Abstract

We present a novel molecular imaging technique which combines the 3-D tomographic imaging capability of optical coherence tomography with the molecular sensitivity of pump-probe spectroscopy. This technique, based on transient absorption, is sensitive to any molecular chromophore. It is particularly promising for the many important biomarkers, such as hemoglobin, which are poor fluorophores and therefore difficult to image with current optical techniques without chemical labeling. Previous implementations of pump-probe optical coherence tomography have suffered from inefficient pump-probe schemes which hurt the sensitivity and applicability of the technique. Here we optimize the efficiency of the pump-probe approach by avoiding the steady-state kinetics and spontaneous processes exploited in the past in favor of measuring the transient absorption of fully allowed electronic transitions on very short time scales before a steady-state is achieved. In this article, we detail the optimization and characterization of the prototype system, comparing experimental results for the system sensitivity to theoretical predictions. We demonstrate in situ imaging of tissue samples with two different chromophores; the transfectable protein dsRed and the protein hemoglobin. We also demonstrate, with a simple sample vessel and a mixture of human whole blood and rhodamine 6G, the potential to use ground state recovery time to separate the contributions of multiple chromophores to the ground state recovery signal.

© 2006 Optical Society of America

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2005 (5)

2004 (4)

2003 (6)

2002 (1)

D. Magde, R. Wong, P. G. Seybold, "Fluorescence quantum yields and their relations to lifetimes of rhodamine 6G and fluorescien in nine solvents: improved absolute standards for quantum yields," Photochem Photobiol 75, 327-334 (2002).
[CrossRef] [PubMed]

2000 (2)

O. O. Abugo, R. Nair, J. R. Lakowicz, "Fluorescence properties of rhodamine 800 in whole blood and plasma," Anal Biochem 279, 142-150 (2000).
[CrossRef] [PubMed]

M. E. Fuller, S. H. Streger, R. K. Rothmel, B. J. Mailloux, J. A. Hall, T. C. Onstott, J. K. Fredrickson, D. L. Balkwill, M. F. DeFlaun, "Development of a vital fluorescent staining method for monitoring bacterial transport in subsurface environments," Appl Environ Microbiol 66, 4486-4496 (2000).
[CrossRef] [PubMed]

1999 (1)

D. Magde, G. E. Rojas, P. G. Seybold, "Solvent dependence of the fluorescence lifetimes of xanthene dyes," Photochem Photobiol 70, 737-744 (1999).
[CrossRef]

1989 (1)

R. Richards-Kortum, R. P. Rava, M. Fitzmaurice, L. L. Tong, N. B. Ratliff, J. R. Kramer, M. S. Feld, "A one-layer model of laser-induced fluorescence for diagnosis of disease in human tissue: applications to atherosclerosis," IEEE Trans. Biomed. Eng. 36, 1222-1232 (1989).
[CrossRef] [PubMed]

1987 (1)

W. A. Wyatt, F. V. Bright, G. M. Hieftje, "Characterization and Comparison of 3 Fiberoptic Sensors for Iodide Determination Based on Dynamic Fluorescence Quenching of Rhodamine-6G," Anal. Chem. 59, 2272-2276 (1987).
[CrossRef]

1985 (1)

H. A. Wilson, B. E. Seligmann, T. M. Chused, "Voltage-sensitive cyanine dye fluorescence signals in lymphocytes: plasma membrane and mitochondrial components," J Cell Physiol 125, 61-71 (1985).
[CrossRef] [PubMed]

Abugo, O. O.

O. O. Abugo, R. Nair, J. R. Lakowicz, "Fluorescence properties of rhodamine 800 in whole blood and plasma," Anal Biochem 279, 142-150 (2000).
[CrossRef] [PubMed]

Applegate, B. E.

Au, L.

J. Chen, F. Saeki, B. J. Wiley, H. Cang, M. J. Cobb, Z.-Y. Li, L. Au, H. Zhang, M. B. Kimmey, X. D. Li, Y. Xia, "Gold Nanocages: Bioconjugation and Their Potential Use as Optical Imaging Contrast Agents," Nano Lett. 5, 473-477 (2005).
[CrossRef] [PubMed]

Balkwill, D. L.

M. E. Fuller, S. H. Streger, R. K. Rothmel, B. J. Mailloux, J. A. Hall, T. C. Onstott, J. K. Fredrickson, D. L. Balkwill, M. F. DeFlaun, "Development of a vital fluorescent staining method for monitoring bacterial transport in subsurface environments," Appl Environ Microbiol 66, 4486-4496 (2000).
[CrossRef] [PubMed]

Boppart, S. A.

Bouma, B. E.

Bredfeldt, J. S.

Bright, F. V.

W. A. Wyatt, F. V. Bright, G. M. Hieftje, "Characterization and Comparison of 3 Fiberoptic Sensors for Iodide Determination Based on Dynamic Fluorescence Quenching of Rhodamine-6G," Anal. Chem. 59, 2272-2276 (1987).
[CrossRef]

Cang, H.

J. Chen, F. Saeki, B. J. Wiley, H. Cang, M. J. Cobb, Z.-Y. Li, L. Au, H. Zhang, M. B. Kimmey, X. D. Li, Y. Xia, "Gold Nanocages: Bioconjugation and Their Potential Use as Optical Imaging Contrast Agents," Nano Lett. 5, 473-477 (2005).
[CrossRef] [PubMed]

Cense, B.

Chen, J.

J. Chen, F. Saeki, B. J. Wiley, H. Cang, M. J. Cobb, Z.-Y. Li, L. Au, H. Zhang, M. B. Kimmey, X. D. Li, Y. Xia, "Gold Nanocages: Bioconjugation and Their Potential Use as Optical Imaging Contrast Agents," Nano Lett. 5, 473-477 (2005).
[CrossRef] [PubMed]

Chen, M.

Z. Gong, H. Wan, T. L. Tay, H. Wang, M. Chen, T. Yan, "Development of trangenic fish for ornamental and bioreactor by strong expression of fluorescent proteins in skeletal muscle," Biochem. Biophys. Res. Commun. 308, 58-63 (2003).
[CrossRef] [PubMed]

Chen, Z.

Choma, M. A.

Chused, T. M.

H. A. Wilson, B. E. Seligmann, T. M. Chused, "Voltage-sensitive cyanine dye fluorescence signals in lymphocytes: plasma membrane and mitochondrial components," J Cell Physiol 125, 61-71 (1985).
[CrossRef] [PubMed]

Cobb, M. J.

J. Chen, F. Saeki, B. J. Wiley, H. Cang, M. J. Cobb, Z.-Y. Li, L. Au, H. Zhang, M. B. Kimmey, X. D. Li, Y. Xia, "Gold Nanocages: Bioconjugation and Their Potential Use as Optical Imaging Contrast Agents," Nano Lett. 5, 473-477 (2005).
[CrossRef] [PubMed]

de Boer, J. F.

DeFlaun, M. F.

M. E. Fuller, S. H. Streger, R. K. Rothmel, B. J. Mailloux, J. A. Hall, T. C. Onstott, J. K. Fredrickson, D. L. Balkwill, M. F. DeFlaun, "Development of a vital fluorescent staining method for monitoring bacterial transport in subsurface environments," Appl Environ Microbiol 66, 4486-4496 (2000).
[CrossRef] [PubMed]

Feld, M. S.

R. Richards-Kortum, R. P. Rava, M. Fitzmaurice, L. L. Tong, N. B. Ratliff, J. R. Kramer, M. S. Feld, "A one-layer model of laser-induced fluorescence for diagnosis of disease in human tissue: applications to atherosclerosis," IEEE Trans. Biomed. Eng. 36, 1222-1232 (1989).
[CrossRef] [PubMed]

Fercher, A. F.

Fitzmaurice, M.

R. Richards-Kortum, R. P. Rava, M. Fitzmaurice, L. L. Tong, N. B. Ratliff, J. R. Kramer, M. S. Feld, "A one-layer model of laser-induced fluorescence for diagnosis of disease in human tissue: applications to atherosclerosis," IEEE Trans. Biomed. Eng. 36, 1222-1232 (1989).
[CrossRef] [PubMed]

Fredrickson, J. K.

M. E. Fuller, S. H. Streger, R. K. Rothmel, B. J. Mailloux, J. A. Hall, T. C. Onstott, J. K. Fredrickson, D. L. Balkwill, M. F. DeFlaun, "Development of a vital fluorescent staining method for monitoring bacterial transport in subsurface environments," Appl Environ Microbiol 66, 4486-4496 (2000).
[CrossRef] [PubMed]

Fuller, M. E.

M. E. Fuller, S. H. Streger, R. K. Rothmel, B. J. Mailloux, J. A. Hall, T. C. Onstott, J. K. Fredrickson, D. L. Balkwill, M. F. DeFlaun, "Development of a vital fluorescent staining method for monitoring bacterial transport in subsurface environments," Appl Environ Microbiol 66, 4486-4496 (2000).
[CrossRef] [PubMed]

Gong, Z.

Z. Gong, H. Wan, T. L. Tay, H. Wang, M. Chen, T. Yan, "Development of trangenic fish for ornamental and bioreactor by strong expression of fluorescent proteins in skeletal muscle," Biochem. Biophys. Res. Commun. 308, 58-63 (2003).
[CrossRef] [PubMed]

Hall, J. A.

M. E. Fuller, S. H. Streger, R. K. Rothmel, B. J. Mailloux, J. A. Hall, T. C. Onstott, J. K. Fredrickson, D. L. Balkwill, M. F. DeFlaun, "Development of a vital fluorescent staining method for monitoring bacterial transport in subsurface environments," Appl Environ Microbiol 66, 4486-4496 (2000).
[CrossRef] [PubMed]

Hieftje, G. M.

W. A. Wyatt, F. V. Bright, G. M. Hieftje, "Characterization and Comparison of 3 Fiberoptic Sensors for Iodide Determination Based on Dynamic Fluorescence Quenching of Rhodamine-6G," Anal. Chem. 59, 2272-2276 (1987).
[CrossRef]

Hitzenberger, C. K.

Izatt, J. A.

Jiang, Y.

Kimmey, M. B.

J. Chen, F. Saeki, B. J. Wiley, H. Cang, M. J. Cobb, Z.-Y. Li, L. Au, H. Zhang, M. B. Kimmey, X. D. Li, Y. Xia, "Gold Nanocages: Bioconjugation and Their Potential Use as Optical Imaging Contrast Agents," Nano Lett. 5, 473-477 (2005).
[CrossRef] [PubMed]

Kramer, J. R.

R. Richards-Kortum, R. P. Rava, M. Fitzmaurice, L. L. Tong, N. B. Ratliff, J. R. Kramer, M. S. Feld, "A one-layer model of laser-induced fluorescence for diagnosis of disease in human tissue: applications to atherosclerosis," IEEE Trans. Biomed. Eng. 36, 1222-1232 (1989).
[CrossRef] [PubMed]

Lakowicz, J. R.

O. O. Abugo, R. Nair, J. R. Lakowicz, "Fluorescence properties of rhodamine 800 in whole blood and plasma," Anal Biochem 279, 142-150 (2000).
[CrossRef] [PubMed]

Lamb, L. E.

Lee, T. M.

Leitgeb, R.

Li, X. D.

J. Chen, F. Saeki, B. J. Wiley, H. Cang, M. J. Cobb, Z.-Y. Li, L. Au, H. Zhang, M. B. Kimmey, X. D. Li, Y. Xia, "Gold Nanocages: Bioconjugation and Their Potential Use as Optical Imaging Contrast Agents," Nano Lett. 5, 473-477 (2005).
[CrossRef] [PubMed]

Li, Z.-Y.

J. Chen, F. Saeki, B. J. Wiley, H. Cang, M. J. Cobb, Z.-Y. Li, L. Au, H. Zhang, M. B. Kimmey, X. D. Li, Y. Xia, "Gold Nanocages: Bioconjugation and Their Potential Use as Optical Imaging Contrast Agents," Nano Lett. 5, 473-477 (2005).
[CrossRef] [PubMed]

Luo, W.

Magde, D.

D. Magde, R. Wong, P. G. Seybold, "Fluorescence quantum yields and their relations to lifetimes of rhodamine 6G and fluorescien in nine solvents: improved absolute standards for quantum yields," Photochem Photobiol 75, 327-334 (2002).
[CrossRef] [PubMed]

D. Magde, G. E. Rojas, P. G. Seybold, "Solvent dependence of the fluorescence lifetimes of xanthene dyes," Photochem Photobiol 70, 737-744 (1999).
[CrossRef]

Mailloux, B. J.

M. E. Fuller, S. H. Streger, R. K. Rothmel, B. J. Mailloux, J. A. Hall, T. C. Onstott, J. K. Fredrickson, D. L. Balkwill, M. F. DeFlaun, "Development of a vital fluorescent staining method for monitoring bacterial transport in subsurface environments," Appl Environ Microbiol 66, 4486-4496 (2000).
[CrossRef] [PubMed]

Marks, D. L.

McGuckin, L. E. L.

Nair, R.

O. O. Abugo, R. Nair, J. R. Lakowicz, "Fluorescence properties of rhodamine 800 in whole blood and plasma," Anal Biochem 279, 142-150 (2000).
[CrossRef] [PubMed]

Oldenburg, A. L.

Onstott, T. C.

M. E. Fuller, S. H. Streger, R. K. Rothmel, B. J. Mailloux, J. A. Hall, T. C. Onstott, J. K. Fredrickson, D. L. Balkwill, M. F. DeFlaun, "Development of a vital fluorescent staining method for monitoring bacterial transport in subsurface environments," Appl Environ Microbiol 66, 4486-4496 (2000).
[CrossRef] [PubMed]

Park, B. H.

Pierce, M. C.

Rao, K. D.

Ratliff, N. B.

R. Richards-Kortum, R. P. Rava, M. Fitzmaurice, L. L. Tong, N. B. Ratliff, J. R. Kramer, M. S. Feld, "A one-layer model of laser-induced fluorescence for diagnosis of disease in human tissue: applications to atherosclerosis," IEEE Trans. Biomed. Eng. 36, 1222-1232 (1989).
[CrossRef] [PubMed]

Rava, R. P.

R. Richards-Kortum, R. P. Rava, M. Fitzmaurice, L. L. Tong, N. B. Ratliff, J. R. Kramer, M. S. Feld, "A one-layer model of laser-induced fluorescence for diagnosis of disease in human tissue: applications to atherosclerosis," IEEE Trans. Biomed. Eng. 36, 1222-1232 (1989).
[CrossRef] [PubMed]

Richards-Kortum, R.

R. Richards-Kortum, R. P. Rava, M. Fitzmaurice, L. L. Tong, N. B. Ratliff, J. R. Kramer, M. S. Feld, "A one-layer model of laser-induced fluorescence for diagnosis of disease in human tissue: applications to atherosclerosis," IEEE Trans. Biomed. Eng. 36, 1222-1232 (1989).
[CrossRef] [PubMed]

Rojas, G. E.

D. Magde, G. E. Rojas, P. G. Seybold, "Solvent dependence of the fluorescence lifetimes of xanthene dyes," Photochem Photobiol 70, 737-744 (1999).
[CrossRef]

Rollins, A. M.

Rothmel, R. K.

M. E. Fuller, S. H. Streger, R. K. Rothmel, B. J. Mailloux, J. A. Hall, T. C. Onstott, J. K. Fredrickson, D. L. Balkwill, M. F. DeFlaun, "Development of a vital fluorescent staining method for monitoring bacterial transport in subsurface environments," Appl Environ Microbiol 66, 4486-4496 (2000).
[CrossRef] [PubMed]

Saeki, F.

J. Chen, F. Saeki, B. J. Wiley, H. Cang, M. J. Cobb, Z.-Y. Li, L. Au, H. Zhang, M. B. Kimmey, X. D. Li, Y. Xia, "Gold Nanocages: Bioconjugation and Their Potential Use as Optical Imaging Contrast Agents," Nano Lett. 5, 473-477 (2005).
[CrossRef] [PubMed]

Sarunic, M. V.

Seligmann, B. E.

H. A. Wilson, B. E. Seligmann, T. M. Chused, "Voltage-sensitive cyanine dye fluorescence signals in lymphocytes: plasma membrane and mitochondrial components," J Cell Physiol 125, 61-71 (1985).
[CrossRef] [PubMed]

Seybold, P. G.

D. Magde, R. Wong, P. G. Seybold, "Fluorescence quantum yields and their relations to lifetimes of rhodamine 6G and fluorescien in nine solvents: improved absolute standards for quantum yields," Photochem Photobiol 75, 327-334 (2002).
[CrossRef] [PubMed]

D. Magde, G. E. Rojas, P. G. Seybold, "Solvent dependence of the fluorescence lifetimes of xanthene dyes," Photochem Photobiol 70, 737-744 (1999).
[CrossRef]

Simon, J. D.

Sitafalwalla, S.

Streger, S. H.

M. E. Fuller, S. H. Streger, R. K. Rothmel, B. J. Mailloux, J. A. Hall, T. C. Onstott, J. K. Fredrickson, D. L. Balkwill, M. F. DeFlaun, "Development of a vital fluorescent staining method for monitoring bacterial transport in subsurface environments," Appl Environ Microbiol 66, 4486-4496 (2000).
[CrossRef] [PubMed]

Suslick, K. S.

Tay, T. L.

Z. Gong, H. Wan, T. L. Tay, H. Wang, M. Chen, T. Yan, "Development of trangenic fish for ornamental and bioreactor by strong expression of fluorescent proteins in skeletal muscle," Biochem. Biophys. Res. Commun. 308, 58-63 (2003).
[CrossRef] [PubMed]

Tearney, G. J.

Tomov, I.

Tong, L. L.

R. Richards-Kortum, R. P. Rava, M. Fitzmaurice, L. L. Tong, N. B. Ratliff, J. R. Kramer, M. S. Feld, "A one-layer model of laser-induced fluorescence for diagnosis of disease in human tissue: applications to atherosclerosis," IEEE Trans. Biomed. Eng. 36, 1222-1232 (1989).
[CrossRef] [PubMed]

Toublan, F. J.-J.

Vinegoni, C.

Wan, H.

Z. Gong, H. Wan, T. L. Tay, H. Wang, M. Chen, T. Yan, "Development of trangenic fish for ornamental and bioreactor by strong expression of fluorescent proteins in skeletal muscle," Biochem. Biophys. Res. Commun. 308, 58-63 (2003).
[CrossRef] [PubMed]

Wang, H.

Z. Gong, H. Wan, T. L. Tay, H. Wang, M. Chen, T. Yan, "Development of trangenic fish for ornamental and bioreactor by strong expression of fluorescent proteins in skeletal muscle," Biochem. Biophys. Res. Commun. 308, 58-63 (2003).
[CrossRef] [PubMed]

Wang, Y.

Wei, A.

Wiley, B. J.

J. Chen, F. Saeki, B. J. Wiley, H. Cang, M. J. Cobb, Z.-Y. Li, L. Au, H. Zhang, M. B. Kimmey, X. D. Li, Y. Xia, "Gold Nanocages: Bioconjugation and Their Potential Use as Optical Imaging Contrast Agents," Nano Lett. 5, 473-477 (2005).
[CrossRef] [PubMed]

Wilson, H. A.

H. A. Wilson, B. E. Seligmann, T. M. Chused, "Voltage-sensitive cyanine dye fluorescence signals in lymphocytes: plasma membrane and mitochondrial components," J Cell Physiol 125, 61-71 (1985).
[CrossRef] [PubMed]

Wong, R.

D. Magde, R. Wong, P. G. Seybold, "Fluorescence quantum yields and their relations to lifetimes of rhodamine 6G and fluorescien in nine solvents: improved absolute standards for quantum yields," Photochem Photobiol 75, 327-334 (2002).
[CrossRef] [PubMed]

Wyatt, W. A.

W. A. Wyatt, F. V. Bright, G. M. Hieftje, "Characterization and Comparison of 3 Fiberoptic Sensors for Iodide Determination Based on Dynamic Fluorescence Quenching of Rhodamine-6G," Anal. Chem. 59, 2272-2276 (1987).
[CrossRef]

Xia, Y.

J. Chen, F. Saeki, B. J. Wiley, H. Cang, M. J. Cobb, Z.-Y. Li, L. Au, H. Zhang, M. B. Kimmey, X. D. Li, Y. Xia, "Gold Nanocages: Bioconjugation and Their Potential Use as Optical Imaging Contrast Agents," Nano Lett. 5, 473-477 (2005).
[CrossRef] [PubMed]

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Figures (7)

Fig. 1.
Fig. 1.

Energy level diagram for a ground-state recovery pump-probe experiment. The pump radiation transfers ground state population into the excited state. The probe radiation then measures the population transfer induced by the pump, which is manifested as a reduction in ground state absorption and an increase in excited state stimulated emission.

Fig. 2.
Fig. 2.

Schematic diagram of the prototype time-domain gsrPPOCT system. Abbreviations are as follows; DM dichroic mirror, BS 50/50 beamsplitter, EOM electro-optic modulator, PBS polarizing beamsplitter, GT Glan-Thomson polarizer.

Fig. 3.
Fig. 3.

A) Cartoon of the sample vessel used for characterizing the gsrPPOCT system. The vertical dimension of the cartoon is on the same scale as the A-lines in B, C, and D. B) OCT A-line recorded at 96 kHz. C) gsrPPOCT A-line recorded simultaneously with the OCT A-line in panel A at 66 kHz. D) gsrPPOCT A-line with amplitude modulation of the pump beam turned off.

Fig. 4.
Fig. 4.

A) Measured SNR as a function of probe power using a 56 µM sample of rhodamine 6G. B) Measured SNR as a function of pump power using a 56 µM sample of rhodamine 6G. C) Measured SNR as a function of rhodamine 6G concentration. The theoretical curves are based upon predictions using eq. 1.

Fig. 5.
Fig. 5.

A) Photo of transgenic zebra danio fish expressing dsRed in its skeletal muscle. B) OCT cross-section recorded through the back of the fish, anterior to the dorsal fin as indicated by the top white box in the photo. C) Overlay of the corresponding gsrPPOCT image onto the OCT image in B. The color bar indicates the SNR of the gsrPPOCT signal (max 47 dB). D) Derivative image derived from panel C. E, F, G) Same as B, C, and D except recorded along a cross-section (bottom white box) bisecting the pectoral fin (PF) and continuing into the lateral line (LL). The maximum recorded SNRgsrPPOCT in panel E was 37 dB. The scale box is 200 µm×200 µm.

Fig. 6.
Fig. 6.

A) Photo of the gills of a euthanized adult wild-type zebra danio fish. The operculum was removed in order to expose the gills. The three images on the right (B, C, and D) were produced by summing the pixels along the axial direction of a 300 µm×500 µm 3-D volume set. The filament arteries appear as dark stripes, due to shadows created by the strong absorption by hemoglobin. E) OCT B-scan taken from the 3-D volume. F) Overlay of the corresponding gsrPPOCT image onto the OCT image in E. The color bar indicates the SNR of the gsrPPOCT signal (max 19 dB). The scale box is 50 µm x 50 µm. G) Derivative image derived from panel F.

Fig. 7.
Fig. 7.

gsrPPOCT signal plotted as a function of pump-probe delay time using the sample vessel depicted in Fig. 3. The experimental points and fit are for the maximum of the recorded peak from the mirror interface. A) 156 µM solution of rhodamine 6G and human whole blood diluted with distilled water to ~20% by volume. B) Mixture of rhodamine 6G and human whole blood.

Equations (5)

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SNR = R ρ P pr 2 Be e 2 σ 1 ( N 1 ( t ) N 2 ( t ) ) z ,
with N 1 ( t ) N 2 ( t ) = N 1 0 ( 1 exp ( 2 σ 1 λ pu P pu cos 2 ( ω t ) h c π r 2 ) )
and SNR R ρ P pr 2 Be ( σ 1 2 z N 1 0 λ pu p pu h c π r 2 f 0 ) 2
z ( ( SNR gsrPPOCT SNR OCT ) 1 2 ) = σ 1 2 N 1 0 λ pu P pu h c π r 2 f 0 .
S ( t d ) = i n a i exp ( t d τ i ) .

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