Abstract

A method to non-invasively and quantitatively characterize thick biological tissues by combining both experimental and computational approaches in tissue optical spectroscopy was developed and validated on fifteen porcine articular cartilage (AC) tissue samples. To the best of our knowledge, this study is the first to couple non-invasive reflectance and fluorescence spectroscopic measurements on freshly harvested tissues with Monte Carlo computational modeling of time-resolved propagation of both excitation light and multi-fluorophore emission. For reflectance, quantitative agreement between simulation and experiment was achieved to better than 11%. Fluorescence data and simulations were used to extract the ratio of the absorption coefficients of constituent fluorophores for each measured AC tissue sample. This ratio could be used to monitor relative changes in concentration of the constituent fluorophores over time. The samples studied possessed the complexity and variability not found in artificial tissue-simulating phantoms and serve as a model for future optical molecular sensing studies on tissue engineered constructs intended for use in human therapeutics. An optical technique that could non-invasively and quantitatively assess soft tissue composition or physiologic status would represent a significant advance in tissue engineering. Moreover, the general approach described here for optical characterization should be broadly applicable to quantitative, non-invasive molecular sensing applications in complex, three-dimensional biological tissues.

© 2006 Optical Society of America

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2005 (1)

2004 (2)

K. Vishwanath, and M.-A. Mycek, "Do fluorescence decays remitted from tissues accurately reflect intrinsic fluorophore lifetimes?," Opt. Lett. 29, 1512-1514 (2004).
[CrossRef] [PubMed]

P. Å. Öberg, T. Sundqvist, and A. Johansson, "Asessment of cartilage thickness utilising reflectance spectroscopy," Med. Biol. Eng. Comput. 42, 3-8 (2004).
[CrossRef] [PubMed]

2003 (1)

D. Y. Churmakov, I. V. Meglinski, S. A. Piletsky, and D. A. Greenhalgh, "Analysis of skin tissues spatial fluorescence distrubution by the Monte Carlo simulation," J. Physics D: Appl. Phys. 36, 1722-1728 (2003).
[CrossRef]

2002 (1)

K. Vishwanath, B. W. Pogue, and M.-A. Mycek, "Quantitative fluorescence lifetime spectroscopy in turbid media: comparison of theoretical, experimental and computational methods," Phys. Med. Biol. 47, 3387-3405 (2002).
[CrossRef] [PubMed]

2001 (2)

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

J. D. Pitts and M.-A. Mycek, "Design and development of a rapid acquisition laser-based fluorometer with simultaneous spectral and temporal resolution.," Rev. Sci. Instrum. 72, 3061-3072 (2001).
[CrossRef]

2000 (1)

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Müller, 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. R. R. Dasari, I. I. Itzkan, J. J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

1998 (1)

M.-A. Mycek, K. Schomacker, and N. Nishioka, "Colonic polyp differentiation using time resolved autofluorescence spectroscopy," Gastrointest. Endosc. 48, 390-394 (1998).
[CrossRef] [PubMed]

1997 (5)

I. Bigio, and J. Mourant, "Ultraviolet and visible spectroscopies for tissue diagnostics: fluorescence spectroscopy and elastic-scattering spectroscopy," Phys. Med. Biol. 42, 803-814 (1997).
[CrossRef] [PubMed]

S. Andersson-Engels, C. Klinteberg, K. Svanberg, and S. Svanberg, "In vivo fluorescence imaging for tissue diagnostics," Phys. Med. Biol. 42, 815-824 (1997).
[CrossRef] [PubMed]

J. A. Buckwalter, and H. J. Mankin, "Instructional course lectures, The American Academy of Orthopaedic Surgeons-Articular Cartilage. Part I: Tissue Design and Chondrocyte-Matrix Interactions," J. Bone and Jt. Surg. (American) 79, 600-611 (1997).

H. Zeng, C. MacAulay, D. I. McLean, and B. Palcic, "Reconstruction of in vivo skin auto fluorescence spectrum from microscopic properties by Monte-Carlo simulation," J. Photochem. Photobiol. B 38, 234-240 (1997).
[CrossRef] [PubMed]

J. F. Beek, P. Blokland, P. Posthumus, M. Aalders, J. W. Pickering, H. J. C. M. Sterenborg, and M. J. C. van Gemert, "In vitro double-integrating-sphere optical properties of tissues between 630 and 1064 nm," Phys. Med. Biol. 42, 2255-2261 (1997).
[CrossRef] [PubMed]

1996 (3)

B. Pogue, and T. Hasan, "Fluorophore quantitation in tissue simulating media with confocal detection," IEEE J. Sel. Top. Quantum Electron. 2, 959-964 (1996).
[CrossRef]

G. Zonios, R. Cothren, J. Arendt, J. Wu, J. Van Dam, J. Crawford, R. Manoharan, and M. Feld, "Morphological model of human colon tissue fluorescence," IEEE Trans. Biomed. Eng. 43, 113-122 (1996).
[CrossRef] [PubMed]

R. Richards-Kortum, and E. Sevick-Muraca, "Quantitative optical spectroscopy for tissue diagnosis," Annu. Rev. Phys. Chem. 47, 555-606 (1996).
[CrossRef] [PubMed]

1995 (1)

L. Wang, S. L. Jacques, and L. Zheng, "MCML-Monte Carlo modeling of photon transport in multi-layered tissues," Computer Methods and Programs in Biomedicine 47, 131-146 (1995).
[CrossRef] [PubMed]

1994 (2)

N. Ramanujam, M. F. Mitchell, A. Mahadevan, S. Warren, S. Thomsen, E. Silva, and R. Richards-Kortum, "In vivo diagnosis of cervical intraepithelial neoplasia using 337-nm-excited laser-induced fluorescence," inProceedings of the National Academy of Science, USA, 91, 10193-10197 (1994).

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

1993 (2)

1992 (1)

K. T. Schomacker, J. K. Frisoli, C. C. Compton, T. J. Flotte, J. M. Richter, and T. F. Deutsch, "Ultraviolet laser-induced fluorescence of colonic polyps," Gastroenterology 102, 1155-1160 (1992).
[PubMed]

1990 (1)

B. Wilson, and S. Jacques, "Optical reflectance and transmittance of tissues: principles and applications," IEEE J. Quantum Electron. 26, 2186-2199 (1990).
[CrossRef]

1989 (1)

1988 (1)

W. M. Star, J. P. A. Marijnissen, and M. J. C. van-Gemert, "Light Dosimetry in optical phantoms in tissues: I. Multiple flux and transport theory," Phys. Med. Biol 33, 437-454 (1988).
[CrossRef] [PubMed]

1985 (1)

L. Lindqvist, B. Czochralska, and I. Grigorov, "Determination of the mechanism of photo-ionization of NADH in aqueous solution on laser excitation at 355 nm," Chem. Phys. Lett. 119, 494-497 (1985).
[CrossRef]

Aalders, M.

J. F. Beek, P. Blokland, P. Posthumus, M. Aalders, J. W. Pickering, H. J. C. M. Sterenborg, and M. J. C. van Gemert, "In vitro double-integrating-sphere optical properties of tissues between 630 and 1064 nm," Phys. Med. Biol. 42, 2255-2261 (1997).
[CrossRef] [PubMed]

Andersson-Engels, S.

S. Andersson-Engels, C. Klinteberg, K. Svanberg, and S. Svanberg, "In vivo fluorescence imaging for tissue diagnostics," Phys. Med. Biol. 42, 815-824 (1997).
[CrossRef] [PubMed]

Arendt, J.

G. Zonios, R. Cothren, J. Arendt, J. Wu, J. Van Dam, J. Crawford, R. Manoharan, and M. Feld, "Morphological model of human colon tissue fluorescence," IEEE Trans. Biomed. Eng. 43, 113-122 (1996).
[CrossRef] [PubMed]

Arendt, J. T.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Müller, 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. R. R. Dasari, I. I. Itzkan, J. J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Backman, V.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Müller, 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. R. R. Dasari, I. I. Itzkan, J. J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Badizadegan, K.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Müller, 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. R. R. Dasari, I. I. Itzkan, J. J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Beek, J. F.

J. F. Beek, P. Blokland, P. Posthumus, M. Aalders, J. W. Pickering, H. J. C. M. Sterenborg, and M. J. C. van Gemert, "In vitro double-integrating-sphere optical properties of tissues between 630 and 1064 nm," Phys. Med. Biol. 42, 2255-2261 (1997).
[CrossRef] [PubMed]

Bigio, I.

I. Bigio, and J. Mourant, "Ultraviolet and visible spectroscopies for tissue diagnostics: fluorescence spectroscopy and elastic-scattering spectroscopy," Phys. Med. Biol. 42, 803-814 (1997).
[CrossRef] [PubMed]

Blokland, P.

J. F. Beek, P. Blokland, P. Posthumus, M. Aalders, J. W. Pickering, H. J. C. M. Sterenborg, and M. J. C. van Gemert, "In vitro double-integrating-sphere optical properties of tissues between 630 and 1064 nm," Phys. Med. Biol. 42, 2255-2261 (1997).
[CrossRef] [PubMed]

Boiko, I.

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

Buckwalter, J. A.

J. A. Buckwalter, and H. J. Mankin, "Instructional course lectures, The American Academy of Orthopaedic Surgeons-Articular Cartilage. Part I: Tissue Design and Chondrocyte-Matrix Interactions," J. Bone and Jt. Surg. (American) 79, 600-611 (1997).

Churmakov, D. Y.

D. Y. Churmakov, I. V. Meglinski, S. A. Piletsky, and D. A. Greenhalgh, "Analysis of skin tissues spatial fluorescence distrubution by the Monte Carlo simulation," J. Physics D: Appl. Phys. 36, 1722-1728 (2003).
[CrossRef]

Compton, C. C.

K. T. Schomacker, J. K. Frisoli, C. C. Compton, T. J. Flotte, J. M. Richter, and T. F. Deutsch, "Ultraviolet laser-induced fluorescence of colonic polyps," Gastroenterology 102, 1155-1160 (1992).
[PubMed]

Cothren, R.

G. Zonios, R. Cothren, J. Arendt, J. Wu, J. Van Dam, J. Crawford, R. Manoharan, and M. Feld, "Morphological model of human colon tissue fluorescence," IEEE Trans. Biomed. Eng. 43, 113-122 (1996).
[CrossRef] [PubMed]

Crawford, J.

G. Zonios, R. Cothren, J. Arendt, J. Wu, J. Van Dam, J. Crawford, R. Manoharan, and M. Feld, "Morphological model of human colon tissue fluorescence," IEEE Trans. Biomed. Eng. 43, 113-122 (1996).
[CrossRef] [PubMed]

Crawford, J. M.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Müller, 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. R. R. Dasari, I. I. Itzkan, J. J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Czochralska, B.

L. Lindqvist, B. Czochralska, and I. Grigorov, "Determination of the mechanism of photo-ionization of NADH in aqueous solution on laser excitation at 355 nm," Chem. Phys. Lett. 119, 494-497 (1985).
[CrossRef]

Dasari, R. R. R. R.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Müller, 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. R. R. Dasari, I. I. Itzkan, J. J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Deutsch, T. F.

K. T. Schomacker, J. K. Frisoli, C. C. Compton, T. J. Flotte, J. M. Richter, and T. F. Deutsch, "Ultraviolet laser-induced fluorescence of colonic polyps," Gastroenterology 102, 1155-1160 (1992).
[PubMed]

Drezek, R.

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

Feld, M.

G. Zonios, R. Cothren, J. Arendt, J. Wu, J. Van Dam, J. Crawford, R. Manoharan, and M. Feld, "Morphological model of human colon tissue fluorescence," IEEE Trans. Biomed. Eng. 43, 113-122 (1996).
[CrossRef] [PubMed]

J. Wu, M. Feld, and R. Rava, "Analytical model for extracting intrinsic fluorescence in turbid media," Appl. Opt. 32, 3585-3595 (1993).
[CrossRef] [PubMed]

Feld, M. S.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Müller, 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. R. R. Dasari, I. I. Itzkan, J. J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Fitzmaurice, M.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Müller, 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. R. R. Dasari, I. I. Itzkan, J. J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Flotte, T. J.

K. T. Schomacker, J. K. Frisoli, C. C. Compton, T. J. Flotte, J. M. Richter, and T. F. Deutsch, "Ultraviolet laser-induced fluorescence of colonic polyps," Gastroenterology 102, 1155-1160 (1992).
[PubMed]

Follen, M.

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

Frisoli, J. K.

K. T. Schomacker, J. K. Frisoli, C. C. Compton, T. J. Flotte, J. M. Richter, and T. F. Deutsch, "Ultraviolet laser-induced fluorescence of colonic polyps," Gastroenterology 102, 1155-1160 (1992).
[PubMed]

Greenhalgh, D. A.

D. Y. Churmakov, I. V. Meglinski, S. A. Piletsky, and D. A. Greenhalgh, "Analysis of skin tissues spatial fluorescence distrubution by the Monte Carlo simulation," J. Physics D: Appl. Phys. 36, 1722-1728 (2003).
[CrossRef]

Grigorov, I.

L. Lindqvist, B. Czochralska, and I. Grigorov, "Determination of the mechanism of photo-ionization of NADH in aqueous solution on laser excitation at 355 nm," Chem. Phys. Lett. 119, 494-497 (1985).
[CrossRef]

Gurjar, R.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Müller, 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. R. R. Dasari, I. I. Itzkan, J. J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Hasan, T.

B. Pogue, and T. Hasan, "Fluorophore quantitation in tissue simulating media with confocal detection," IEEE J. Sel. Top. Quantum Electron. 2, 959-964 (1996).
[CrossRef]

Itzkan, I. I.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Müller, 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. R. R. Dasari, I. I. Itzkan, J. J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Jacques, S.

B. Wilson, and S. Jacques, "Optical reflectance and transmittance of tissues: principles and applications," IEEE J. Quantum Electron. 26, 2186-2199 (1990).
[CrossRef]

Jacques, S. L.

L. Wang, S. L. Jacques, and L. Zheng, "MCML-Monte Carlo modeling of photon transport in multi-layered tissues," Computer Methods and Programs in Biomedicine 47, 131-146 (1995).
[CrossRef] [PubMed]

S. L. Jacques, "Time resolved propagation of ultrashort laser pulses within turbid tissue," Appl. Opt. 28, 2223-2229 (1989).
[CrossRef] [PubMed]

Johansson, A.

P. Å. Öberg, T. Sundqvist, and A. Johansson, "Asessment of cartilage thickness utilising reflectance spectroscopy," Med. Biol. Eng. Comput. 42, 3-8 (2004).
[CrossRef] [PubMed]

Kabani, S.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Müller, 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. R. R. Dasari, I. I. Itzkan, J. J. Van Dam, and M. S. Feld, "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. Müller, 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. R. R. Dasari, I. I. Itzkan, J. J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Klinteberg, C.

S. Andersson-Engels, C. Klinteberg, K. Svanberg, and S. Svanberg, "In vivo fluorescence imaging for tissue diagnostics," Phys. Med. Biol. 42, 815-824 (1997).
[CrossRef] [PubMed]

Levin, H. S.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Müller, 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. R. R. Dasari, I. I. Itzkan, J. J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Lindqvist, L.

L. Lindqvist, B. Czochralska, and I. Grigorov, "Determination of the mechanism of photo-ionization of NADH in aqueous solution on laser excitation at 355 nm," Chem. Phys. Lett. 119, 494-497 (1985).
[CrossRef]

MacAulay, C.

H. Zeng, C. MacAulay, D. I. McLean, and B. Palcic, "Reconstruction of in vivo skin auto fluorescence spectrum from microscopic properties by Monte-Carlo simulation," J. Photochem. Photobiol. B 38, 234-240 (1997).
[CrossRef] [PubMed]

Mahadevan, A.

N. Ramanujam, M. F. Mitchell, A. Mahadevan, S. Warren, S. Thomsen, E. Silva, and R. Richards-Kortum, "In vivo diagnosis of cervical intraepithelial neoplasia using 337-nm-excited laser-induced fluorescence," inProceedings of the National Academy of Science, USA, 91, 10193-10197 (1994).

Malpica, A.

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

Mankin, H. J.

J. A. Buckwalter, and H. J. Mankin, "Instructional course lectures, The American Academy of Orthopaedic Surgeons-Articular Cartilage. Part I: Tissue Design and Chondrocyte-Matrix Interactions," J. Bone and Jt. Surg. (American) 79, 600-611 (1997).

Manoharan, R.

G. Zonios, R. Cothren, J. Arendt, J. Wu, J. Van Dam, J. Crawford, R. Manoharan, and M. Feld, "Morphological model of human colon tissue fluorescence," IEEE Trans. Biomed. Eng. 43, 113-122 (1996).
[CrossRef] [PubMed]

Marijnissen, J. P. A.

W. M. Star, J. P. A. Marijnissen, and M. J. C. van-Gemert, "Light Dosimetry in optical phantoms in tissues: I. Multiple flux and transport theory," Phys. Med. Biol 33, 437-454 (1988).
[CrossRef] [PubMed]

McGillican, T.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Müller, 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. R. R. Dasari, I. I. Itzkan, J. J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

McLean, D. I.

H. Zeng, C. MacAulay, D. I. McLean, and B. Palcic, "Reconstruction of in vivo skin auto fluorescence spectrum from microscopic properties by Monte-Carlo simulation," J. Photochem. Photobiol. B 38, 234-240 (1997).
[CrossRef] [PubMed]

Meglinski, I. V.

D. Y. Churmakov, I. V. Meglinski, S. A. Piletsky, and D. A. Greenhalgh, "Analysis of skin tissues spatial fluorescence distrubution by the Monte Carlo simulation," J. Physics D: Appl. Phys. 36, 1722-1728 (2003).
[CrossRef]

Mitchell, M. F.

N. Ramanujam, M. F. Mitchell, A. Mahadevan, S. Warren, S. Thomsen, E. Silva, and R. Richards-Kortum, "In vivo diagnosis of cervical intraepithelial neoplasia using 337-nm-excited laser-induced fluorescence," inProceedings of the National Academy of Science, USA, 91, 10193-10197 (1994).

Mourant, J.

I. Bigio, and J. Mourant, "Ultraviolet and visible spectroscopies for tissue diagnostics: fluorescence spectroscopy and elastic-scattering spectroscopy," Phys. Med. Biol. 42, 803-814 (1997).
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Müller, M. G.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Müller, 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. R. R. Dasari, I. I. Itzkan, J. J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Mycek, M.-A.

K. Vishwanath, and M.-A. Mycek, "Time-resolved photon migration in bi-layered tissue models," Opt. Express 13, 7466-7482 (2005).
[CrossRef] [PubMed]

K. Vishwanath, and M.-A. Mycek, "Do fluorescence decays remitted from tissues accurately reflect intrinsic fluorophore lifetimes?," Opt. Lett. 29, 1512-1514 (2004).
[CrossRef] [PubMed]

K. Vishwanath, B. W. Pogue, and M.-A. Mycek, "Quantitative fluorescence lifetime spectroscopy in turbid media: comparison of theoretical, experimental and computational methods," Phys. Med. Biol. 47, 3387-3405 (2002).
[CrossRef] [PubMed]

J. D. Pitts and M.-A. Mycek, "Design and development of a rapid acquisition laser-based fluorometer with simultaneous spectral and temporal resolution.," Rev. Sci. Instrum. 72, 3061-3072 (2001).
[CrossRef]

M.-A. Mycek, K. Schomacker, and N. Nishioka, "Colonic polyp differentiation using time resolved autofluorescence spectroscopy," Gastrointest. Endosc. 48, 390-394 (1998).
[CrossRef] [PubMed]

Nishioka, N.

M.-A. Mycek, K. Schomacker, and N. Nishioka, "Colonic polyp differentiation using time resolved autofluorescence spectroscopy," Gastrointest. Endosc. 48, 390-394 (1998).
[CrossRef] [PubMed]

Öberg, P. Å.

P. Å. Öberg, T. Sundqvist, and A. Johansson, "Asessment of cartilage thickness utilising reflectance spectroscopy," Med. Biol. Eng. Comput. 42, 3-8 (2004).
[CrossRef] [PubMed]

Palcic, B.

H. Zeng, C. MacAulay, D. I. McLean, and B. Palcic, "Reconstruction of in vivo skin auto fluorescence spectrum from microscopic properties by Monte-Carlo simulation," J. Photochem. Photobiol. B 38, 234-240 (1997).
[CrossRef] [PubMed]

Patterson, M. S.

Perelman, L. T.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Müller, 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. R. R. Dasari, I. I. Itzkan, J. J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Pickering, J. W.

J. F. Beek, P. Blokland, P. Posthumus, M. Aalders, J. W. Pickering, H. J. C. M. Sterenborg, and M. J. C. van Gemert, "In vitro double-integrating-sphere optical properties of tissues between 630 and 1064 nm," Phys. Med. Biol. 42, 2255-2261 (1997).
[CrossRef] [PubMed]

Piletsky, S. A.

D. Y. Churmakov, I. V. Meglinski, S. A. Piletsky, and D. A. Greenhalgh, "Analysis of skin tissues spatial fluorescence distrubution by the Monte Carlo simulation," J. Physics D: Appl. Phys. 36, 1722-1728 (2003).
[CrossRef]

Pitts, J. D.

J. D. Pitts and M.-A. Mycek, "Design and development of a rapid acquisition laser-based fluorometer with simultaneous spectral and temporal resolution.," Rev. Sci. Instrum. 72, 3061-3072 (2001).
[CrossRef]

Pogue, B.

B. Pogue, and T. Hasan, "Fluorophore quantitation in tissue simulating media with confocal detection," IEEE J. Sel. Top. Quantum Electron. 2, 959-964 (1996).
[CrossRef]

Pogue, B. W.

K. Vishwanath, B. W. Pogue, and M.-A. Mycek, "Quantitative fluorescence lifetime spectroscopy in turbid media: comparison of theoretical, experimental and computational methods," Phys. Med. Biol. 47, 3387-3405 (2002).
[CrossRef] [PubMed]

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

Posthumus, P.

J. F. Beek, P. Blokland, P. Posthumus, M. Aalders, J. W. Pickering, H. J. C. M. Sterenborg, and M. J. C. van Gemert, "In vitro double-integrating-sphere optical properties of tissues between 630 and 1064 nm," Phys. Med. Biol. 42, 2255-2261 (1997).
[CrossRef] [PubMed]

Prahl, S. A.

Ramanujam, N.

N. Ramanujam, M. F. Mitchell, A. Mahadevan, S. Warren, S. Thomsen, E. Silva, and R. Richards-Kortum, "In vivo diagnosis of cervical intraepithelial neoplasia using 337-nm-excited laser-induced fluorescence," inProceedings of the National Academy of Science, USA, 91, 10193-10197 (1994).

Rava, R.

Richards-Kortum, R.

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

R. Richards-Kortum, and E. Sevick-Muraca, "Quantitative optical spectroscopy for tissue diagnosis," Annu. Rev. Phys. Chem. 47, 555-606 (1996).
[CrossRef] [PubMed]

N. Ramanujam, M. F. Mitchell, A. Mahadevan, S. Warren, S. Thomsen, E. Silva, and R. Richards-Kortum, "In vivo diagnosis of cervical intraepithelial neoplasia using 337-nm-excited laser-induced fluorescence," inProceedings of the National Academy of Science, USA, 91, 10193-10197 (1994).

Richter, J. M.

K. T. Schomacker, J. K. Frisoli, C. C. Compton, T. J. Flotte, J. M. Richter, and T. F. Deutsch, "Ultraviolet laser-induced fluorescence of colonic polyps," Gastroenterology 102, 1155-1160 (1992).
[PubMed]

Schomacker, K.

M.-A. Mycek, K. Schomacker, and N. Nishioka, "Colonic polyp differentiation using time resolved autofluorescence spectroscopy," Gastrointest. Endosc. 48, 390-394 (1998).
[CrossRef] [PubMed]

Schomacker, K. T.

K. T. Schomacker, J. K. Frisoli, C. C. Compton, T. J. Flotte, J. M. Richter, and T. F. Deutsch, "Ultraviolet laser-induced fluorescence of colonic polyps," Gastroenterology 102, 1155-1160 (1992).
[PubMed]

Seiler, M.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Müller, 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. R. R. Dasari, I. I. Itzkan, J. J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Sevick-Muraca, E.

R. Richards-Kortum, and E. Sevick-Muraca, "Quantitative optical spectroscopy for tissue diagnosis," Annu. Rev. Phys. Chem. 47, 555-606 (1996).
[CrossRef] [PubMed]

Shapshay, S.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Müller, 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. R. R. Dasari, I. I. Itzkan, J. J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Silva, E.

N. Ramanujam, M. F. Mitchell, A. Mahadevan, S. Warren, S. Thomsen, E. Silva, and R. Richards-Kortum, "In vivo diagnosis of cervical intraepithelial neoplasia using 337-nm-excited laser-induced fluorescence," inProceedings of the National Academy of Science, USA, 91, 10193-10197 (1994).

Sokolov, K.

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

Star, W. M.

W. M. Star, J. P. A. Marijnissen, and M. J. C. van-Gemert, "Light Dosimetry in optical phantoms in tissues: I. Multiple flux and transport theory," Phys. Med. Biol 33, 437-454 (1988).
[CrossRef] [PubMed]

Sterenborg, H. J. C. M.

J. F. Beek, P. Blokland, P. Posthumus, M. Aalders, J. W. Pickering, H. J. C. M. Sterenborg, and M. J. C. van Gemert, "In vitro double-integrating-sphere optical properties of tissues between 630 and 1064 nm," Phys. Med. Biol. 42, 2255-2261 (1997).
[CrossRef] [PubMed]

Sundqvist, T.

P. Å. Öberg, T. Sundqvist, and A. Johansson, "Asessment of cartilage thickness utilising reflectance spectroscopy," Med. Biol. Eng. Comput. 42, 3-8 (2004).
[CrossRef] [PubMed]

Svanberg, K.

S. Andersson-Engels, C. Klinteberg, K. Svanberg, and S. Svanberg, "In vivo fluorescence imaging for tissue diagnostics," Phys. Med. Biol. 42, 815-824 (1997).
[CrossRef] [PubMed]

Svanberg, S.

S. Andersson-Engels, C. Klinteberg, K. Svanberg, and S. Svanberg, "In vivo fluorescence imaging for tissue diagnostics," Phys. Med. Biol. 42, 815-824 (1997).
[CrossRef] [PubMed]

Thomsen, S.

N. Ramanujam, M. F. Mitchell, A. Mahadevan, S. Warren, S. Thomsen, E. Silva, and R. Richards-Kortum, "In vivo diagnosis of cervical intraepithelial neoplasia using 337-nm-excited laser-induced fluorescence," inProceedings of the National Academy of Science, USA, 91, 10193-10197 (1994).

Utzinger, U.

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

Valdez, T.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Müller, 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. R. R. Dasari, I. I. Itzkan, J. J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Van Dam, J.

G. Zonios, R. Cothren, J. Arendt, J. Wu, J. Van Dam, J. Crawford, R. Manoharan, and M. Feld, "Morphological model of human colon tissue fluorescence," IEEE Trans. Biomed. Eng. 43, 113-122 (1996).
[CrossRef] [PubMed]

Van Dam, J. J.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Müller, 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. R. R. Dasari, I. I. Itzkan, J. J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

van Gemert, M. J. C.

J. F. Beek, P. Blokland, P. Posthumus, M. Aalders, J. W. Pickering, H. J. C. M. Sterenborg, and M. J. C. van Gemert, "In vitro double-integrating-sphere optical properties of tissues between 630 and 1064 nm," Phys. Med. Biol. 42, 2255-2261 (1997).
[CrossRef] [PubMed]

S. A. Prahl, M. J. C. van Gemert, and A. J. Welch, "Determining the optical properties of turbid media by using the adding-doubling method," Appl. Opt. 32, 559-568 (1993).
[CrossRef] [PubMed]

van-Gemert, M. J. C.

W. M. Star, J. P. A. Marijnissen, and M. J. C. van-Gemert, "Light Dosimetry in optical phantoms in tissues: I. Multiple flux and transport theory," Phys. Med. Biol 33, 437-454 (1988).
[CrossRef] [PubMed]

Vishwanath, K.

Wallace, M. B.

V. Backman, M. B. Wallace, L. T. Perelman, J. T. Arendt, R. Gurjar, M. G. Müller, 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. R. R. Dasari, I. I. Itzkan, J. J. Van Dam, and M. S. Feld, "Detection of preinvasive cancer cells," Nature 406, 35-36 (2000).
[CrossRef] [PubMed]

Wang, L.

L. Wang, S. L. Jacques, and L. Zheng, "MCML-Monte Carlo modeling of photon transport in multi-layered tissues," Computer Methods and Programs in Biomedicine 47, 131-146 (1995).
[CrossRef] [PubMed]

Warren, S.

N. Ramanujam, M. F. Mitchell, A. Mahadevan, S. Warren, S. Thomsen, E. Silva, and R. Richards-Kortum, "In vivo diagnosis of cervical intraepithelial neoplasia using 337-nm-excited laser-induced fluorescence," inProceedings of the National Academy of Science, USA, 91, 10193-10197 (1994).

Welch, A. J.

Wilson, B.

B. Wilson, and S. Jacques, "Optical reflectance and transmittance of tissues: principles and applications," IEEE J. Quantum Electron. 26, 2186-2199 (1990).
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Figures (8)

Fig. 1.
Fig. 1.

Immunohistochemical staining for collagen type II (brown) found in the extracellular matrix (ECM) (blue arrows) of porcine knee articular cartilage (AC). Red arrows indicate cells (chondrocytes) where NADH is found.

Fig. 2.
Fig. 2.

Schematic of the Reflectance and Fluorescence Lifetime Spectrometer (RFLS) (ND - neutral density filter, L - lens, LP - long-pass filter, BP- band-pass filter, APD - avalanche photo diode, ICCD - intensified charge coupled device). The inset shows a schematic of the geometry of the fiber optic probe.

Fig. 3.
Fig. 3.

Spectrally weighted fluorescence emission W(λ) (see text) for two fluorophores in the AC tissue. These spectra were measured on the RFLS for powdered collagen II (blue line) and for 70 µM NADH in DI-H2O (red dashed line). The black dashed lines indicate the spectral position of band-pass filters that were employed for obtaining time-resolved fluorescence measurements from porcine AC samples.

Fig. 4.
Fig. 4.

(a) Schematic for diffuse reflectance and transmittance measurements using an integrating sphere. (b) Schematic for collimated transmittance measurements. (L- Lens; LP – long-pass filter; SP – short-pass filter; BP – band-pass filter; PMT – photomultiplier tube; Port 1 – sample port; Port 2 – detection port; Port 3 – reflectance port).

Fig. 5.
Fig. 5.

Model for articular cartilage tissue showing fluorescence from two uniformly distributed fluorophores (intracellular NADH and extracellular collagen) relative to the excitation-detection fiber probes, as simulated by the MC code.

Fig. 6.
Fig. 6.

(a) Measured EEM of articular cartilage (AC) tissue showing fluorescence emission primarily associated with extracellular collagen and intracellular NADH. (b) Same EEM expanded to highlight the area between white dotted lines in (a). RFLS excitation occurred at 355 nm. The EEM data was measured on the Fluorolog-3 spectrofluorometer.

Fig. 7.
Fig. 7.

Average, measured (gray, solid line) and simulated (black, triangles) normalized reflectance spectra from porcine AC. The normalization was done by setting reflectance at 540 nm to unity. The model inputs at each indicated wavelength were obtained from integrating sphere measurements. The error bars represent the results of the variations in the optical properties (see Table 1) input to produce the simulations.

Fig. 8.
Fig. 8.

(a) Autofluorescence spectrum of AC tissue (black line) acquired on the RFLS. Blue and red boxes indicate band-pass (BP) filters placed at 400 and 540 nm to measure fluorescence decay times for photons from those parts of the spectrum. (b) Time-resolved fluorescence of the tissue with a BP filter of 400 nm (solid blue line) and a BP filter of 540 nm (dashed red line). The black dotted line shows the excitation pulse temporal profile (instrument response).

Tables (2)

Tables Icon

Table 1. Scattering and absorption coefficients for AC tissue (g=0.9)

Tables Icon

Table 2. Porcine articular cartilage (AC) sample preparation, experimental and, computational results.

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