Abstract

Optical molecular imaging of small animals in vivo has witnessed dramatic growth during the past decade. Most commercial systems are based on continuous wave technology and measure solely bioluminescence or fluorescence intensity. Time domain (TD) technology enables the measurement of both intensity and fluorescence lifetime as an additional imaging metric. We have developed a novel, in-house, full-field TD system with dramatically faster acquisition times than available from a commercial TD system. Recent in vivo data from a mouse imaged with the full-field TD system has demonstrated the potential to monitor and discriminate two fluorophores injected simultaneously based on their fluorescence lifetime contrast.

© 2009 Optical Society of America

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References

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  5. W. Zhang, J. Feng, S. Harris, P. Contag, D. Stevenson, and C. Contag, “Rapid in vivo functional analysis of transgenes in mice using whole body imaging of luciferase expression,” Transgenic Res. 10, 423-434 (2001).
    [CrossRef] [PubMed]
  6. B. Rice, M. Cable, and M. Nelson, “In vivo imaging of light-emitting probes,” J. Biomed. Opt. 6, 432-440 (2001).
    [CrossRef] [PubMed]
  7. V. Ntziachristos and R. Weissleder, “Experimental three-dimensional fluorescence reconstruction of diffuse media using a normalized Born approximation,” Opt. Lett. 26, 893-895 (2001).
    [CrossRef]
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    [CrossRef]
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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
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    [CrossRef]

2008

S. Patwardhan and J. P. Culver, “Quantitative diffuse optical tomography for small animal using an ultrafast gated image intensifier,” J. Biomed. Opt. 13, 011009 (2008).
[CrossRef] [PubMed]

A. T. N. Kumar, S. Raymond, A. Dunn, B. Bacskai, and D. Boas, “A time domain fluorescence tomography system for small animal imaging,” IEEE Trans. Med. Imaging 27, 1152-1163(2008).
[CrossRef] [PubMed]

S. Han and D. J. Hall, “Estimating the depth and lifetime of a fluorescent inclusion in a turbid medium using a simple time-domain optical method,” Opt. Lett. 33, 1035-1037(2008).
[CrossRef] [PubMed]

2007

E. M. C. Hillman and A. Moore, “All-optical anatomical coregistration for small animal molecular imaging using dynamic contrast,” Nat. Photon. 1, 526-530 (2007).
[CrossRef]

D. J. Hall and S. Han, “Preliminary results from a multi-wavelength time domain optical molecular imaging system,” Proc. SPIE 6430, 64300T (2007).
[CrossRef]

R. Splinter and B. Hooper, An Introduction to Biomedical Optics (CRC Press, 2007).

H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. Regino, Y. Urano, and P. Choyke, “Simultaneous mulitcolor imaging of five different lymphatic basins using quantum dots,” Nano Lett. 7, 1711-1716 (2007).
[CrossRef] [PubMed]

2005

D. J. Hall, D. R. Vera, and R. F. Mattrey, “Full-field time domain optical molecular imaging system,” Proc. SPIE 5693, 330-335 (2005).
[CrossRef]

A. T. N. Kumar, J. Skoch, B. Backsaki, D. Boas, and A. Dunn, “Fluorescence-lifetime-based tomography for turbid medium,” Opt. Lett. 30, 3347-3349 (2005).
[CrossRef]

2004

2003

2002

V. Ntziachristos and R. Weissleder, “CCD-based scanner for tomography of fluorescent near-infrared probes in turbid media,” Med. Phys. 29, 803-809 (2002).
[CrossRef] [PubMed]

2001

W. Zhang, J. Feng, S. Harris, P. Contag, D. Stevenson, and C. Contag, “Rapid in vivo functional analysis of transgenes in mice using whole body imaging of luciferase expression,” Transgenic Res. 10, 423-434 (2001).
[CrossRef] [PubMed]

B. Rice, M. Cable, and M. Nelson, “In vivo imaging of light-emitting probes,” J. Biomed. Opt. 6, 432-440 (2001).
[CrossRef] [PubMed]

V. Ntziachristos and R. Weissleder, “Experimental three-dimensional fluorescence reconstruction of diffuse media using a normalized Born approximation,” Opt. Lett. 26, 893-895 (2001).
[CrossRef]

1999

K. K. Sharman, A. Periasamy, H. Ashworth, J. Demas, and N. Snow, “Error analysis of the rapid lifetime determination method for double-exponential decays and new windowing schemes,” Anal. Chem. 71, 947-952 (1999).
[CrossRef] [PubMed]

Ashworth, H.

K. K. Sharman, A. Periasamy, H. Ashworth, J. Demas, and N. Snow, “Error analysis of the rapid lifetime determination method for double-exponential decays and new windowing schemes,” Anal. Chem. 71, 947-952 (1999).
[CrossRef] [PubMed]

Backsaki, B.

Bacskai, B.

A. T. N. Kumar, S. Raymond, A. Dunn, B. Bacskai, and D. Boas, “A time domain fluorescence tomography system for small animal imaging,” IEEE Trans. Med. Imaging 27, 1152-1163(2008).
[CrossRef] [PubMed]

Barrett, T.

H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. Regino, Y. Urano, and P. Choyke, “Simultaneous mulitcolor imaging of five different lymphatic basins using quantum dots,” Nano Lett. 7, 1711-1716 (2007).
[CrossRef] [PubMed]

Boas, D.

A. T. N. Kumar, S. Raymond, A. Dunn, B. Bacskai, and D. Boas, “A time domain fluorescence tomography system for small animal imaging,” IEEE Trans. Med. Imaging 27, 1152-1163(2008).
[CrossRef] [PubMed]

A. T. N. Kumar, J. Skoch, B. Backsaki, D. Boas, and A. Dunn, “Fluorescence-lifetime-based tomography for turbid medium,” Opt. Lett. 30, 3347-3349 (2005).
[CrossRef]

Cable, M.

B. Rice, M. Cable, and M. Nelson, “In vivo imaging of light-emitting probes,” J. Biomed. Opt. 6, 432-440 (2001).
[CrossRef] [PubMed]

Choyke, P.

H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. Regino, Y. Urano, and P. Choyke, “Simultaneous mulitcolor imaging of five different lymphatic basins using quantum dots,” Nano Lett. 7, 1711-1716 (2007).
[CrossRef] [PubMed]

Contag, C.

W. Zhang, J. Feng, S. Harris, P. Contag, D. Stevenson, and C. Contag, “Rapid in vivo functional analysis of transgenes in mice using whole body imaging of luciferase expression,” Transgenic Res. 10, 423-434 (2001).
[CrossRef] [PubMed]

Contag, P.

W. Zhang, J. Feng, S. Harris, P. Contag, D. Stevenson, and C. Contag, “Rapid in vivo functional analysis of transgenes in mice using whole body imaging of luciferase expression,” Transgenic Res. 10, 423-434 (2001).
[CrossRef] [PubMed]

Culver, J. P.

S. Patwardhan and J. P. Culver, “Quantitative diffuse optical tomography for small animal using an ultrafast gated image intensifier,” J. Biomed. Opt. 13, 011009 (2008).
[CrossRef] [PubMed]

Demas, J.

K. K. Sharman, A. Periasamy, H. Ashworth, J. Demas, and N. Snow, “Error analysis of the rapid lifetime determination method for double-exponential decays and new windowing schemes,” Anal. Chem. 71, 947-952 (1999).
[CrossRef] [PubMed]

Dunn, A.

A. T. N. Kumar, S. Raymond, A. Dunn, B. Bacskai, and D. Boas, “A time domain fluorescence tomography system for small animal imaging,” IEEE Trans. Med. Imaging 27, 1152-1163(2008).
[CrossRef] [PubMed]

A. T. N. Kumar, J. Skoch, B. Backsaki, D. Boas, and A. Dunn, “Fluorescence-lifetime-based tomography for turbid medium,” Opt. Lett. 30, 3347-3349 (2005).
[CrossRef]

Elson, D.

Feng, J.

W. Zhang, J. Feng, S. Harris, P. Contag, D. Stevenson, and C. Contag, “Rapid in vivo functional analysis of transgenes in mice using whole body imaging of luciferase expression,” Transgenic Res. 10, 423-434 (2001).
[CrossRef] [PubMed]

Hall, D. J.

Hama, Y.

H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. Regino, Y. Urano, and P. Choyke, “Simultaneous mulitcolor imaging of five different lymphatic basins using quantum dots,” Nano Lett. 7, 1711-1716 (2007).
[CrossRef] [PubMed]

Han, S.

S. Han and D. J. Hall, “Estimating the depth and lifetime of a fluorescent inclusion in a turbid medium using a simple time-domain optical method,” Opt. Lett. 33, 1035-1037(2008).
[CrossRef] [PubMed]

D. J. Hall and S. Han, “Preliminary results from a multi-wavelength time domain optical molecular imaging system,” Proc. SPIE 6430, 64300T (2007).
[CrossRef]

Harris, S.

W. Zhang, J. Feng, S. Harris, P. Contag, D. Stevenson, and C. Contag, “Rapid in vivo functional analysis of transgenes in mice using whole body imaging of luciferase expression,” Transgenic Res. 10, 423-434 (2001).
[CrossRef] [PubMed]

Hawrysz, D.

Hillman, E. M. C.

E. M. C. Hillman and A. Moore, “All-optical anatomical coregistration for small animal molecular imaging using dynamic contrast,” Nat. Photon. 1, 526-530 (2007).
[CrossRef]

Hooper, B.

R. Splinter and B. Hooper, An Introduction to Biomedical Optics (CRC Press, 2007).

Kobayashi, H.

H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. Regino, Y. Urano, and P. Choyke, “Simultaneous mulitcolor imaging of five different lymphatic basins using quantum dots,” Nano Lett. 7, 1711-1716 (2007).
[CrossRef] [PubMed]

Koyama, Y.

H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. Regino, Y. Urano, and P. Choyke, “Simultaneous mulitcolor imaging of five different lymphatic basins using quantum dots,” Nano Lett. 7, 1711-1716 (2007).
[CrossRef] [PubMed]

Kumar, A. T. N.

A. T. N. Kumar, S. Raymond, A. Dunn, B. Bacskai, and D. Boas, “A time domain fluorescence tomography system for small animal imaging,” IEEE Trans. Med. Imaging 27, 1152-1163(2008).
[CrossRef] [PubMed]

A. T. N. Kumar, J. Skoch, B. Backsaki, D. Boas, and A. Dunn, “Fluorescence-lifetime-based tomography for turbid medium,” Opt. Lett. 30, 3347-3349 (2005).
[CrossRef]

Lee, K.

Lesage, F.

Ma, G.

Mattrey, R. F.

D. J. Hall, D. R. Vera, and R. F. Mattrey, “Full-field time domain optical molecular imaging system,” Proc. SPIE 5693, 330-335 (2005).
[CrossRef]

Moore, A.

E. M. C. Hillman and A. Moore, “All-optical anatomical coregistration for small animal molecular imaging using dynamic contrast,” Nat. Photon. 1, 526-530 (2007).
[CrossRef]

Nelson, M.

B. Rice, M. Cable, and M. Nelson, “In vivo imaging of light-emitting probes,” J. Biomed. Opt. 6, 432-440 (2001).
[CrossRef] [PubMed]

Ntziachristos, V.

R. Weissleder and V. Ntziachristos, “Shedding light onto live molecular targets,” Nature Med. 9, 123-128 (2003).
[CrossRef] [PubMed]

V. Ntziachristos and R. Weissleder, “CCD-based scanner for tomography of fluorescent near-infrared probes in turbid media,” Med. Phys. 29, 803-809 (2002).
[CrossRef] [PubMed]

V. Ntziachristos and R. Weissleder, “Experimental three-dimensional fluorescence reconstruction of diffuse media using a normalized Born approximation,” Opt. Lett. 26, 893-895 (2001).
[CrossRef]

Patwardhan, S.

S. Patwardhan and J. P. Culver, “Quantitative diffuse optical tomography for small animal using an ultrafast gated image intensifier,” J. Biomed. Opt. 13, 011009 (2008).
[CrossRef] [PubMed]

Periasamy, A.

K. K. Sharman, A. Periasamy, H. Ashworth, J. Demas, and N. Snow, “Error analysis of the rapid lifetime determination method for double-exponential decays and new windowing schemes,” Anal. Chem. 71, 947-952 (1999).
[CrossRef] [PubMed]

Raymond, S.

A. T. N. Kumar, S. Raymond, A. Dunn, B. Bacskai, and D. Boas, “A time domain fluorescence tomography system for small animal imaging,” IEEE Trans. Med. Imaging 27, 1152-1163(2008).
[CrossRef] [PubMed]

Regino, C.

H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. Regino, Y. Urano, and P. Choyke, “Simultaneous mulitcolor imaging of five different lymphatic basins using quantum dots,” Nano Lett. 7, 1711-1716 (2007).
[CrossRef] [PubMed]

Rice, B.

B. Rice, M. Cable, and M. Nelson, “In vivo imaging of light-emitting probes,” J. Biomed. Opt. 6, 432-440 (2001).
[CrossRef] [PubMed]

Sevick-Muraca, E. M.

Sharman, K. K.

K. K. Sharman, A. Periasamy, H. Ashworth, J. Demas, and N. Snow, “Error analysis of the rapid lifetime determination method for double-exponential decays and new windowing schemes,” Anal. Chem. 71, 947-952 (1999).
[CrossRef] [PubMed]

Siegel, J.

Skoch, J.

Snow, N.

K. K. Sharman, A. Periasamy, H. Ashworth, J. Demas, and N. Snow, “Error analysis of the rapid lifetime determination method for double-exponential decays and new windowing schemes,” Anal. Chem. 71, 947-952 (1999).
[CrossRef] [PubMed]

Splinter, R.

R. Splinter and B. Hooper, An Introduction to Biomedical Optics (CRC Press, 2007).

Stevenson, D.

W. Zhang, J. Feng, S. Harris, P. Contag, D. Stevenson, and C. Contag, “Rapid in vivo functional analysis of transgenes in mice using whole body imaging of luciferase expression,” Transgenic Res. 10, 423-434 (2001).
[CrossRef] [PubMed]

Thompson, A. B.

Troy, T.

T. Troy, “Quantitative comparison of the detection sensitivity of bioluminescent and fluorescent reporters in animal models,” presented at Fluorescent Proteins for Cellular Imaging and Drug Development, La Jolla, Calif., 16-17 November 2005.

Urano, Y.

H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. Regino, Y. Urano, and P. Choyke, “Simultaneous mulitcolor imaging of five different lymphatic basins using quantum dots,” Nano Lett. 7, 1711-1716 (2007).
[CrossRef] [PubMed]

Vera, D. R.

D. J. Hall, D. R. Vera, and R. F. Mattrey, “Full-field time domain optical molecular imaging system,” Proc. SPIE 5693, 330-335 (2005).
[CrossRef]

Vlandas, A.

Vo-Dinh, T.

T. Vo-Dinh, Biomedical Photonics Handbook (CRC Press, 2003).
[CrossRef]

Webb, S.

Weissleder, R.

R. Weissleder and V. Ntziachristos, “Shedding light onto live molecular targets,” Nature Med. 9, 123-128 (2003).
[CrossRef] [PubMed]

V. Ntziachristos and R. Weissleder, “CCD-based scanner for tomography of fluorescent near-infrared probes in turbid media,” Med. Phys. 29, 803-809 (2002).
[CrossRef] [PubMed]

V. Ntziachristos and R. Weissleder, “Experimental three-dimensional fluorescence reconstruction of diffuse media using a normalized Born approximation,” Opt. Lett. 26, 893-895 (2001).
[CrossRef]

Yong, W.

Zhang, W.

W. Zhang, J. Feng, S. Harris, P. Contag, D. Stevenson, and C. Contag, “Rapid in vivo functional analysis of transgenes in mice using whole body imaging of luciferase expression,” Transgenic Res. 10, 423-434 (2001).
[CrossRef] [PubMed]

Anal. Chem.

K. K. Sharman, A. Periasamy, H. Ashworth, J. Demas, and N. Snow, “Error analysis of the rapid lifetime determination method for double-exponential decays and new windowing schemes,” Anal. Chem. 71, 947-952 (1999).
[CrossRef] [PubMed]

Appl. Opt.

IEEE Trans. Med. Imaging

A. T. N. Kumar, S. Raymond, A. Dunn, B. Bacskai, and D. Boas, “A time domain fluorescence tomography system for small animal imaging,” IEEE Trans. Med. Imaging 27, 1152-1163(2008).
[CrossRef] [PubMed]

J. Biomed. Opt.

B. Rice, M. Cable, and M. Nelson, “In vivo imaging of light-emitting probes,” J. Biomed. Opt. 6, 432-440 (2001).
[CrossRef] [PubMed]

S. Patwardhan and J. P. Culver, “Quantitative diffuse optical tomography for small animal using an ultrafast gated image intensifier,” J. Biomed. Opt. 13, 011009 (2008).
[CrossRef] [PubMed]

Med. Phys.

V. Ntziachristos and R. Weissleder, “CCD-based scanner for tomography of fluorescent near-infrared probes in turbid media,” Med. Phys. 29, 803-809 (2002).
[CrossRef] [PubMed]

Nano Lett.

H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. Regino, Y. Urano, and P. Choyke, “Simultaneous mulitcolor imaging of five different lymphatic basins using quantum dots,” Nano Lett. 7, 1711-1716 (2007).
[CrossRef] [PubMed]

Nat. Photon.

E. M. C. Hillman and A. Moore, “All-optical anatomical coregistration for small animal molecular imaging using dynamic contrast,” Nat. Photon. 1, 526-530 (2007).
[CrossRef]

Nature Med.

R. Weissleder and V. Ntziachristos, “Shedding light onto live molecular targets,” Nature Med. 9, 123-128 (2003).
[CrossRef] [PubMed]

Opt. Lett.

Proc. SPIE

D. J. Hall and S. Han, “Preliminary results from a multi-wavelength time domain optical molecular imaging system,” Proc. SPIE 6430, 64300T (2007).
[CrossRef]

D. J. Hall, D. R. Vera, and R. F. Mattrey, “Full-field time domain optical molecular imaging system,” Proc. SPIE 5693, 330-335 (2005).
[CrossRef]

Transgenic Res.

W. Zhang, J. Feng, S. Harris, P. Contag, D. Stevenson, and C. Contag, “Rapid in vivo functional analysis of transgenes in mice using whole body imaging of luciferase expression,” Transgenic Res. 10, 423-434 (2001).
[CrossRef] [PubMed]

Other

T. Vo-Dinh, Biomedical Photonics Handbook (CRC Press, 2003).
[CrossRef]

R. Splinter and B. Hooper, An Introduction to Biomedical Optics (CRC Press, 2007).

T. Troy, “Quantitative comparison of the detection sensitivity of bioluminescent and fluorescent reporters in animal models,” presented at Fluorescent Proteins for Cellular Imaging and Drug Development, La Jolla, Calif., 16-17 November 2005.

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Figures (5)

Fig. 1
Fig. 1

Schematic of the full-field TD optical molecular imaging system.

Fig. 2
Fig. 2

In vitro time-gated intensity image series of Qdot800 (bottom vial) and Cy7 (top vial) from 0.5 to 2.5 ns .

Fig. 3
Fig. 3

In vitro fluorescence TPSFs from Qdot800 and Cy7.

Fig. 4
Fig. 4

(a) In vivo fluorescence intensity images over the 50 min experiment. (b) Corresponding fluorescence TPSFs from the (left) liver and (right) bladder.

Fig. 5
Fig. 5

Change in relative contribution of fluorophores in the (a) liver and (b) bladder.

Equations (11)

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

2 ns
0.5 ns
6 ns
9.8   s
5 min
50 min
I ( t ) = RC Qdot 800 e t / 6 . 56 + RC Cy 7 e t / 0 . 60 .
10   s
9.8   s
50 min
50 min

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