues with polarized light,” Lasers Surgery Med. 26, 119–129 (2000).
[CrossRef]

1999

C. Streuli, “Extracellular matrix remodeling and cellular differentiation,” Curr. Opin. Cell Biol. 11, 634–640 (1999).
[CrossRef] [PubMed]

V. Backman, R. Gurjar, K. Badizadegan, I. Itzkan, R. Dasari, L. T. Perelman, M. S. Feld, “Polarized light scattering spectroscopy for quantitative measurements of epithelial cellular structures in situ,” IEEE J. Sel. Top. Quantum Electron. 5, 1019–1026 (1999).
[CrossRef]

W. M. White, M. Rajadhyaksha, S. Gonzalez, R. L. Fabian, R. R. Anderson, “Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy,” Laryngoscope 109, 1709–1717 (1999).
[CrossRef] [PubMed]

K. Sokolov, R. Drezek, K. Gossage, R. Richards-Kortum, “Reflectance spectroscopy with polarized light: is it sensitive to cellular and nuclear morphology,” Opt. Express 5, 302–317 (1999).
[CrossRef] [PubMed]

R. Drezek, A. Dunn, R. Richards-Kortum, “Light scattering from cells: finite-difference time-domain simulations and goniometric measurements,” Appl. Opt. 38, 3651–3661 (1999).
[CrossRef]

1998

1997

W. K. Hong, M. B. Sporn, “Recent advances in chemoprevention of cancer,” Science 278, 1073–1077 (1997).
[CrossRef] [PubMed]

I. J. Bigio, J. R. Mourant, “Ultraviolet and visible spectroscopies for tissue diagnostics: fluorescence spectroscopy and elastic-scattering spectroscopy,” Phys. Med. Biol. 42, 603–614 (1997).
[CrossRef]

J. R. Mourant, T. Fuselier, J. Boyer, T. M. Johnson, I. J. Bigio, “Predictions and measurements of scattering and absorption over broad wavelength ranges in tissue phantoms,” Appl. Opt. 36, 949–957 (1997).
[CrossRef] [PubMed]

A. Dunn, C. Smithpeter, A. J. Welch, R. Richards-Kortum, “FDTD simulations of light scattering from single cells,” J. Biomed. Opt. 2, 262–266 (1997).
[CrossRef] [PubMed]

A. H. Hielscher, J. R. Mourant, I. J. Bigio, “Influence of particle size and concentration on the diffuse backscattering of polarized light from tissue phantoms and biological cell suspensions,” Appl. Opt. 36, 125–135 (1997).
[CrossRef] [PubMed]

1996

L. T. Perelman, V. Backman, M. Wallace, G. Zonios, R. Manoharan, A. Nusrat, S. Shields, M. Seiler, C. Lima, T. Hamano, I. Itzkan, J. Van Dam, J. M. Crawford, M. S. Feld, “Observation of periodic fine structure in reflectance from biological tissue: a new technique for measuring nuclear size distribution,” Phys. Rev. Lett. 60, 627–630 (1996).

R. Richards-Kortum, E. Sevick-Muraca, “Quantitative optical spectroscopy for tissue diagnosis,” Annu. Rev. Chem. 47, 555–606 (1996).
[CrossRef]

1991

R. R. Anderson, “Polarized light examination and photography of the skin,” Arch. Dermatol. 127, 1000–1005 (1991).
[CrossRef] [PubMed]

1974

A. Brunsting, P. F. Mullaney, “Differential light scattering from spherical mammalian cells,” Biophys. J. 14, 439–453 (1974).
[CrossRef] [PubMed]

Anderson, R. R.

W. M. White, M. Rajadhyaksha, S. Gonzalez, R. L. Fabian, R. R. Anderson, “Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy,” Laryngoscope 109, 1709–1717 (1999).
[CrossRef] [PubMed]

R. R. Anderson, “Polarized light examination and photography of the skin,” Arch. Dermatol. 127, 1000–1005 (1991).
[CrossRef] [PubMed]

Arendt, J. T.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

Arifler, D.

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

Backman, V.

I. Georgakoudi, E. Sheets, M. G. Muller, V. Backman, C. P. Crum, K. Badizadegan, R. R. Dasari, M. S. Feld, G. R. Harrison, “Trimodal spectroscopy for the detection and characterization of cervical precancers in vivo,” Am. J. Obstet. Gynecol. 166, 374–362 (2002).
[CrossRef]

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

V. Backman, R. Gurjar, K. Badizadegan, I. Itzkan, R. Dasari, L. T. Perelman, M. S. Feld, “Polarized light scattering spectroscopy for quantitative measurements of epithelial cellular structures in situ,” IEEE J. Sel. Top. Quantum Electron. 5, 1019–1026 (1999).
[CrossRef]

L. T. Perelman, V. Backman, M. Wallace, G. Zonios, R. Manoharan, A. Nusrat, S. Shields, M. Seiler, C. Lima, T. Hamano, I. Itzkan, J. Van Dam, J. M. Crawford, M. S. Feld, “Observation of periodic fine structure in reflectance from biological tissue: a new technique for measuring nuclear size distribution,” Phys. Rev. Lett. 60, 627–630 (1996).

Badizadegan, K.

I. Georgakoudi, E. Sheets, M. G. Muller, V. Backman, C. P. Crum, K. Badizadegan, R. R. Dasari, M. S. Feld, G. R. Harrison, “Trimodal spectroscopy for the detection and characterization of cervical precancers in vivo,” Am. J. Obstet. Gynecol. 166, 374–362 (2002).
[CrossRef]

I. Georgakoudi, B. C. Jacobson, M. G. Muller, E. E. Sheets, K. Badizadegan, D. L. Carr-Locke, C. P. Crum, C. W. Boone, R. R. Dasari, J. Van Dam, M. S. Feld, “NAD(P)H and collagen as in vivo quantitative fluorescent biomarkers of epithelial precancerous changes,” Cancer Res. 62, 682–687 (2002).
[PubMed]

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

V. Backman, R. Gurjar, K. Badizadegan, I. Itzkan, R. Dasari, L. T. Perelman, M. S. Feld, “Polarized light scattering spectroscopy for quantitative measurements of epithelial cellular structures in situ,” IEEE J. Sel. Top. Quantum Electron. 5, 1019–1026 (1999).
[CrossRef]

Bigio, I. J.

Boiko, I.

R. Drezek, M. Guillaud, T. Collier, I. Boiko, A. Malpica, C. Macaulay, M. Follen, R. Richards-Kortum, “Light scattering from cervical cells throughout neoplastic progression: influence of nuclear morphology, DNA content, and chromatin texture,” J. Biomed. Opt. 8, 7–16 (2001).
[CrossRef]

R. Drezek, C. Brookner, I. Pavlova, I. Boiko, A. Malpica, R. Lotan, M. Follen, R. Richards-Kortum, “Autofluorescence microscopy of fresh cervical-tissue sections reveals alterations in tissue biochemistry with dysplasia,” Photochem. Photobiol. 73, 636–641 (2001).
[CrossRef] [PubMed]

Boone, C. W.

I. Georgakoudi, B. C. Jacobson, M. G. Muller, E. E. Sheets, K. Badizadegan, D. L. Carr-Locke, C. P. Crum, C. W. Boone, R. R. Dasari, J. Van Dam, M. S. Feld, “NAD(P)H and collagen as in vivo quantitative fluorescent biomarkers of epithelial precancerous changes,” Cancer Res. 62, 682–687 (2002).
[PubMed]

Boyer, J.

Brookner, C.

R. Drezek, C. Brookner, I. Pavlova, I. Boiko, A. Malpica, R. Lotan, M. Follen, R. Richards-Kortum, “Autofluorescence microscopy of fresh cervical-tissue sections reveals alterations in tissue biochemistry with dysplasia,” Photochem. Photobiol. 73, 636–641 (2001).
[CrossRef] [PubMed]

Brunsting, A.

A. Brunsting, P. F. Mullaney, “Differential light scattering from spherical mammalian cells,” Biophys. J. 14, 439–453 (1974).
[CrossRef] [PubMed]

Bykowski, J.

G. Zonios, J. Bykowski, N. Kollias, “Skin melanin, hemoglobin, and light scattering properties can be quantitatively assessed in vivo using diffuse reflectance spectroscopy,” J. Investigat. Dermatol. 117, 1452–1457 (2001).
[CrossRef]

Carr-Locke, D. L.

I. Georgakoudi, B. C. Jacobson, M. G. Muller, E. E. Sheets, K. Badizadegan, D. L. Carr-Locke, C. P. Crum, C. W. Boone, R. R. Dasari, J. Van Dam, M. S. Feld, “NAD(P)H and collagen as in vivo quantitative fluorescent biomarkers of epithelial precancerous changes,” Cancer Res. 62, 682–687 (2002).
[PubMed]

Coffey, D. S.

N. Takaha, A. L. Hawkins, C. A. Griffin, W. B. Isaacs, D. S. Coffey, “High mobility group protein I (Y): a candidate architectural protein for chromosomal rearrangements in prostate cancer cells,” Cancer Res. 62, 647–651 (2002).
[PubMed]

Collier, T.

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

R. Drezek, M. Guillaud, T. Collier, I. Boiko, A. Malpica, C. Macaulay, M. Follen, R. Richards-Kortum, “Light scattering from cervical cells throughout neoplastic progression: influence of nuclear morphology, DNA content, and chromatin texture,” J. Biomed. Opt. 8, 7–16 (2001).
[CrossRef]

Cotran, R.

R. Cotran, V. Kumar, S. Robbins, Pathologic Basis of Disease, 5th ed. (Saunders, Philadelphia, 1994), chap. 7.

Crawford, J. M.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

L. T. Perelman, V. Backman, M. Wallace, G. Zonios, R. Manoharan, A. Nusrat, S. Shields, M. Seiler, C. Lima, T. Hamano, I. Itzkan, J. Van Dam, J. M. Crawford, M. S. Feld, “Observation of periodic fine structure in reflectance from biological tissue: a new technique for measuring nuclear size distribution,” Phys. Rev. Lett. 60, 627–630 (1996).

Crum, C. P.

I. Georgakoudi, E. Sheets, M. G. Muller, V. Backman, C. P. Crum, K. Badizadegan, R. R. Dasari, M. S. Feld, G. R. Harrison, “Trimodal spectroscopy for the detection and characterization of cervical precancers in vivo,” Am. J. Obstet. Gynecol. 166, 374–362 (2002).
[CrossRef]

I. Georgakoudi, B. C. Jacobson, M. G. Muller, E. E. Sheets, K. Badizadegan, D. L. Carr-Locke, C. P. Crum, C. W. Boone, R. R. Dasari, J. Van Dam, M. S. Feld, “NAD(P)H and collagen as in vivo quantitative fluorescent biomarkers of epithelial precancerous changes,” Cancer Res. 62, 682–687 (2002).
[PubMed]

Dasari, R.

V. Backman, R. Gurjar, K. Badizadegan, I. Itzkan, R. Dasari, L. T. Perelman, M. S. Feld, “Polarized light scattering spectroscopy for quantitative measurements of epithelial cellular structures in situ,” IEEE J. Sel. Top. Quantum Electron. 5, 1019–1026 (1999).
[CrossRef]

Dasari, R. R.

I. Georgakoudi, E. Sheets, M. G. Muller, V. Backman, C. P. Crum, K. Badizadegan, R. R. Dasari, M. S. Feld, G. R. Harrison, “Trimodal spectroscopy for the detection and characterization of cervical precancers in vivo,” Am. J. Obstet. Gynecol. 166, 374–362 (2002).
[CrossRef]

I. Georgakoudi, B. C. Jacobson, M. G. Muller, E. E. Sheets, K. Badizadegan, D. L. Carr-Locke, C. P. Crum, C. W. Boone, R. R. Dasari, J. Van Dam, M. S. Feld, “NAD(P)H and collagen as in vivo quantitative fluorescent biomarkers of epithelial precancerous changes,” Cancer Res. 62, 682–687 (2002).
[PubMed]

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

Drezek, R.

I. Pavlova, K. Sokolov, R. Drezek, A. Malpica, M. Follen, R. Richards-Kortum, “Microanatomical and biochemical origins of normal and precancerous cervical autofluorescence using laser scanning fluorescence confocal microscopy,” Photochem. Photobiol. 77, 550–555 (2003).
[CrossRef] [PubMed]

R. Drezek, M. Guillaud, T. Collier, I. Boiko, A. Malpica, C. Macaulay, M. Follen, R. Richards-Kortum, “Light scattering from cervical cells throughout neoplastic progression: influence of nuclear morphology, DNA content, and chromatin texture,” J. Biomed. Opt. 8, 7–16 (2001).
[CrossRef]

R. Drezek, C. Brookner, I. Pavlova, I. Boiko, A. Malpica, R. Lotan, M. Follen, R. Richards-Kortum, “Autofluorescence microscopy of fresh cervical-tissue sections reveals alterations in tissue biochemistry with dysplasia,” Photochem. Photobiol. 73, 636–641 (2001).
[CrossRef] [PubMed]

K. Sokolov, R. Drezek, K. Gossage, R. Richards-Kortum, “Reflectance spectroscopy with polarized light: is it sensitive to cellular and nuclear morphology,” Opt. Express 5, 302–317 (1999).
[CrossRef] [PubMed]

R. Drezek, A. Dunn, R. Richards-Kortum, “Light scattering from cells: finite-difference time-domain simulations and goniometric measurements,” Appl. Opt. 38, 3651–3661 (1999).
[CrossRef]

Dunn, A.

R. Drezek, A. Dunn, R. Richards-Kortum, “Light scattering from cells: finite-difference time-domain simulations and goniometric measurements,” Appl. Opt. 38, 3651–3661 (1999).
[CrossRef]

A. Dunn, C. Smithpeter, A. J. Welch, R. Richards-Kortum, “FDTD simulations of light scattering from single cells,” J. Biomed. Opt. 2, 262–266 (1997).
[CrossRef] [PubMed]

Ediger, M. N.

Eick, A. A.

J. R. Mourant, J. P. Freyer, A. H. Hielscher, A. A. Eick, D. Shen, T. M. Johnson, “Mechanism of light scattering from biological cells relevant to noninvasive optical-tissue diagnostics,” Appl. Opt. 37, 3586–3593 (1998).
[CrossRef]

J. R. Mourant, A. H. Hielscher, A. A. Eick, T. M. Johnson, J. P. Freyer, “Evidence of intrinsic differences in the light scattering properties of tumorigenic and nontumorigenic cells,” Cancer 84, 366–374 (1998).
[CrossRef]

Fabian, R. L.

W. M. White, M. Rajadhyaksha, S. Gonzalez, R. L. Fabian, R. R. Anderson, “Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy,” Laryngoscope 109, 1709–1717 (1999).
[CrossRef] [PubMed]

Feld, M. S.

I. Georgakoudi, B. C. Jacobson, M. G. Muller, E. E. Sheets, K. Badizadegan, D. L. Carr-Locke, C. P. Crum, C. W. Boone, R. R. Dasari, J. Van Dam, M. S. Feld, “NAD(P)H and collagen as in vivo quantitative fluorescent biomarkers of epithelial precancerous changes,” Cancer Res. 62, 682–687 (2002).
[PubMed]

I. Georgakoudi, E. Sheets, M. G. Muller, V. Backman, C. P. Crum, K. Badizadegan, R. R. Dasari, M. S. Feld, G. R. Harrison, “Trimodal spectroscopy for the detection and characterization of cervical precancers in vivo,” Am. J. Obstet. Gynecol. 166, 374–362 (2002).
[CrossRef]

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

V. Backman, R. Gurjar, K. Badizadegan, I. Itzkan, R. Dasari, L. T. Perelman, M. S. Feld, “Polarized light scattering spectroscopy for quantitative measurements of epithelial cellular structures in situ,” IEEE J. Sel. Top. Quantum Electron. 5, 1019–1026 (1999).
[CrossRef]

L. T. Perelman, V. Backman, M. Wallace, G. Zonios, R. Manoharan, A. Nusrat, S. Shields, M. Seiler, C. Lima, T. Hamano, I. Itzkan, J. Van Dam, J. M. Crawford, M. S. Feld, “Observation of periodic fine structure in reflectance from biological tissue: a new technique for measuring nuclear size distribution,” Phys. Rev. Lett. 60, 627–630 (1996).

Fitzmaurice, M.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

Follen, M.

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

I. Pavlova, K. Sokolov, R. Drezek, A. Malpica, M. Follen, R. Richards-Kortum, “Microanatomical and biochemical origins of normal and precancerous cervical autofluorescence using laser scanning fluorescence confocal microscopy,” Photochem. Photobiol. 77, 550–555 (2003).
[CrossRef] [PubMed]

K. Sokolov, M. Follen, R. Richards-Kortum, “Optical spectroscopy for detection of neoplasia,” Curr. Opin. Chem. Biol. 6, 651–658 (2002).
[CrossRef] [PubMed]

R. Drezek, C. Brookner, I. Pavlova, I. Boiko, A. Malpica, R. Lotan, M. Follen, R. Richards-Kortum, “Autofluorescence microscopy of fresh cervical-tissue sections reveals alterations in tissue biochemistry with dysplasia,” Photochem. Photobiol. 73, 636–641 (2001).
[CrossRef] [PubMed]

R. Drezek, M. Guillaud, T. Collier, I. Boiko, A. Malpica, C. Macaulay, M. Follen, R. Richards-Kortum, “Light scattering from cervical cells throughout neoplastic progression: influence of nuclear morphology, DNA content, and chromatin texture,” J. Biomed. Opt. 8, 7–16 (2001).
[CrossRef]

Freyer, J. P.

Fuselier, T.

Galvan, J.

K. Sokolov, J. Galvan, A. Myakov, A. Lacy, R. Lotan, R. Richards-Kortum, “Realistic three-dimensional epithelial tissue phantoms for biomedical optics,” J. Biomed. Opt. 7, 1–9 (2002).
[CrossRef]

Georgakoudi, I.

I. Georgakoudi, E. Sheets, M. G. Muller, V. Backman, C. P. Crum, K. Badizadegan, R. R. Dasari, M. S. Feld, G. R. Harrison, “Trimodal spectroscopy for the detection and characterization of cervical precancers in vivo,” Am. J. Obstet. Gynecol. 166, 374–362 (2002).
[CrossRef]

I. Georgakoudi, B. C. Jacobson, M. G. Muller, E. E. Sheets, K. Badizadegan, D. L. Carr-Locke, C. P. Crum, C. W. Boone, R. R. Dasari, J. Van Dam, M. S. Feld, “NAD(P)H and collagen as in vivo quantitative fluorescent biomarkers of epithelial precancerous changes,” Cancer Res. 62, 682–687 (2002).
[PubMed]

Gonzalez, S.

W. M. White, M. Rajadhyaksha, S. Gonzalez, R. L. Fabian, R. R. Anderson, “Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy,” Laryngoscope 109, 1709–1717 (1999).
[CrossRef] [PubMed]

Gossage, K.

Griffin, C. A.

N. Takaha, A. L. Hawkins, C. A. Griffin, W. B. Isaacs, D. S. Coffey, “High mobility group protein I (Y): a candidate architectural protein for chromosomal rearrangements in prostate cancer cells,” Cancer Res. 62, 647–651 (2002).
[PubMed]

Guillaud, M.

R. Drezek, M. Guillaud, T. Collier, I. Boiko, A. Malpica, C. Macaulay, M. Follen, R. Richards-Kortum, “Light scattering from cervical cells throughout neoplastic progression: influence of nuclear morphology, DNA content, and chromatin texture,” J. Biomed. Opt. 8, 7–16 (2001).
[CrossRef]

Gurjar, R.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

V. Backman, R. Gurjar, K. Badizadegan, I. Itzkan, R. Dasari, L. T. Perelman, M. S. Feld, “Polarized light scattering spectroscopy for quantitative measurements of epithelial cellular structures in situ,” IEEE J. Sel. Top. Quantum Electron. 5, 1019–1026 (1999).
[CrossRef]

Hamano, T.

L. T. Perelman, V. Backman, M. Wallace, G. Zonios, R. Manoharan, A. Nusrat, S. Shields, M. Seiler, C. Lima, T. Hamano, I. Itzkan, J. Van Dam, J. M. Crawford, M. S. Feld, “Observation of periodic fine structure in reflectance from biological tissue: a new technique for measuring nuclear size distribution,” Phys. Rev. Lett. 60, 627–630 (1996).

Harrison, G. R.

I. Georgakoudi, E. Sheets, M. G. Muller, V. Backman, C. P. Crum, K. Badizadegan, R. R. Dasari, M. S. Feld, G. R. Harrison, “Trimodal spectroscopy for the detection and characterization of cervical precancers in vivo,” Am. J. Obstet. Gynecol. 166, 374–362 (2002).
[CrossRef]

Hawkins, A. L.

N. Takaha, A. L. Hawkins, C. A. Griffin, W. B. Isaacs, D. S. Coffey, “High mobility group protein I (Y): a candidate architectural protein for chromosomal rearrangements in prostate cancer cells,” Cancer Res. 62, 647–651 (2002).
[PubMed]

Hielscher, A. H.

Hong, W. K.

W. K. Hong, M. B. Sporn, “Recent advances in chemoprevention of cancer,” Science 278, 1073–1077 (1997).
[CrossRef] [PubMed]

Isaacs, W. B.

N. Takaha, A. L. Hawkins, C. A. Griffin, W. B. Isaacs, D. S. Coffey, “High mobility group protein I (Y): a candidate architectural protein for chromosomal rearrangements in prostate cancer cells,” Cancer Res. 62, 647–651 (2002).
[PubMed]

Itzkan, I.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

V. Backman, R. Gurjar, K. Badizadegan, I. Itzkan, R. Dasari, L. T. Perelman, M. S. Feld, “Polarized light scattering spectroscopy for quantitative measurements of epithelial cellular structures in situ,” IEEE J. Sel. Top. Quantum Electron. 5, 1019–1026 (1999).
[CrossRef]

L. T. Perelman, V. Backman, M. Wallace, G. Zonios, R. Manoharan, A. Nusrat, S. Shields, M. Seiler, C. Lima, T. Hamano, I. Itzkan, J. Van Dam, J. M. Crawford, M. S. Feld, “Observation of periodic fine structure in reflectance from biological tissue: a new technique for measuring nuclear size distribution,” Phys. Rev. Lett. 60, 627–630 (1996).

Jacobson, B. C.

I. Georgakoudi, B. C. Jacobson, M. G. Muller, E. E. Sheets, K. Badizadegan, D. L. Carr-Locke, C. P. Crum, C. W. Boone, R. R. Dasari, J. Van Dam, M. S. Feld, “NAD(P)H and collagen as in vivo quantitative fluorescent biomarkers of epithelial precancerous changes,” Cancer Res. 62, 682–687 (2002).
[PubMed]

Jacques, S. L.

S. L. Jacques, J. C. Ramella-Roman, K. Lee, “Imaging skin pathology with polarized light,” J. Biomed. Opt. 7, 329–340 (2002).
[CrossRef] [PubMed]

S. L. Jacques, J. Roman, K. Lee, “Imaging superficial tissues with polarized light,” Lasers Surgery Med. 26, 119–129 (2000).
[CrossRef]

Johnson, T. M.

Kabani, S.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

Kline, E.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

Kollias, N.

G. Zonios, J. Bykowski, N. Kollias, “Skin melanin, hemoglobin, and light scattering properties can be quantitatively assessed in vivo using diffuse reflectance spectroscopy,” J. Investigat. Dermatol. 117, 1452–1457 (2001).
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Kumar, G.

Kumar, V.

R. Cotran, V. Kumar, S. Robbins, Pathologic Basis of Disease, 5th ed. (Saunders, Philadelphia, 1994), chap. 7.

Lacy, A.

K. Sokolov, J. Galvan, A. Myakov, A. Lacy, R. Lotan, R. Richards-Kortum, “Realistic three-dimensional epithelial tissue phantoms for biomedical optics,” J. Biomed. Opt. 7, 1–9 (2002).
[CrossRef]

Lee, K.

S. L. Jacques, J. C. Ramella-Roman, K. Lee, “Imaging skin pathology with polarized light,” J. Biomed. Opt. 7, 329–340 (2002).
[CrossRef] [PubMed]

S. L. Jacques, J. Roman, K. Lee, “Imaging superficial tissues with polarized light,” Lasers Surgery Med. 26, 119–129 (2000).
[CrossRef]

Levin, H. S.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

Lima, C.

L. T. Perelman, V. Backman, M. Wallace, G. Zonios, R. Manoharan, A. Nusrat, S. Shields, M. Seiler, C. Lima, T. Hamano, I. Itzkan, J. Van Dam, J. M. Crawford, M. S. Feld, “Observation of periodic fine structure in reflectance from biological tissue: a new technique for measuring nuclear size distribution,” Phys. Rev. Lett. 60, 627–630 (1996).

Lotan, R.

K. Sokolov, J. Galvan, A. Myakov, A. Lacy, R. Lotan, R. Richards-Kortum, “Realistic three-dimensional epithelial tissue phantoms for biomedical optics,” J. Biomed. Opt. 7, 1–9 (2002).
[CrossRef]

R. Drezek, C. Brookner, I. Pavlova, I. Boiko, A. Malpica, R. Lotan, M. Follen, R. Richards-Kortum, “Autofluorescence microscopy of fresh cervical-tissue sections reveals alterations in tissue biochemistry with dysplasia,” Photochem. Photobiol. 73, 636–641 (2001).
[CrossRef] [PubMed]

Macaulay, C.

R. Drezek, M. Guillaud, T. Collier, I. Boiko, A. Malpica, C. Macaulay, M. Follen, R. Richards-Kortum, “Light scattering from cervical cells throughout neoplastic progression: influence of nuclear morphology, DNA content, and chromatin texture,” J. Biomed. Opt. 8, 7–16 (2001).
[CrossRef]

Malpica, A.

I. Pavlova, K. Sokolov, R. Drezek, A. Malpica, M. Follen, R. Richards-Kortum, “Microanatomical and biochemical origins of normal and precancerous cervical autofluorescence using laser scanning fluorescence confocal microscopy,” Photochem. Photobiol. 77, 550–555 (2003).
[CrossRef] [PubMed]

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

R. Drezek, M. Guillaud, T. Collier, I. Boiko, A. Malpica, C. Macaulay, M. Follen, R. Richards-Kortum, “Light scattering from cervical cells throughout neoplastic progression: influence of nuclear morphology, DNA content, and chromatin texture,” J. Biomed. Opt. 8, 7–16 (2001).
[CrossRef]

R. Drezek, C. Brookner, I. Pavlova, I. Boiko, A. Malpica, R. Lotan, M. Follen, R. Richards-Kortum, “Autofluorescence microscopy of fresh cervical-tissue sections reveals alterations in tissue biochemistry with dysplasia,” Photochem. Photobiol. 73, 636–641 (2001).
[CrossRef] [PubMed]

Manoharan, R.

L. T. Perelman, V. Backman, M. Wallace, G. Zonios, R. Manoharan, A. Nusrat, S. Shields, M. Seiler, C. Lima, T. Hamano, I. Itzkan, J. Van Dam, J. M. Crawford, M. S. Feld, “Observation of periodic fine structure in reflectance from biological tissue: a new technique for measuring nuclear size distribution,” Phys. Rev. Lett. 60, 627–630 (1996).

McGillican, T.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

Mourant, J. R.

Mullaney, P. F.

A. Brunsting, P. F. Mullaney, “Differential light scattering from spherical mammalian cells,” Biophys. J. 14, 439–453 (1974).
[CrossRef] [PubMed]

Muller, M. G.

I. Georgakoudi, B. C. Jacobson, M. G. Muller, E. E. Sheets, K. Badizadegan, D. L. Carr-Locke, C. P. Crum, C. W. Boone, R. R. Dasari, J. Van Dam, M. S. Feld, “NAD(P)H and collagen as in vivo quantitative fluorescent biomarkers of epithelial precancerous changes,” Cancer Res. 62, 682–687 (2002).
[PubMed]

I. Georgakoudi, E. Sheets, M. G. Muller, V. Backman, C. P. Crum, K. Badizadegan, R. R. Dasari, M. S. Feld, G. R. Harrison, “Trimodal spectroscopy for the detection and characterization of cervical precancers in vivo,” Am. J. Obstet. Gynecol. 166, 374–362 (2002).
[CrossRef]

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

Myakov, A.

K. Sokolov, J. Galvan, A. Myakov, A. Lacy, R. Lotan, R. Richards-Kortum, “Realistic three-dimensional epithelial tissue phantoms for biomedical optics,” J. Biomed. Opt. 7, 1–9 (2002).
[CrossRef]

A. Myakov, L. Nieman, L. Wicky, U. Utzinger, R. Richards-Kortum, K. Sokolov, “Fiber optic probe for polarized reflectance spectroscopy in vivo: design and performance,” J. Biomed. Opt. 7, 388–397 (2002).
[CrossRef] [PubMed]

Nieman, L.

A. Myakov, L. Nieman, L. Wicky, U. Utzinger, R. Richards-Kortum, K. Sokolov, “Fiber optic probe for polarized reflectance spectroscopy in vivo: design and performance,” J. Biomed. Opt. 7, 388–397 (2002).
[CrossRef] [PubMed]

Nishioka, N. S.

Nusrat, A.

L. T. Perelman, V. Backman, M. Wallace, G. Zonios, R. Manoharan, A. Nusrat, S. Shields, M. Seiler, C. Lima, T. Hamano, I. Itzkan, J. Van Dam, J. M. Crawford, M. S. Feld, “Observation of periodic fine structure in reflectance from biological tissue: a new technique for measuring nuclear size distribution,” Phys. Rev. Lett. 60, 627–630 (1996).

Pavlova, I.

I. Pavlova, K. Sokolov, R. Drezek, A. Malpica, M. Follen, R. Richards-Kortum, “Microanatomical and biochemical origins of normal and precancerous cervical autofluorescence using laser scanning fluorescence confocal microscopy,” Photochem. Photobiol. 77, 550–555 (2003).
[CrossRef] [PubMed]

R. Drezek, C. Brookner, I. Pavlova, I. Boiko, A. Malpica, R. Lotan, M. Follen, R. Richards-Kortum, “Autofluorescence microscopy of fresh cervical-tissue sections reveals alterations in tissue biochemistry with dysplasia,” Photochem. Photobiol. 73, 636–641 (2001).
[CrossRef] [PubMed]

Perelman, L. T.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

V. Backman, R. Gurjar, K. Badizadegan, I. Itzkan, R. Dasari, L. T. Perelman, M. S. Feld, “Polarized light scattering spectroscopy for quantitative measurements of epithelial cellular structures in situ,” IEEE J. Sel. Top. Quantum Electron. 5, 1019–1026 (1999).
[CrossRef]

L. T. Perelman, V. Backman, M. Wallace, G. Zonios, R. Manoharan, A. Nusrat, S. Shields, M. Seiler, C. Lima, T. Hamano, I. Itzkan, J. Van Dam, J. M. Crawford, M. S. Feld, “Observation of periodic fine structure in reflectance from biological tissue: a new technique for measuring nuclear size distribution,” Phys. Rev. Lett. 60, 627–630 (1996).

Pfefer, T. J.

Quan, L.

Rajadhyaksha, M.

W. M. White, M. Rajadhyaksha, S. Gonzalez, R. L. Fabian, R. R. Anderson, “Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy,” Laryngoscope 109, 1709–1717 (1999).
[CrossRef] [PubMed]

Ramanujam, N.

Ramella-Roman, J. C.

S. L. Jacques, J. C. Ramella-Roman, K. Lee, “Imaging skin pathology with polarized light,” J. Biomed. Opt. 7, 329–340 (2002).
[CrossRef] [PubMed]

Richards-Kortum, R.

I. Pavlova, K. Sokolov, R. Drezek, A. Malpica, M. Follen, R. Richards-Kortum, “Microanatomical and biochemical origins of normal and precancerous cervical autofluorescence using laser scanning fluorescence confocal microscopy,” Photochem. Photobiol. 77, 550–555 (2003).
[CrossRef] [PubMed]

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

U. Utzinger, R. Richards-Kortum, “Fiber optic probes for biomedical optical spectroscopy,” J. Biomed. Opt. 8, 121–147 (2003).
[CrossRef] [PubMed]

K. Sokolov, M. Follen, R. Richards-Kortum, “Optical spectroscopy for detection of neoplasia,” Curr. Opin. Chem. Biol. 6, 651–658 (2002).
[CrossRef] [PubMed]

K. Sokolov, J. Galvan, A. Myakov, A. Lacy, R. Lotan, R. Richards-Kortum, “Realistic three-dimensional epithelial tissue phantoms for biomedical optics,” J. Biomed. Opt. 7, 1–9 (2002).
[CrossRef]

A. Myakov, L. Nieman, L. Wicky, U. Utzinger, R. Richards-Kortum, K. Sokolov, “Fiber optic probe for polarized reflectance spectroscopy in vivo: design and performance,” J. Biomed. Opt. 7, 388–397 (2002).
[CrossRef] [PubMed]

R. Drezek, C. Brookner, I. Pavlova, I. Boiko, A. Malpica, R. Lotan, M. Follen, R. Richards-Kortum, “Autofluorescence microscopy of fresh cervical-tissue sections reveals alterations in tissue biochemistry with dysplasia,” Photochem. Photobiol. 73, 636–641 (2001).
[CrossRef] [PubMed]

R. Drezek, M. Guillaud, T. Collier, I. Boiko, A. Malpica, C. Macaulay, M. Follen, R. Richards-Kortum, “Light scattering from cervical cells throughout neoplastic progression: influence of nuclear morphology, DNA content, and chromatin texture,” J. Biomed. Opt. 8, 7–16 (2001).
[CrossRef]

K. Sokolov, R. Drezek, K. Gossage, R. Richards-Kortum, “Reflectance spectroscopy with polarized light: is it sensitive to cellular and nuclear morphology,” Opt. Express 5, 302–317 (1999).
[CrossRef] [PubMed]

R. Drezek, A. Dunn, R. Richards-Kortum, “Light scattering from cells: finite-difference time-domain simulations and goniometric measurements,” Appl. Opt. 38, 3651–3661 (1999).
[CrossRef]

A. Dunn, C. Smithpeter, A. J. Welch, R. Richards-Kortum, “FDTD simulations of light scattering from single cells,” J. Biomed. Opt. 2, 262–266 (1997).
[CrossRef] [PubMed]

R. Richards-Kortum, E. Sevick-Muraca, “Quantitative optical spectroscopy for tissue diagnosis,” Annu. Rev. Chem. 47, 555–606 (1996).
[CrossRef]

Robbins, S.

R. Cotran, V. Kumar, S. Robbins, Pathologic Basis of Disease, 5th ed. (Saunders, Philadelphia, 1994), chap. 7.

Roman, J.

S. L. Jacques, J. Roman, K. Lee, “Imaging superficial tissues with polarized light,” Lasers Surgery Med. 26, 119–129 (2000).
[CrossRef]

Schmitt, J. M.

Schomacker, K. T.

Seiler, M.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

L. T. Perelman, V. Backman, M. Wallace, G. Zonios, R. Manoharan, A. Nusrat, S. Shields, M. Seiler, C. Lima, T. Hamano, I. Itzkan, J. Van Dam, J. M. Crawford, M. S. Feld, “Observation of periodic fine structure in reflectance from biological tissue: a new technique for measuring nuclear size distribution,” Phys. Rev. Lett. 60, 627–630 (1996).

Sevick-Muraca, E.

R. Richards-Kortum, E. Sevick-Muraca, “Quantitative optical spectroscopy for tissue diagnosis,” Annu. Rev. Chem. 47, 555–606 (1996).
[CrossRef]

Shapshay, S.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

Sheets, E.

I. Georgakoudi, E. Sheets, M. G. Muller, V. Backman, C. P. Crum, K. Badizadegan, R. R. Dasari, M. S. Feld, G. R. Harrison, “Trimodal spectroscopy for the detection and characterization of cervical precancers in vivo,” Am. J. Obstet. Gynecol. 166, 374–362 (2002).
[CrossRef]

Sheets, E. E.

I. Georgakoudi, B. C. Jacobson, M. G. Muller, E. E. Sheets, K. Badizadegan, D. L. Carr-Locke, C. P. Crum, C. W. Boone, R. R. Dasari, J. Van Dam, M. S. Feld, “NAD(P)H and collagen as in vivo quantitative fluorescent biomarkers of epithelial precancerous changes,” Cancer Res. 62, 682–687 (2002).
[PubMed]

Shen, D.

Shields, S.

L. T. Perelman, V. Backman, M. Wallace, G. Zonios, R. Manoharan, A. Nusrat, S. Shields, M. Seiler, C. Lima, T. Hamano, I. Itzkan, J. Van Dam, J. M. Crawford, M. S. Feld, “Observation of periodic fine structure in reflectance from biological tissue: a new technique for measuring nuclear size distribution,” Phys. Rev. Lett. 60, 627–630 (1996).

Smithpeter, C.

A. Dunn, C. Smithpeter, A. J. Welch, R. Richards-Kortum, “FDTD simulations of light scattering from single cells,” J. Biomed. Opt. 2, 262–266 (1997).
[CrossRef] [PubMed]

Sokolov, K.

I. Pavlova, K. Sokolov, R. Drezek, A. Malpica, M. Follen, R. Richards-Kortum, “Microanatomical and biochemical origins of normal and precancerous cervical autofluorescence using laser scanning fluorescence confocal microscopy,” Photochem. Photobiol. 77, 550–555 (2003).
[CrossRef] [PubMed]

A. Myakov, L. Nieman, L. Wicky, U. Utzinger, R. Richards-Kortum, K. Sokolov, “Fiber optic probe for polarized reflectance spectroscopy in vivo: design and performance,” J. Biomed. Opt. 7, 388–397 (2002).
[CrossRef] [PubMed]

K. Sokolov, J. Galvan, A. Myakov, A. Lacy, R. Lotan, R. Richards-Kortum, “Realistic three-dimensional epithelial tissue phantoms for biomedical optics,” J. Biomed. Opt. 7, 1–9 (2002).
[CrossRef]

K. Sokolov, M. Follen, R. Richards-Kortum, “Optical spectroscopy for detection of neoplasia,” Curr. Opin. Chem. Biol. 6, 651–658 (2002).
[CrossRef] [PubMed]

K. Sokolov, R. Drezek, K. Gossage, R. Richards-Kortum, “Reflectance spectroscopy with polarized light: is it sensitive to cellular and nuclear morphology,” Opt. Express 5, 302–317 (1999).
[CrossRef] [PubMed]

Sporn, M. B.

W. K. Hong, M. B. Sporn, “Recent advances in chemoprevention of cancer,” Science 278, 1073–1077 (1997).
[CrossRef] [PubMed]

Streuli, C.

C. Streuli, “Extracellular matrix remodeling and cellular differentiation,” Curr. Opin. Cell Biol. 11, 634–640 (1999).
[CrossRef] [PubMed]

Takaha, N.

N. Takaha, A. L. Hawkins, C. A. Griffin, W. B. Isaacs, D. S. Coffey, “High mobility group protein I (Y): a candidate architectural protein for chromosomal rearrangements in prostate cancer cells,” Cancer Res. 62, 647–651 (2002).
[PubMed]

Utzinger, U.

U. Utzinger, R. Richards-Kortum, “Fiber optic probes for biomedical optical spectroscopy,” J. Biomed. Opt. 8, 121–147 (2003).
[CrossRef] [PubMed]

A. Myakov, L. Nieman, L. Wicky, U. Utzinger, R. Richards-Kortum, K. Sokolov, “Fiber optic probe for polarized reflectance spectroscopy in vivo: design and performance,” J. Biomed. Opt. 7, 388–397 (2002).
[CrossRef] [PubMed]

Valdez, T.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

Van Dam, J.

I. Georgakoudi, B. C. Jacobson, M. G. Muller, E. E. Sheets, K. Badizadegan, D. L. Carr-Locke, C. P. Crum, C. W. Boone, R. R. Dasari, J. Van Dam, M. S. Feld, “NAD(P)H and collagen as in vivo quantitative fluorescent biomarkers of epithelial precancerous changes,” Cancer Res. 62, 682–687 (2002).
[PubMed]

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

L. T. Perelman, V. Backman, M. Wallace, G. Zonios, R. Manoharan, A. Nusrat, S. Shields, M. Seiler, C. Lima, T. Hamano, I. Itzkan, J. Van Dam, J. M. Crawford, M. S. Feld, “Observation of periodic fine structure in reflectance from biological tissue: a new technique for measuring nuclear size distribution,” Phys. Rev. Lett. 60, 627–630 (1996).

Wallace, M.

L. T. Perelman, V. Backman, M. Wallace, G. Zonios, R. Manoharan, A. Nusrat, S. Shields, M. Seiler, C. Lima, T. Hamano, I. Itzkan, J. Van Dam, J. M. Crawford, M. S. Feld, “Observation of periodic fine structure in reflectance from biological tissue: a new technique for measuring nuclear size distribution,” Phys. Rev. Lett. 60, 627–630 (1996).

Wallace, M. B.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

Welch, A. J.

A. Dunn, C. Smithpeter, A. J. Welch, R. Richards-Kortum, “FDTD simulations of light scattering from single cells,” J. Biomed. Opt. 2, 262–266 (1997).
[CrossRef] [PubMed]

White, W. M.

W. M. White, M. Rajadhyaksha, S. Gonzalez, R. L. Fabian, R. R. Anderson, “Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy,” Laryngoscope 109, 1709–1717 (1999).
[CrossRef] [PubMed]

Wicky, L.

A. Myakov, L. Nieman, L. Wicky, U. Utzinger, R. Richards-Kortum, K. Sokolov, “Fiber optic probe for polarized reflectance spectroscopy in vivo: design and performance,” J. Biomed. Opt. 7, 388–397 (2002).
[CrossRef] [PubMed]

Zhang, Q.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

Zonios, G.

G. Zonios, J. Bykowski, N. Kollias, “Skin melanin, hemoglobin, and light scattering properties can be quantitatively assessed in vivo using diffuse reflectance spectroscopy,” J. Investigat. Dermatol. 117, 1452–1457 (2001).
[CrossRef]

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

L. T. Perelman, V. Backman, M. Wallace, G. Zonios, R. Manoharan, A. Nusrat, S. Shields, M. Seiler, C. Lima, T. Hamano, I. Itzkan, J. Van Dam, J. M. Crawford, M. S. Feld, “Observation of periodic fine structure in reflectance from biological tissue: a new technique for measuring nuclear size distribution,” Phys. Rev. Lett. 60, 627–630 (1996).

Am. J. Obstet. Gynecol.

I. Georgakoudi, E. Sheets, M. G. Muller, V. Backman, C. P. Crum, K. Badizadegan, R. R. Dasari, M. S. Feld, G. R. Harrison, “Trimodal spectroscopy for the detection and characterization of cervical precancers in vivo,” Am. J. Obstet. Gynecol. 166, 374–362 (2002).
[CrossRef]

Annu. Rev. Chem.

R. Richards-Kortum, E. Sevick-Muraca, “Quantitative optical spectroscopy for tissue diagnosis,” Annu. Rev. Chem. 47, 555–606 (1996).
[CrossRef]

Appl. Opt.

Arch. Dermatol.

R. R. Anderson, “Polarized light examination and photography of the skin,” Arch. Dermatol. 127, 1000–1005 (1991).
[CrossRef] [PubMed]

Biophys. J.

A. Brunsting, P. F. Mullaney, “Differential light scattering from spherical mammalian cells,” Biophys. J. 14, 439–453 (1974).
[CrossRef] [PubMed]

Cancer

J. R. Mourant, A. H. Hielscher, A. A. Eick, T. M. Johnson, J. P. Freyer, “Evidence of intrinsic differences in the light scattering properties of tumorigenic and nontumorigenic cells,” Cancer 84, 366–374 (1998).
[CrossRef]

Cancer Res.

I. Georgakoudi, B. C. Jacobson, M. G. Muller, E. E. Sheets, K. Badizadegan, D. L. Carr-Locke, C. P. Crum, C. W. Boone, R. R. Dasari, J. Van Dam, M. S. Feld, “NAD(P)H and collagen as in vivo quantitative fluorescent biomarkers of epithelial precancerous changes,” Cancer Res. 62, 682–687 (2002).
[PubMed]

N. Takaha, A. L. Hawkins, C. A. Griffin, W. B. Isaacs, D. S. Coffey, “High mobility group protein I (Y): a candidate architectural protein for chromosomal rearrangements in prostate cancer cells,” Cancer Res. 62, 647–651 (2002).
[PubMed]

Curr. Opin. Cell Biol.

C. Streuli, “Extracellular matrix remodeling and cellular differentiation,” Curr. Opin. Cell Biol. 11, 634–640 (1999).
[CrossRef] [PubMed]

Curr. Opin. Chem. Biol.

K. Sokolov, M. Follen, R. Richards-Kortum, “Optical spectroscopy for detection of neoplasia,” Curr. Opin. Chem. Biol. 6, 651–658 (2002).
[CrossRef] [PubMed]

IEEE J. Sel. Top. Quantum Electron.

V. Backman, R. Gurjar, K. Badizadegan, I. Itzkan, R. Dasari, L. T. Perelman, M. S. Feld, “Polarized light scattering spectroscopy for quantitative measurements of epithelial cellular structures in situ,” IEEE J. Sel. Top. Quantum Electron. 5, 1019–1026 (1999).
[CrossRef]

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

J. Biomed. Opt.

A. Dunn, C. Smithpeter, A. J. Welch, R. Richards-Kortum, “FDTD simulations of light scattering from single cells,” J. Biomed. Opt. 2, 262–266 (1997).
[CrossRef] [PubMed]

A. Myakov, L. Nieman, L. Wicky, U. Utzinger, R. Richards-Kortum, K. Sokolov, “Fiber optic probe for polarized reflectance spectroscopy in vivo: design and performance,” J. Biomed. Opt. 7, 388–397 (2002).
[CrossRef] [PubMed]

U. Utzinger, R. Richards-Kortum, “Fiber optic probes for biomedical optical spectroscopy,” J. Biomed. Opt. 8, 121–147 (2003).
[CrossRef] [PubMed]

K. Sokolov, J. Galvan, A. Myakov, A. Lacy, R. Lotan, R. Richards-Kortum, “Realistic three-dimensional epithelial tissue phantoms for biomedical optics,” J. Biomed. Opt. 7, 1–9 (2002).
[CrossRef]

R. Drezek, M. Guillaud, T. Collier, I. Boiko, A. Malpica, C. Macaulay, M. Follen, R. Richards-Kortum, “Light scattering from cervical cells throughout neoplastic progression: influence of nuclear morphology, DNA content, and chromatin texture,” J. Biomed. Opt. 8, 7–16 (2001).
[CrossRef]

S. L. Jacques, J. C. Ramella-Roman, K. Lee, “Imaging skin pathology with polarized light,” J. Biomed. Opt. 7, 329–340 (2002).
[CrossRef] [PubMed]

J. Investigat. Dermatol.

G. Zonios, J. Bykowski, N. Kollias, “Skin melanin, hemoglobin, and light scattering properties can be quantitatively assessed in vivo using diffuse reflectance spectroscopy,” J. Investigat. Dermatol. 117, 1452–1457 (2001).
[CrossRef]

Laryngoscope

W. M. White, M. Rajadhyaksha, S. Gonzalez, R. L. Fabian, R. R. Anderson, “Noninvasive imaging of human oral mucosa in vivo by confocal reflectance microscopy,” Laryngoscope 109, 1709–1717 (1999).
[CrossRef] [PubMed]

Lasers Surgery Med.

S. L. Jacques, J. Roman, K. Lee, “Imaging superficial tissues with polarized light,” Lasers Surgery Med. 26, 119–129 (2000).
[CrossRef]

Nature

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Muller, Q. Zhang, G. Zonios, E. Kline, T. McGillican, S. Shapshay, T. Valdez, K. Badizadegan, J. M. Crawford, M. Fitzmaurice, S. Kabani, H. S. Levin, M. Seiler, R. R. Dasari, I. Itzkan, J. Van Dam, M. S. Feld, “Cancer screening: detection of preinvasive cancer cells,” Nature 406, 35–36 (2000).
[CrossRef] [PubMed]

Opt. Express

Opt. Lett.

Photochem. Photobiol.

I. Pavlova, K. Sokolov, R. Drezek, A. Malpica, M. Follen, R. Richards-Kortum, “Microanatomical and biochemical origins of normal and precancerous cervical autofluorescence using laser scanning fluorescence confocal microscopy,” Photochem. Photobiol. 77, 550–555 (2003).
[CrossRef] [PubMed]

R. Drezek, C. Brookner, I. Pavlova, I. Boiko, A. Malpica, R. Lotan, M. Follen, R. Richards-Kortum, “Autofluorescence microscopy of fresh cervical-tissue sections reveals alterations in tissue biochemistry with dysplasia,” Photochem. Photobiol. 73, 636–641 (2001).
[CrossRef] [PubMed]

Phys. Med. Biol.

I. J. Bigio, J. R. Mourant, “Ultraviolet and visible spectroscopies for tissue diagnostics: fluorescence spectroscopy and elastic-scattering spectroscopy,” Phys. Med. Biol. 42, 603–614 (1997).
[CrossRef]

Phys. Rev. Lett.

L. T. Perelman, V. Backman, M. Wallace, G. Zonios, R. Manoharan, A. Nusrat, S. Shields, M. Seiler, C. Lima, T. Hamano, I. Itzkan, J. Van Dam, J. M. Crawford, M. S. Feld, “Observation of periodic fine structure in reflectance from biological tissue: a new technique for measuring nuclear size distribution,” Phys. Rev. Lett. 60, 627–630 (1996).

Science

W. K. Hong, M. B. Sporn, “Recent advances in chemoprevention of cancer,” Science 278, 1073–1077 (1997).
[CrossRef] [PubMed]

Other

R. Cotran, V. Kumar, S. Robbins, Pathologic Basis of Disease, 5th ed. (Saunders, Philadelphia, 1994), chap. 7.

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Figures (7)

Fig. 1
Fig. 1

(a) Schematic of in vivo probe design. The center fiber delivers linearly polarized light to the tissue. The outer fibers collected the scattered light with polarization parallel and perpendicular to the incident polarization. Tilting the collection fibers allows overlap of illumination and collection acceptance cones within the epithelial layer. (b) Orientation of the polarizing film on the distal end of the probe. The transmission axes of the polarizing film are indicated by arrows. (c) Distal end of the probe; scale bar, 1 mm. (d) Distal end of the probe in a fluorescing medium. Overlap of the collection acceptance cones is clearly seen when light is channeled through the collection fibers. (e) Overlap of the illumination cone and the collection acceptance cones when light is delivered through all three fibers, scale bar, 1 mm. (f) Intensity of scattered light collected by a single collection fiber from a diffusely scattering substrate as a function of probe-substrate separations.

Fig. 2
Fig. 2

(a) Two-layer bead phantom. The upper layer is composed of 6.30 μm polystyrene beads embedded in a collagen gel. The lower layer is a collagen gel. (b) Transmittance image of a transverse section of the phantom. Beads are seen as black dots. (c) Corresponding reflectance image. Beads are seen as white dots. Scale bars, 100 μm.

Fig. 3
Fig. 3

(a) Two-layer cell phantom: The upper layer is composed of densely packed SiHa cervical cancer cells, and the lower layer is a collagen gel. (b) Transmittance image illustrating the dense packing of SiHa cells; scale bar, 30 μm. (c) Transmittance image of the cell phantom at a lower magnification; scale bar, 100 μm. A distinct boundary can be seen between the cell and the collagen layers.

Fig. 4
Fig. 4

Mechanisms for detection of forward scattering in epithelial tissue for a backscattering collection geometry: (a), (b), interface effect; (c), (d), volume effect. (a) A photon undergoes diffuse reflection at the cell-collagen interface owing to the refractive index mismatch, then is forward scattered by a cell nucleus. (b) A photon is first forward scattered by a cell nucleus, then is reflected back toward the detector at the cell-collagen interface. (c) A photon is backscattered inside the collagen layer, then is forward scattered by a cell nucleus. (d) A photon is first forward scattered by a cell nucleus, then is backscattered in the collagen layer toward the detector.

Fig. 5
Fig. 5

Depth-resolved polarized reflectance measurements in a two-layer bead phantom. (a) Depolarization ratio spectra for a series of probe-sample separations: curve i, 800 μm; ii, 500 μm; iii, 400 μm; iv, 1000 μm; v, 0 μm. (b) Close-up of depolarization ratio curve ii. Each measured point is indicated by a dot. (c) Dependence of the total integrated backscattering signal from beads and scattering from the lower collagen layer on probe-sample separation: the integrated bead backscattering signal and the integrated collagen scattering obtained from the measured depolarization ratio spectra are shown as the solid and the dashed curve, respectively. The theoretical simulation of the bead scattering is plotted as a dashed-dotted line.

Fig. 6
Fig. 6

Depth-resolved polarized reflectance measurements in a two-layer cell phantom. (a) Depolarization ratio spectra for a series of probe-sample separations: curve i, 800 μm; ii, 600 μm; iii, 400 μm; iv, 200 μm; v, 0 μm. (b) Close-up of depolarization ratio curve ii showing the spectral sampling. Each measured point is indicated by a dot. (c) Contour plot of the sum square error of the fit for the morphologically important parameters of nuclear size and nuclear size distribution. A single distinct minimum is shown as a small white circle. The extracted average nuclear size and nuclear size distribution are 7.5 and 0.7 μm, respectively. (d) Dependence of the total integrated forward scattering signal from cells on probe-sample separation: integrated forward scattering signal from SiHa obtained from experimental depolarization ratio spectra (solid curve) and theoretically predicted curve (dash-dotted curve with circles). The theoretical curve was obtained by using a linear combination of scattering from two sources: the cell-collagen interface (dotted curve with diamonds) and scattering from the lower collagen layer (dotted curve with squares).

Fig. 7
Fig. 7

In vivo polarized reflectance measurements: (a) experimental depolarization ratio spectrum (dotted curve), corresponding fit (solid curve), and parallel (dashed-dotted curve) and perpendicular (dashed curve) spectra obtained from a normal volunteer. (b) Bar graph of nuclear sizes calculated for six normal volunteers. Three sites within the oral cavity were measured for each volunteer: lower lip, right buccal, and left buccal mucosa. The average nuclear size calculated for all sites is 8.6 μm.

Equations (2)

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Dλ=Iλ-IλISλ+ISλ,
Dλ=aρBλ+bρSλFλ+cSλ+DC,

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