Abstract

We present a new method for high-resolution, three-dimensional fluorescence imaging. In contrast to beam-scanning confocal microscopy, where the laser focus must be scanned both laterally and axially to collect a volume, we obtain depth information without the necessity of depth scanning. In this method, the emitted fluorescence is collected in the backward direction and is sent through a phase plate that encodes the depth information into the phase of a spectrally resolved interference pattern. We demonstrate that decoding this phase information allows for depth localization accuracy better than 4 µm over a 500 µm depth-of-field. In a high numerical aperture configuration with a much smaller depth of field, a localization accuracy of tens of nanometers can be achieved. This approach is ideally suited for miniature endoscopes, where space limitations at the endoscope tip render depth scanning difficult. We illustrate the potential for 3D visualization of complex biological samples by constructing a three-dimensional volume of the microvasculature of ex vivo murine heart tissue from a single 2D scan.

© 2012 OSA

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  1. L. Sampath, S. Kwon, S. Ke, W. Wang, R. Schiff, M. E. Mawad, and E. M. Sevick-Muraca, “Dual-labeled trastuzumab-based imaging agent for the detection of human epidermal growth factor receptor 2 overexpression in breast cancer,” J. Nucl. Med.48(9), 1501–1510 (2007).
    [CrossRef] [PubMed]
  2. P. Zou, S. Xu, S. P. Povoski, A. Wang, M. A. Johnson, E. W. Martin, V. Subramaniam, R. Xu, and D. Sun, “Near-infrared fluorescence labeled anti-TAG-72 monoclonal antibodies for tumor imaging in colorectal cancer xenograft mice,” Mol. Pharm.6, 428–440 (2009).
    [CrossRef] [PubMed]
  3. E. A. te Velde, T. Veerman, V. Subramaniam, and T. Ruers, “The use of fluorescent dyes and probes in surgical oncology,” Eur. J. Surg. Oncol.36(1), 6–15 (2010).
    [CrossRef] [PubMed]
  4. A. G. T. Terwisscha van Scheltinga, G. M. van Dam, W. B. Nagengast, V. Ntziachristos, H. Hollema, J. L. Herek, C. P. Schröder, J. G. W. Kosterink, M. N. Lub-de Hoog, and E. G. E. de Vries, “Intraoperative near-infrared fluorescence tumor imaging with vascular endothelial growth factor and human epidermal growth factor receptor 2 targeting antibodies,” J. Nucl. Med.52(11), 1778–1785 (2011).
    [CrossRef] [PubMed]
  5. G. M. van Dam, G. Themelis, L. M. Crane, N. J. Harlaar, R. G. Pleijhuis, W. Kelder, A. Sarantopoulos, J. S. de Jong, H. J. Arts, A. G. van der Zee, J. Bart, P. S. Low, and V. Ntziachristos, “Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results,” Nat. Med.17(10), 1315–1319 (2011).
    [CrossRef] [PubMed]
  6. K. E. Drabe, G. Cnossen, and D. A. Wiersma, “Localization of spontaneous emission in front of a mirror,” Opt. Commun.73(2), 91–95 (1989).
    [CrossRef]
  7. A. K. Swan, L. A. Moiseev, C. R. Cantor, B. Davis, S. B. Ippolito, W. C. Karl, B. B. Goldberg, and M. S. Unlu, “Toward nanometer-scale resolution in fluorescence microscopy using spectral self-interference,” IEEE J. Sel. Top. Quantum Electron.9(2), 294–300 (2003).
    [CrossRef]
  8. M. Dogan, M. I. Aksun, A. K. Swan, B. B. Goldberg, and M. S. Unlü, “Closed-form representations of field components of fluorescent emitters in layered media,” J. Opt. Soc. Am. A26(6), 1458–1466 (2009).
    [CrossRef] [PubMed]
  9. A. Bilenca, A. Ozcan, B. Bouma, and G. Tearney, “Fluorescence coherence tomography,” Opt. Express14(16), 7134–7143 (2006).
    [CrossRef] [PubMed]
  10. G. Shtengel, J. A. Galbraith, C. G. Galbraith, J. Lippincott-Schwartz, J. M. Gillette, S. Manley, R. Sougrat, C. M. Waterman, P. Kanchanawong, M. W. Davidson, R. D. Fetter, and H. F. Hess, “Interferometric fluorescent super-resolution microscopy resolves 3D cellular ultrastructure,” Proc. Natl. Acad. Sci. U.S.A.106(9), 3125–3130 (2009).
    [CrossRef] [PubMed]
  11. B. Park, M. C. Pierce, B. Cense, S.-H. Yun, M. Mujat, G. Tearney, B. Bouma, and J. de Boer, “Real-time fiber-based multi-functional spectral-domain optical coherence tomography at 1.3 microm,” Opt. Express13(11), 3931–3944 (2005).
    [CrossRef] [PubMed]
  12. S. L. K. Bowers, T. K. Borg, and T. A. Baudino, “The dynamics of fibroblast-myocyte-capillary interactions in the heart,” Ann. N. Y. Acad. Sci.1188(1), 143–152 (2010).
    [CrossRef] [PubMed]
  13. I. J. LeGrice, B. H. Smaill, L. Z. Chai, S. G. Edgar, J. B. Gavin, and P. J. Hunter, “Laminar structure of the heart: ventricular myocyte arrangement and connective tissue architecture in the dog,” Am. J. Physiol.269(2 Pt 2), H571–H582 (1995).
    [PubMed]

2011

A. G. T. Terwisscha van Scheltinga, G. M. van Dam, W. B. Nagengast, V. Ntziachristos, H. Hollema, J. L. Herek, C. P. Schröder, J. G. W. Kosterink, M. N. Lub-de Hoog, and E. G. E. de Vries, “Intraoperative near-infrared fluorescence tumor imaging with vascular endothelial growth factor and human epidermal growth factor receptor 2 targeting antibodies,” J. Nucl. Med.52(11), 1778–1785 (2011).
[CrossRef] [PubMed]

G. M. van Dam, G. Themelis, L. M. Crane, N. J. Harlaar, R. G. Pleijhuis, W. Kelder, A. Sarantopoulos, J. S. de Jong, H. J. Arts, A. G. van der Zee, J. Bart, P. S. Low, and V. Ntziachristos, “Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results,” Nat. Med.17(10), 1315–1319 (2011).
[CrossRef] [PubMed]

2010

E. A. te Velde, T. Veerman, V. Subramaniam, and T. Ruers, “The use of fluorescent dyes and probes in surgical oncology,” Eur. J. Surg. Oncol.36(1), 6–15 (2010).
[CrossRef] [PubMed]

S. L. K. Bowers, T. K. Borg, and T. A. Baudino, “The dynamics of fibroblast-myocyte-capillary interactions in the heart,” Ann. N. Y. Acad. Sci.1188(1), 143–152 (2010).
[CrossRef] [PubMed]

2009

G. Shtengel, J. A. Galbraith, C. G. Galbraith, J. Lippincott-Schwartz, J. M. Gillette, S. Manley, R. Sougrat, C. M. Waterman, P. Kanchanawong, M. W. Davidson, R. D. Fetter, and H. F. Hess, “Interferometric fluorescent super-resolution microscopy resolves 3D cellular ultrastructure,” Proc. Natl. Acad. Sci. U.S.A.106(9), 3125–3130 (2009).
[CrossRef] [PubMed]

M. Dogan, M. I. Aksun, A. K. Swan, B. B. Goldberg, and M. S. Unlü, “Closed-form representations of field components of fluorescent emitters in layered media,” J. Opt. Soc. Am. A26(6), 1458–1466 (2009).
[CrossRef] [PubMed]

P. Zou, S. Xu, S. P. Povoski, A. Wang, M. A. Johnson, E. W. Martin, V. Subramaniam, R. Xu, and D. Sun, “Near-infrared fluorescence labeled anti-TAG-72 monoclonal antibodies for tumor imaging in colorectal cancer xenograft mice,” Mol. Pharm.6, 428–440 (2009).
[CrossRef] [PubMed]

2007

L. Sampath, S. Kwon, S. Ke, W. Wang, R. Schiff, M. E. Mawad, and E. M. Sevick-Muraca, “Dual-labeled trastuzumab-based imaging agent for the detection of human epidermal growth factor receptor 2 overexpression in breast cancer,” J. Nucl. Med.48(9), 1501–1510 (2007).
[CrossRef] [PubMed]

2006

A. Bilenca, A. Ozcan, B. Bouma, and G. Tearney, “Fluorescence coherence tomography,” Opt. Express14(16), 7134–7143 (2006).
[CrossRef] [PubMed]

2005

B. Park, M. C. Pierce, B. Cense, S.-H. Yun, M. Mujat, G. Tearney, B. Bouma, and J. de Boer, “Real-time fiber-based multi-functional spectral-domain optical coherence tomography at 1.3 microm,” Opt. Express13(11), 3931–3944 (2005).
[CrossRef] [PubMed]

2003

A. K. Swan, L. A. Moiseev, C. R. Cantor, B. Davis, S. B. Ippolito, W. C. Karl, B. B. Goldberg, and M. S. Unlu, “Toward nanometer-scale resolution in fluorescence microscopy using spectral self-interference,” IEEE J. Sel. Top. Quantum Electron.9(2), 294–300 (2003).
[CrossRef]

1995

I. J. LeGrice, B. H. Smaill, L. Z. Chai, S. G. Edgar, J. B. Gavin, and P. J. Hunter, “Laminar structure of the heart: ventricular myocyte arrangement and connective tissue architecture in the dog,” Am. J. Physiol.269(2 Pt 2), H571–H582 (1995).
[PubMed]

1989

K. E. Drabe, G. Cnossen, and D. A. Wiersma, “Localization of spontaneous emission in front of a mirror,” Opt. Commun.73(2), 91–95 (1989).
[CrossRef]

Aksun, M. I.

M. Dogan, M. I. Aksun, A. K. Swan, B. B. Goldberg, and M. S. Unlü, “Closed-form representations of field components of fluorescent emitters in layered media,” J. Opt. Soc. Am. A26(6), 1458–1466 (2009).
[CrossRef] [PubMed]

Arts, H. J.

G. M. van Dam, G. Themelis, L. M. Crane, N. J. Harlaar, R. G. Pleijhuis, W. Kelder, A. Sarantopoulos, J. S. de Jong, H. J. Arts, A. G. van der Zee, J. Bart, P. S. Low, and V. Ntziachristos, “Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results,” Nat. Med.17(10), 1315–1319 (2011).
[CrossRef] [PubMed]

Bart, J.

G. M. van Dam, G. Themelis, L. M. Crane, N. J. Harlaar, R. G. Pleijhuis, W. Kelder, A. Sarantopoulos, J. S. de Jong, H. J. Arts, A. G. van der Zee, J. Bart, P. S. Low, and V. Ntziachristos, “Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results,” Nat. Med.17(10), 1315–1319 (2011).
[CrossRef] [PubMed]

Baudino, T. A.

S. L. K. Bowers, T. K. Borg, and T. A. Baudino, “The dynamics of fibroblast-myocyte-capillary interactions in the heart,” Ann. N. Y. Acad. Sci.1188(1), 143–152 (2010).
[CrossRef] [PubMed]

Bilenca, A.

A. Bilenca, A. Ozcan, B. Bouma, and G. Tearney, “Fluorescence coherence tomography,” Opt. Express14(16), 7134–7143 (2006).
[CrossRef] [PubMed]

Borg, T. K.

S. L. K. Bowers, T. K. Borg, and T. A. Baudino, “The dynamics of fibroblast-myocyte-capillary interactions in the heart,” Ann. N. Y. Acad. Sci.1188(1), 143–152 (2010).
[CrossRef] [PubMed]

Bouma, B.

A. Bilenca, A. Ozcan, B. Bouma, and G. Tearney, “Fluorescence coherence tomography,” Opt. Express14(16), 7134–7143 (2006).
[CrossRef] [PubMed]

B. Park, M. C. Pierce, B. Cense, S.-H. Yun, M. Mujat, G. Tearney, B. Bouma, and J. de Boer, “Real-time fiber-based multi-functional spectral-domain optical coherence tomography at 1.3 microm,” Opt. Express13(11), 3931–3944 (2005).
[CrossRef] [PubMed]

Bowers, S. L. K.

S. L. K. Bowers, T. K. Borg, and T. A. Baudino, “The dynamics of fibroblast-myocyte-capillary interactions in the heart,” Ann. N. Y. Acad. Sci.1188(1), 143–152 (2010).
[CrossRef] [PubMed]

Cantor, C. R.

A. K. Swan, L. A. Moiseev, C. R. Cantor, B. Davis, S. B. Ippolito, W. C. Karl, B. B. Goldberg, and M. S. Unlu, “Toward nanometer-scale resolution in fluorescence microscopy using spectral self-interference,” IEEE J. Sel. Top. Quantum Electron.9(2), 294–300 (2003).
[CrossRef]

Cense, B.

B. Park, M. C. Pierce, B. Cense, S.-H. Yun, M. Mujat, G. Tearney, B. Bouma, and J. de Boer, “Real-time fiber-based multi-functional spectral-domain optical coherence tomography at 1.3 microm,” Opt. Express13(11), 3931–3944 (2005).
[CrossRef] [PubMed]

Chai, L. Z.

I. J. LeGrice, B. H. Smaill, L. Z. Chai, S. G. Edgar, J. B. Gavin, and P. J. Hunter, “Laminar structure of the heart: ventricular myocyte arrangement and connective tissue architecture in the dog,” Am. J. Physiol.269(2 Pt 2), H571–H582 (1995).
[PubMed]

Cnossen, G.

K. E. Drabe, G. Cnossen, and D. A. Wiersma, “Localization of spontaneous emission in front of a mirror,” Opt. Commun.73(2), 91–95 (1989).
[CrossRef]

Crane, L. M.

G. M. van Dam, G. Themelis, L. M. Crane, N. J. Harlaar, R. G. Pleijhuis, W. Kelder, A. Sarantopoulos, J. S. de Jong, H. J. Arts, A. G. van der Zee, J. Bart, P. S. Low, and V. Ntziachristos, “Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results,” Nat. Med.17(10), 1315–1319 (2011).
[CrossRef] [PubMed]

Davidson, M. W.

G. Shtengel, J. A. Galbraith, C. G. Galbraith, J. Lippincott-Schwartz, J. M. Gillette, S. Manley, R. Sougrat, C. M. Waterman, P. Kanchanawong, M. W. Davidson, R. D. Fetter, and H. F. Hess, “Interferometric fluorescent super-resolution microscopy resolves 3D cellular ultrastructure,” Proc. Natl. Acad. Sci. U.S.A.106(9), 3125–3130 (2009).
[CrossRef] [PubMed]

Davis, B.

A. K. Swan, L. A. Moiseev, C. R. Cantor, B. Davis, S. B. Ippolito, W. C. Karl, B. B. Goldberg, and M. S. Unlu, “Toward nanometer-scale resolution in fluorescence microscopy using spectral self-interference,” IEEE J. Sel. Top. Quantum Electron.9(2), 294–300 (2003).
[CrossRef]

de Boer, J.

B. Park, M. C. Pierce, B. Cense, S.-H. Yun, M. Mujat, G. Tearney, B. Bouma, and J. de Boer, “Real-time fiber-based multi-functional spectral-domain optical coherence tomography at 1.3 microm,” Opt. Express13(11), 3931–3944 (2005).
[CrossRef] [PubMed]

de Jong, J. S.

G. M. van Dam, G. Themelis, L. M. Crane, N. J. Harlaar, R. G. Pleijhuis, W. Kelder, A. Sarantopoulos, J. S. de Jong, H. J. Arts, A. G. van der Zee, J. Bart, P. S. Low, and V. Ntziachristos, “Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results,” Nat. Med.17(10), 1315–1319 (2011).
[CrossRef] [PubMed]

de Vries, E. G. E.

A. G. T. Terwisscha van Scheltinga, G. M. van Dam, W. B. Nagengast, V. Ntziachristos, H. Hollema, J. L. Herek, C. P. Schröder, J. G. W. Kosterink, M. N. Lub-de Hoog, and E. G. E. de Vries, “Intraoperative near-infrared fluorescence tumor imaging with vascular endothelial growth factor and human epidermal growth factor receptor 2 targeting antibodies,” J. Nucl. Med.52(11), 1778–1785 (2011).
[CrossRef] [PubMed]

Dogan, M.

M. Dogan, M. I. Aksun, A. K. Swan, B. B. Goldberg, and M. S. Unlü, “Closed-form representations of field components of fluorescent emitters in layered media,” J. Opt. Soc. Am. A26(6), 1458–1466 (2009).
[CrossRef] [PubMed]

Drabe, K. E.

K. E. Drabe, G. Cnossen, and D. A. Wiersma, “Localization of spontaneous emission in front of a mirror,” Opt. Commun.73(2), 91–95 (1989).
[CrossRef]

Edgar, S. G.

I. J. LeGrice, B. H. Smaill, L. Z. Chai, S. G. Edgar, J. B. Gavin, and P. J. Hunter, “Laminar structure of the heart: ventricular myocyte arrangement and connective tissue architecture in the dog,” Am. J. Physiol.269(2 Pt 2), H571–H582 (1995).
[PubMed]

Fetter, R. D.

G. Shtengel, J. A. Galbraith, C. G. Galbraith, J. Lippincott-Schwartz, J. M. Gillette, S. Manley, R. Sougrat, C. M. Waterman, P. Kanchanawong, M. W. Davidson, R. D. Fetter, and H. F. Hess, “Interferometric fluorescent super-resolution microscopy resolves 3D cellular ultrastructure,” Proc. Natl. Acad. Sci. U.S.A.106(9), 3125–3130 (2009).
[CrossRef] [PubMed]

Galbraith, C. G.

G. Shtengel, J. A. Galbraith, C. G. Galbraith, J. Lippincott-Schwartz, J. M. Gillette, S. Manley, R. Sougrat, C. M. Waterman, P. Kanchanawong, M. W. Davidson, R. D. Fetter, and H. F. Hess, “Interferometric fluorescent super-resolution microscopy resolves 3D cellular ultrastructure,” Proc. Natl. Acad. Sci. U.S.A.106(9), 3125–3130 (2009).
[CrossRef] [PubMed]

Galbraith, J. A.

G. Shtengel, J. A. Galbraith, C. G. Galbraith, J. Lippincott-Schwartz, J. M. Gillette, S. Manley, R. Sougrat, C. M. Waterman, P. Kanchanawong, M. W. Davidson, R. D. Fetter, and H. F. Hess, “Interferometric fluorescent super-resolution microscopy resolves 3D cellular ultrastructure,” Proc. Natl. Acad. Sci. U.S.A.106(9), 3125–3130 (2009).
[CrossRef] [PubMed]

Gavin, J. B.

I. J. LeGrice, B. H. Smaill, L. Z. Chai, S. G. Edgar, J. B. Gavin, and P. J. Hunter, “Laminar structure of the heart: ventricular myocyte arrangement and connective tissue architecture in the dog,” Am. J. Physiol.269(2 Pt 2), H571–H582 (1995).
[PubMed]

Gillette, J. M.

G. Shtengel, J. A. Galbraith, C. G. Galbraith, J. Lippincott-Schwartz, J. M. Gillette, S. Manley, R. Sougrat, C. M. Waterman, P. Kanchanawong, M. W. Davidson, R. D. Fetter, and H. F. Hess, “Interferometric fluorescent super-resolution microscopy resolves 3D cellular ultrastructure,” Proc. Natl. Acad. Sci. U.S.A.106(9), 3125–3130 (2009).
[CrossRef] [PubMed]

Goldberg, B. B.

M. Dogan, M. I. Aksun, A. K. Swan, B. B. Goldberg, and M. S. Unlü, “Closed-form representations of field components of fluorescent emitters in layered media,” J. Opt. Soc. Am. A26(6), 1458–1466 (2009).
[CrossRef] [PubMed]

A. K. Swan, L. A. Moiseev, C. R. Cantor, B. Davis, S. B. Ippolito, W. C. Karl, B. B. Goldberg, and M. S. Unlu, “Toward nanometer-scale resolution in fluorescence microscopy using spectral self-interference,” IEEE J. Sel. Top. Quantum Electron.9(2), 294–300 (2003).
[CrossRef]

Harlaar, N. J.

G. M. van Dam, G. Themelis, L. M. Crane, N. J. Harlaar, R. G. Pleijhuis, W. Kelder, A. Sarantopoulos, J. S. de Jong, H. J. Arts, A. G. van der Zee, J. Bart, P. S. Low, and V. Ntziachristos, “Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results,” Nat. Med.17(10), 1315–1319 (2011).
[CrossRef] [PubMed]

Herek, J. L.

A. G. T. Terwisscha van Scheltinga, G. M. van Dam, W. B. Nagengast, V. Ntziachristos, H. Hollema, J. L. Herek, C. P. Schröder, J. G. W. Kosterink, M. N. Lub-de Hoog, and E. G. E. de Vries, “Intraoperative near-infrared fluorescence tumor imaging with vascular endothelial growth factor and human epidermal growth factor receptor 2 targeting antibodies,” J. Nucl. Med.52(11), 1778–1785 (2011).
[CrossRef] [PubMed]

Hess, H. F.

G. Shtengel, J. A. Galbraith, C. G. Galbraith, J. Lippincott-Schwartz, J. M. Gillette, S. Manley, R. Sougrat, C. M. Waterman, P. Kanchanawong, M. W. Davidson, R. D. Fetter, and H. F. Hess, “Interferometric fluorescent super-resolution microscopy resolves 3D cellular ultrastructure,” Proc. Natl. Acad. Sci. U.S.A.106(9), 3125–3130 (2009).
[CrossRef] [PubMed]

Hollema, H.

A. G. T. Terwisscha van Scheltinga, G. M. van Dam, W. B. Nagengast, V. Ntziachristos, H. Hollema, J. L. Herek, C. P. Schröder, J. G. W. Kosterink, M. N. Lub-de Hoog, and E. G. E. de Vries, “Intraoperative near-infrared fluorescence tumor imaging with vascular endothelial growth factor and human epidermal growth factor receptor 2 targeting antibodies,” J. Nucl. Med.52(11), 1778–1785 (2011).
[CrossRef] [PubMed]

Hunter, P. J.

I. J. LeGrice, B. H. Smaill, L. Z. Chai, S. G. Edgar, J. B. Gavin, and P. J. Hunter, “Laminar structure of the heart: ventricular myocyte arrangement and connective tissue architecture in the dog,” Am. J. Physiol.269(2 Pt 2), H571–H582 (1995).
[PubMed]

Ippolito, S. B.

A. K. Swan, L. A. Moiseev, C. R. Cantor, B. Davis, S. B. Ippolito, W. C. Karl, B. B. Goldberg, and M. S. Unlu, “Toward nanometer-scale resolution in fluorescence microscopy using spectral self-interference,” IEEE J. Sel. Top. Quantum Electron.9(2), 294–300 (2003).
[CrossRef]

Johnson, M. A.

P. Zou, S. Xu, S. P. Povoski, A. Wang, M. A. Johnson, E. W. Martin, V. Subramaniam, R. Xu, and D. Sun, “Near-infrared fluorescence labeled anti-TAG-72 monoclonal antibodies for tumor imaging in colorectal cancer xenograft mice,” Mol. Pharm.6, 428–440 (2009).
[CrossRef] [PubMed]

Kanchanawong, P.

G. Shtengel, J. A. Galbraith, C. G. Galbraith, J. Lippincott-Schwartz, J. M. Gillette, S. Manley, R. Sougrat, C. M. Waterman, P. Kanchanawong, M. W. Davidson, R. D. Fetter, and H. F. Hess, “Interferometric fluorescent super-resolution microscopy resolves 3D cellular ultrastructure,” Proc. Natl. Acad. Sci. U.S.A.106(9), 3125–3130 (2009).
[CrossRef] [PubMed]

Karl, W. C.

A. K. Swan, L. A. Moiseev, C. R. Cantor, B. Davis, S. B. Ippolito, W. C. Karl, B. B. Goldberg, and M. S. Unlu, “Toward nanometer-scale resolution in fluorescence microscopy using spectral self-interference,” IEEE J. Sel. Top. Quantum Electron.9(2), 294–300 (2003).
[CrossRef]

Ke, S.

L. Sampath, S. Kwon, S. Ke, W. Wang, R. Schiff, M. E. Mawad, and E. M. Sevick-Muraca, “Dual-labeled trastuzumab-based imaging agent for the detection of human epidermal growth factor receptor 2 overexpression in breast cancer,” J. Nucl. Med.48(9), 1501–1510 (2007).
[CrossRef] [PubMed]

Kelder, W.

G. M. van Dam, G. Themelis, L. M. Crane, N. J. Harlaar, R. G. Pleijhuis, W. Kelder, A. Sarantopoulos, J. S. de Jong, H. J. Arts, A. G. van der Zee, J. Bart, P. S. Low, and V. Ntziachristos, “Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results,” Nat. Med.17(10), 1315–1319 (2011).
[CrossRef] [PubMed]

Kosterink, J. G. W.

A. G. T. Terwisscha van Scheltinga, G. M. van Dam, W. B. Nagengast, V. Ntziachristos, H. Hollema, J. L. Herek, C. P. Schröder, J. G. W. Kosterink, M. N. Lub-de Hoog, and E. G. E. de Vries, “Intraoperative near-infrared fluorescence tumor imaging with vascular endothelial growth factor and human epidermal growth factor receptor 2 targeting antibodies,” J. Nucl. Med.52(11), 1778–1785 (2011).
[CrossRef] [PubMed]

Kwon, S.

L. Sampath, S. Kwon, S. Ke, W. Wang, R. Schiff, M. E. Mawad, and E. M. Sevick-Muraca, “Dual-labeled trastuzumab-based imaging agent for the detection of human epidermal growth factor receptor 2 overexpression in breast cancer,” J. Nucl. Med.48(9), 1501–1510 (2007).
[CrossRef] [PubMed]

LeGrice, I. J.

I. J. LeGrice, B. H. Smaill, L. Z. Chai, S. G. Edgar, J. B. Gavin, and P. J. Hunter, “Laminar structure of the heart: ventricular myocyte arrangement and connective tissue architecture in the dog,” Am. J. Physiol.269(2 Pt 2), H571–H582 (1995).
[PubMed]

Lippincott-Schwartz, J.

G. Shtengel, J. A. Galbraith, C. G. Galbraith, J. Lippincott-Schwartz, J. M. Gillette, S. Manley, R. Sougrat, C. M. Waterman, P. Kanchanawong, M. W. Davidson, R. D. Fetter, and H. F. Hess, “Interferometric fluorescent super-resolution microscopy resolves 3D cellular ultrastructure,” Proc. Natl. Acad. Sci. U.S.A.106(9), 3125–3130 (2009).
[CrossRef] [PubMed]

Low, P. S.

G. M. van Dam, G. Themelis, L. M. Crane, N. J. Harlaar, R. G. Pleijhuis, W. Kelder, A. Sarantopoulos, J. S. de Jong, H. J. Arts, A. G. van der Zee, J. Bart, P. S. Low, and V. Ntziachristos, “Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results,” Nat. Med.17(10), 1315–1319 (2011).
[CrossRef] [PubMed]

Lub-de Hoog, M. N.

A. G. T. Terwisscha van Scheltinga, G. M. van Dam, W. B. Nagengast, V. Ntziachristos, H. Hollema, J. L. Herek, C. P. Schröder, J. G. W. Kosterink, M. N. Lub-de Hoog, and E. G. E. de Vries, “Intraoperative near-infrared fluorescence tumor imaging with vascular endothelial growth factor and human epidermal growth factor receptor 2 targeting antibodies,” J. Nucl. Med.52(11), 1778–1785 (2011).
[CrossRef] [PubMed]

Manley, S.

G. Shtengel, J. A. Galbraith, C. G. Galbraith, J. Lippincott-Schwartz, J. M. Gillette, S. Manley, R. Sougrat, C. M. Waterman, P. Kanchanawong, M. W. Davidson, R. D. Fetter, and H. F. Hess, “Interferometric fluorescent super-resolution microscopy resolves 3D cellular ultrastructure,” Proc. Natl. Acad. Sci. U.S.A.106(9), 3125–3130 (2009).
[CrossRef] [PubMed]

Martin, E. W.

P. Zou, S. Xu, S. P. Povoski, A. Wang, M. A. Johnson, E. W. Martin, V. Subramaniam, R. Xu, and D. Sun, “Near-infrared fluorescence labeled anti-TAG-72 monoclonal antibodies for tumor imaging in colorectal cancer xenograft mice,” Mol. Pharm.6, 428–440 (2009).
[CrossRef] [PubMed]

Mawad, M. E.

L. Sampath, S. Kwon, S. Ke, W. Wang, R. Schiff, M. E. Mawad, and E. M. Sevick-Muraca, “Dual-labeled trastuzumab-based imaging agent for the detection of human epidermal growth factor receptor 2 overexpression in breast cancer,” J. Nucl. Med.48(9), 1501–1510 (2007).
[CrossRef] [PubMed]

Moiseev, L. A.

A. K. Swan, L. A. Moiseev, C. R. Cantor, B. Davis, S. B. Ippolito, W. C. Karl, B. B. Goldberg, and M. S. Unlu, “Toward nanometer-scale resolution in fluorescence microscopy using spectral self-interference,” IEEE J. Sel. Top. Quantum Electron.9(2), 294–300 (2003).
[CrossRef]

Mujat, M.

B. Park, M. C. Pierce, B. Cense, S.-H. Yun, M. Mujat, G. Tearney, B. Bouma, and J. de Boer, “Real-time fiber-based multi-functional spectral-domain optical coherence tomography at 1.3 microm,” Opt. Express13(11), 3931–3944 (2005).
[CrossRef] [PubMed]

Nagengast, W. B.

A. G. T. Terwisscha van Scheltinga, G. M. van Dam, W. B. Nagengast, V. Ntziachristos, H. Hollema, J. L. Herek, C. P. Schröder, J. G. W. Kosterink, M. N. Lub-de Hoog, and E. G. E. de Vries, “Intraoperative near-infrared fluorescence tumor imaging with vascular endothelial growth factor and human epidermal growth factor receptor 2 targeting antibodies,” J. Nucl. Med.52(11), 1778–1785 (2011).
[CrossRef] [PubMed]

Ntziachristos, V.

A. G. T. Terwisscha van Scheltinga, G. M. van Dam, W. B. Nagengast, V. Ntziachristos, H. Hollema, J. L. Herek, C. P. Schröder, J. G. W. Kosterink, M. N. Lub-de Hoog, and E. G. E. de Vries, “Intraoperative near-infrared fluorescence tumor imaging with vascular endothelial growth factor and human epidermal growth factor receptor 2 targeting antibodies,” J. Nucl. Med.52(11), 1778–1785 (2011).
[CrossRef] [PubMed]

G. M. van Dam, G. Themelis, L. M. Crane, N. J. Harlaar, R. G. Pleijhuis, W. Kelder, A. Sarantopoulos, J. S. de Jong, H. J. Arts, A. G. van der Zee, J. Bart, P. S. Low, and V. Ntziachristos, “Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results,” Nat. Med.17(10), 1315–1319 (2011).
[CrossRef] [PubMed]

Ozcan, A.

A. Bilenca, A. Ozcan, B. Bouma, and G. Tearney, “Fluorescence coherence tomography,” Opt. Express14(16), 7134–7143 (2006).
[CrossRef] [PubMed]

Park, B.

B. Park, M. C. Pierce, B. Cense, S.-H. Yun, M. Mujat, G. Tearney, B. Bouma, and J. de Boer, “Real-time fiber-based multi-functional spectral-domain optical coherence tomography at 1.3 microm,” Opt. Express13(11), 3931–3944 (2005).
[CrossRef] [PubMed]

Pierce, M. C.

B. Park, M. C. Pierce, B. Cense, S.-H. Yun, M. Mujat, G. Tearney, B. Bouma, and J. de Boer, “Real-time fiber-based multi-functional spectral-domain optical coherence tomography at 1.3 microm,” Opt. Express13(11), 3931–3944 (2005).
[CrossRef] [PubMed]

Pleijhuis, R. G.

G. M. van Dam, G. Themelis, L. M. Crane, N. J. Harlaar, R. G. Pleijhuis, W. Kelder, A. Sarantopoulos, J. S. de Jong, H. J. Arts, A. G. van der Zee, J. Bart, P. S. Low, and V. Ntziachristos, “Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results,” Nat. Med.17(10), 1315–1319 (2011).
[CrossRef] [PubMed]

Povoski, S. P.

P. Zou, S. Xu, S. P. Povoski, A. Wang, M. A. Johnson, E. W. Martin, V. Subramaniam, R. Xu, and D. Sun, “Near-infrared fluorescence labeled anti-TAG-72 monoclonal antibodies for tumor imaging in colorectal cancer xenograft mice,” Mol. Pharm.6, 428–440 (2009).
[CrossRef] [PubMed]

Ruers, T.

E. A. te Velde, T. Veerman, V. Subramaniam, and T. Ruers, “The use of fluorescent dyes and probes in surgical oncology,” Eur. J. Surg. Oncol.36(1), 6–15 (2010).
[CrossRef] [PubMed]

Sampath, L.

L. Sampath, S. Kwon, S. Ke, W. Wang, R. Schiff, M. E. Mawad, and E. M. Sevick-Muraca, “Dual-labeled trastuzumab-based imaging agent for the detection of human epidermal growth factor receptor 2 overexpression in breast cancer,” J. Nucl. Med.48(9), 1501–1510 (2007).
[CrossRef] [PubMed]

Sarantopoulos, A.

G. M. van Dam, G. Themelis, L. M. Crane, N. J. Harlaar, R. G. Pleijhuis, W. Kelder, A. Sarantopoulos, J. S. de Jong, H. J. Arts, A. G. van der Zee, J. Bart, P. S. Low, and V. Ntziachristos, “Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results,” Nat. Med.17(10), 1315–1319 (2011).
[CrossRef] [PubMed]

Schiff, R.

L. Sampath, S. Kwon, S. Ke, W. Wang, R. Schiff, M. E. Mawad, and E. M. Sevick-Muraca, “Dual-labeled trastuzumab-based imaging agent for the detection of human epidermal growth factor receptor 2 overexpression in breast cancer,” J. Nucl. Med.48(9), 1501–1510 (2007).
[CrossRef] [PubMed]

Schröder, C. P.

A. G. T. Terwisscha van Scheltinga, G. M. van Dam, W. B. Nagengast, V. Ntziachristos, H. Hollema, J. L. Herek, C. P. Schröder, J. G. W. Kosterink, M. N. Lub-de Hoog, and E. G. E. de Vries, “Intraoperative near-infrared fluorescence tumor imaging with vascular endothelial growth factor and human epidermal growth factor receptor 2 targeting antibodies,” J. Nucl. Med.52(11), 1778–1785 (2011).
[CrossRef] [PubMed]

Sevick-Muraca, E. M.

L. Sampath, S. Kwon, S. Ke, W. Wang, R. Schiff, M. E. Mawad, and E. M. Sevick-Muraca, “Dual-labeled trastuzumab-based imaging agent for the detection of human epidermal growth factor receptor 2 overexpression in breast cancer,” J. Nucl. Med.48(9), 1501–1510 (2007).
[CrossRef] [PubMed]

Shtengel, G.

G. Shtengel, J. A. Galbraith, C. G. Galbraith, J. Lippincott-Schwartz, J. M. Gillette, S. Manley, R. Sougrat, C. M. Waterman, P. Kanchanawong, M. W. Davidson, R. D. Fetter, and H. F. Hess, “Interferometric fluorescent super-resolution microscopy resolves 3D cellular ultrastructure,” Proc. Natl. Acad. Sci. U.S.A.106(9), 3125–3130 (2009).
[CrossRef] [PubMed]

Smaill, B. H.

I. J. LeGrice, B. H. Smaill, L. Z. Chai, S. G. Edgar, J. B. Gavin, and P. J. Hunter, “Laminar structure of the heart: ventricular myocyte arrangement and connective tissue architecture in the dog,” Am. J. Physiol.269(2 Pt 2), H571–H582 (1995).
[PubMed]

Sougrat, R.

G. Shtengel, J. A. Galbraith, C. G. Galbraith, J. Lippincott-Schwartz, J. M. Gillette, S. Manley, R. Sougrat, C. M. Waterman, P. Kanchanawong, M. W. Davidson, R. D. Fetter, and H. F. Hess, “Interferometric fluorescent super-resolution microscopy resolves 3D cellular ultrastructure,” Proc. Natl. Acad. Sci. U.S.A.106(9), 3125–3130 (2009).
[CrossRef] [PubMed]

Subramaniam, V.

E. A. te Velde, T. Veerman, V. Subramaniam, and T. Ruers, “The use of fluorescent dyes and probes in surgical oncology,” Eur. J. Surg. Oncol.36(1), 6–15 (2010).
[CrossRef] [PubMed]

P. Zou, S. Xu, S. P. Povoski, A. Wang, M. A. Johnson, E. W. Martin, V. Subramaniam, R. Xu, and D. Sun, “Near-infrared fluorescence labeled anti-TAG-72 monoclonal antibodies for tumor imaging in colorectal cancer xenograft mice,” Mol. Pharm.6, 428–440 (2009).
[CrossRef] [PubMed]

Sun, D.

P. Zou, S. Xu, S. P. Povoski, A. Wang, M. A. Johnson, E. W. Martin, V. Subramaniam, R. Xu, and D. Sun, “Near-infrared fluorescence labeled anti-TAG-72 monoclonal antibodies for tumor imaging in colorectal cancer xenograft mice,” Mol. Pharm.6, 428–440 (2009).
[CrossRef] [PubMed]

Swan, A. K.

M. Dogan, M. I. Aksun, A. K. Swan, B. B. Goldberg, and M. S. Unlü, “Closed-form representations of field components of fluorescent emitters in layered media,” J. Opt. Soc. Am. A26(6), 1458–1466 (2009).
[CrossRef] [PubMed]

A. K. Swan, L. A. Moiseev, C. R. Cantor, B. Davis, S. B. Ippolito, W. C. Karl, B. B. Goldberg, and M. S. Unlu, “Toward nanometer-scale resolution in fluorescence microscopy using spectral self-interference,” IEEE J. Sel. Top. Quantum Electron.9(2), 294–300 (2003).
[CrossRef]

te Velde, E. A.

E. A. te Velde, T. Veerman, V. Subramaniam, and T. Ruers, “The use of fluorescent dyes and probes in surgical oncology,” Eur. J. Surg. Oncol.36(1), 6–15 (2010).
[CrossRef] [PubMed]

Tearney, G.

A. Bilenca, A. Ozcan, B. Bouma, and G. Tearney, “Fluorescence coherence tomography,” Opt. Express14(16), 7134–7143 (2006).
[CrossRef] [PubMed]

B. Park, M. C. Pierce, B. Cense, S.-H. Yun, M. Mujat, G. Tearney, B. Bouma, and J. de Boer, “Real-time fiber-based multi-functional spectral-domain optical coherence tomography at 1.3 microm,” Opt. Express13(11), 3931–3944 (2005).
[CrossRef] [PubMed]

Terwisscha van Scheltinga, A. G. T.

A. G. T. Terwisscha van Scheltinga, G. M. van Dam, W. B. Nagengast, V. Ntziachristos, H. Hollema, J. L. Herek, C. P. Schröder, J. G. W. Kosterink, M. N. Lub-de Hoog, and E. G. E. de Vries, “Intraoperative near-infrared fluorescence tumor imaging with vascular endothelial growth factor and human epidermal growth factor receptor 2 targeting antibodies,” J. Nucl. Med.52(11), 1778–1785 (2011).
[CrossRef] [PubMed]

Themelis, G.

G. M. van Dam, G. Themelis, L. M. Crane, N. J. Harlaar, R. G. Pleijhuis, W. Kelder, A. Sarantopoulos, J. S. de Jong, H. J. Arts, A. G. van der Zee, J. Bart, P. S. Low, and V. Ntziachristos, “Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results,” Nat. Med.17(10), 1315–1319 (2011).
[CrossRef] [PubMed]

Unlu, M. S.

A. K. Swan, L. A. Moiseev, C. R. Cantor, B. Davis, S. B. Ippolito, W. C. Karl, B. B. Goldberg, and M. S. Unlu, “Toward nanometer-scale resolution in fluorescence microscopy using spectral self-interference,” IEEE J. Sel. Top. Quantum Electron.9(2), 294–300 (2003).
[CrossRef]

Unlü, M. S.

M. Dogan, M. I. Aksun, A. K. Swan, B. B. Goldberg, and M. S. Unlü, “Closed-form representations of field components of fluorescent emitters in layered media,” J. Opt. Soc. Am. A26(6), 1458–1466 (2009).
[CrossRef] [PubMed]

van Dam, G. M.

G. M. van Dam, G. Themelis, L. M. Crane, N. J. Harlaar, R. G. Pleijhuis, W. Kelder, A. Sarantopoulos, J. S. de Jong, H. J. Arts, A. G. van der Zee, J. Bart, P. S. Low, and V. Ntziachristos, “Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results,” Nat. Med.17(10), 1315–1319 (2011).
[CrossRef] [PubMed]

A. G. T. Terwisscha van Scheltinga, G. M. van Dam, W. B. Nagengast, V. Ntziachristos, H. Hollema, J. L. Herek, C. P. Schröder, J. G. W. Kosterink, M. N. Lub-de Hoog, and E. G. E. de Vries, “Intraoperative near-infrared fluorescence tumor imaging with vascular endothelial growth factor and human epidermal growth factor receptor 2 targeting antibodies,” J. Nucl. Med.52(11), 1778–1785 (2011).
[CrossRef] [PubMed]

van der Zee, A. G.

G. M. van Dam, G. Themelis, L. M. Crane, N. J. Harlaar, R. G. Pleijhuis, W. Kelder, A. Sarantopoulos, J. S. de Jong, H. J. Arts, A. G. van der Zee, J. Bart, P. S. Low, and V. Ntziachristos, “Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results,” Nat. Med.17(10), 1315–1319 (2011).
[CrossRef] [PubMed]

Veerman, T.

E. A. te Velde, T. Veerman, V. Subramaniam, and T. Ruers, “The use of fluorescent dyes and probes in surgical oncology,” Eur. J. Surg. Oncol.36(1), 6–15 (2010).
[CrossRef] [PubMed]

Wang, A.

P. Zou, S. Xu, S. P. Povoski, A. Wang, M. A. Johnson, E. W. Martin, V. Subramaniam, R. Xu, and D. Sun, “Near-infrared fluorescence labeled anti-TAG-72 monoclonal antibodies for tumor imaging in colorectal cancer xenograft mice,” Mol. Pharm.6, 428–440 (2009).
[CrossRef] [PubMed]

Wang, W.

L. Sampath, S. Kwon, S. Ke, W. Wang, R. Schiff, M. E. Mawad, and E. M. Sevick-Muraca, “Dual-labeled trastuzumab-based imaging agent for the detection of human epidermal growth factor receptor 2 overexpression in breast cancer,” J. Nucl. Med.48(9), 1501–1510 (2007).
[CrossRef] [PubMed]

Waterman, C. M.

G. Shtengel, J. A. Galbraith, C. G. Galbraith, J. Lippincott-Schwartz, J. M. Gillette, S. Manley, R. Sougrat, C. M. Waterman, P. Kanchanawong, M. W. Davidson, R. D. Fetter, and H. F. Hess, “Interferometric fluorescent super-resolution microscopy resolves 3D cellular ultrastructure,” Proc. Natl. Acad. Sci. U.S.A.106(9), 3125–3130 (2009).
[CrossRef] [PubMed]

Wiersma, D. A.

K. E. Drabe, G. Cnossen, and D. A. Wiersma, “Localization of spontaneous emission in front of a mirror,” Opt. Commun.73(2), 91–95 (1989).
[CrossRef]

Xu, R.

P. Zou, S. Xu, S. P. Povoski, A. Wang, M. A. Johnson, E. W. Martin, V. Subramaniam, R. Xu, and D. Sun, “Near-infrared fluorescence labeled anti-TAG-72 monoclonal antibodies for tumor imaging in colorectal cancer xenograft mice,” Mol. Pharm.6, 428–440 (2009).
[CrossRef] [PubMed]

Xu, S.

P. Zou, S. Xu, S. P. Povoski, A. Wang, M. A. Johnson, E. W. Martin, V. Subramaniam, R. Xu, and D. Sun, “Near-infrared fluorescence labeled anti-TAG-72 monoclonal antibodies for tumor imaging in colorectal cancer xenograft mice,” Mol. Pharm.6, 428–440 (2009).
[CrossRef] [PubMed]

Yun, S.-H.

B. Park, M. C. Pierce, B. Cense, S.-H. Yun, M. Mujat, G. Tearney, B. Bouma, and J. de Boer, “Real-time fiber-based multi-functional spectral-domain optical coherence tomography at 1.3 microm,” Opt. Express13(11), 3931–3944 (2005).
[CrossRef] [PubMed]

Zou, P.

P. Zou, S. Xu, S. P. Povoski, A. Wang, M. A. Johnson, E. W. Martin, V. Subramaniam, R. Xu, and D. Sun, “Near-infrared fluorescence labeled anti-TAG-72 monoclonal antibodies for tumor imaging in colorectal cancer xenograft mice,” Mol. Pharm.6, 428–440 (2009).
[CrossRef] [PubMed]

Am. J. Physiol.

I. J. LeGrice, B. H. Smaill, L. Z. Chai, S. G. Edgar, J. B. Gavin, and P. J. Hunter, “Laminar structure of the heart: ventricular myocyte arrangement and connective tissue architecture in the dog,” Am. J. Physiol.269(2 Pt 2), H571–H582 (1995).
[PubMed]

Ann. N. Y. Acad. Sci.

S. L. K. Bowers, T. K. Borg, and T. A. Baudino, “The dynamics of fibroblast-myocyte-capillary interactions in the heart,” Ann. N. Y. Acad. Sci.1188(1), 143–152 (2010).
[CrossRef] [PubMed]

Eur. J. Surg. Oncol.

E. A. te Velde, T. Veerman, V. Subramaniam, and T. Ruers, “The use of fluorescent dyes and probes in surgical oncology,” Eur. J. Surg. Oncol.36(1), 6–15 (2010).
[CrossRef] [PubMed]

IEEE J. Sel. Top. Quantum Electron.

A. K. Swan, L. A. Moiseev, C. R. Cantor, B. Davis, S. B. Ippolito, W. C. Karl, B. B. Goldberg, and M. S. Unlu, “Toward nanometer-scale resolution in fluorescence microscopy using spectral self-interference,” IEEE J. Sel. Top. Quantum Electron.9(2), 294–300 (2003).
[CrossRef]

J. Nucl. Med.

A. G. T. Terwisscha van Scheltinga, G. M. van Dam, W. B. Nagengast, V. Ntziachristos, H. Hollema, J. L. Herek, C. P. Schröder, J. G. W. Kosterink, M. N. Lub-de Hoog, and E. G. E. de Vries, “Intraoperative near-infrared fluorescence tumor imaging with vascular endothelial growth factor and human epidermal growth factor receptor 2 targeting antibodies,” J. Nucl. Med.52(11), 1778–1785 (2011).
[CrossRef] [PubMed]

L. Sampath, S. Kwon, S. Ke, W. Wang, R. Schiff, M. E. Mawad, and E. M. Sevick-Muraca, “Dual-labeled trastuzumab-based imaging agent for the detection of human epidermal growth factor receptor 2 overexpression in breast cancer,” J. Nucl. Med.48(9), 1501–1510 (2007).
[CrossRef] [PubMed]

J. Opt. Soc. Am. A

M. Dogan, M. I. Aksun, A. K. Swan, B. B. Goldberg, and M. S. Unlü, “Closed-form representations of field components of fluorescent emitters in layered media,” J. Opt. Soc. Am. A26(6), 1458–1466 (2009).
[CrossRef] [PubMed]

Mol. Pharm.

P. Zou, S. Xu, S. P. Povoski, A. Wang, M. A. Johnson, E. W. Martin, V. Subramaniam, R. Xu, and D. Sun, “Near-infrared fluorescence labeled anti-TAG-72 monoclonal antibodies for tumor imaging in colorectal cancer xenograft mice,” Mol. Pharm.6, 428–440 (2009).
[CrossRef] [PubMed]

Nat. Med.

G. M. van Dam, G. Themelis, L. M. Crane, N. J. Harlaar, R. G. Pleijhuis, W. Kelder, A. Sarantopoulos, J. S. de Jong, H. J. Arts, A. G. van der Zee, J. Bart, P. S. Low, and V. Ntziachristos, “Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results,” Nat. Med.17(10), 1315–1319 (2011).
[CrossRef] [PubMed]

Opt. Commun.

K. E. Drabe, G. Cnossen, and D. A. Wiersma, “Localization of spontaneous emission in front of a mirror,” Opt. Commun.73(2), 91–95 (1989).
[CrossRef]

Opt. Express

A. Bilenca, A. Ozcan, B. Bouma, and G. Tearney, “Fluorescence coherence tomography,” Opt. Express14(16), 7134–7143 (2006).
[CrossRef] [PubMed]

B. Park, M. C. Pierce, B. Cense, S.-H. Yun, M. Mujat, G. Tearney, B. Bouma, and J. de Boer, “Real-time fiber-based multi-functional spectral-domain optical coherence tomography at 1.3 microm,” Opt. Express13(11), 3931–3944 (2005).
[CrossRef] [PubMed]

Proc. Natl. Acad. Sci. U.S.A.

G. Shtengel, J. A. Galbraith, C. G. Galbraith, J. Lippincott-Schwartz, J. M. Gillette, S. Manley, R. Sougrat, C. M. Waterman, P. Kanchanawong, M. W. Davidson, R. D. Fetter, and H. F. Hess, “Interferometric fluorescent super-resolution microscopy resolves 3D cellular ultrastructure,” Proc. Natl. Acad. Sci. U.S.A.106(9), 3125–3130 (2009).
[CrossRef] [PubMed]

Supplementary Material (2)

» Media 1: AVI (4536 KB)     
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Figures (6)

Fig. 1
Fig. 1

Principle of SIFM.Light from a fluorescent source in the sample is collimated by the objective lens and passes through a phase plate. The phase plate consists of an inner and an outer ring of different optical thickness, introducing two alternative optical paths. The wave front before and after the phase plate is drawn as a solid red line. The light passing through the thicker outer ring of the phase plate is retarded with respect to the light passing through the hole in the center. The light is focused on a single mode optical fiber, acting as a pinhole. The interference due to the optical path difference leads to a modulation on the detected fluorescence spectrum: for certain wavelengths the interference is destructive while for others it is constructive (top graph). The period of the spectral modulation is determined by the thickness of the plate. The modulation depth depends on the ratio of the integrated amplitude of the source field over the central disk of the phase plate and the outer ring, respectively. When the source is exactly in focus (δ = 0 µm) the wavefronts are flat. When the source is out of focus (δ = 100 µm) the wavefronts are curved (shown exaggerated). This leads to a small extra path length difference Δ opl (δ) and to a shift in the phase of the self-interference spectrum (bottom graph). The phase therefore directly encodes the axial position of the fluorescent source.

Fig. 2
Fig. 2

Schematic representation of the ray matrix model. The rays vinemitted by a source at a defocus distance δ from the focal plane of the objective L0 are traced by multiplication with the free space propagation matrices Si and the lens matrices Li. From the position vout and the angle θout we can calculate the radius of curvature R of the wave front at the phase plate. This allows us to calculate the optical path delay opd(y,δ) which we define as the difference in optical path to the phase plate between a ray intersecting the phase plate at y and the chief ray for which y = 0. Averaging of opd(y,δ) over the inner and outer sections of the phase plate now yields Δopl(δ)the extra path length difference between the field passing through the center and the field passing through the edge of the plate that is caused by the wave front curvature (see Fig. 1).

Fig. 3
Fig. 3

Schematic representation of the SIFM microscope. Excitation light from a fiber coupled laser is sent through a wavelength division multiplexer (wdm) and a collimator (col) before passing through a phase plate (PP). The beam is sent into the microscope (IX71) via a home-built galvanometric x/y-scanner (xy) and is focused onto the sample by the objective (obj). The fluorescence is collected by the same objective and follows the same light path in the opposite direction to the wdm where it is sent to a home-built spectrometer that detects the interference spectra.

Fig. 4
Fig. 4

Phase and SNR. (a) Dependence of the phase of the self-interference spectrum on the axial position of a thin homogenous fluorescent layer with respect to the focal plane of the objective. Each datapoint is the mean value from 1024 spectra. The error bars indicate ± 1 standard deviation. The imaging NA for this measurement was 0.086 (using the approximate definition for the NA of Gaussian beams:NA ≈2λ / πw0) and the Rayleigh lengthzRwas 128 µm. A linear fit of the central section between −2 and 2zRyields a slope dϕ/dz = −1.31 rad/zR. A simple ray optics analysis of the system predicts a slope of −1.33 rad/zRindicated by the solid gray line. (b) Dependence of the standard deviation of a phase measurement on the signal to noise ratio. Here the SNR was varied by scanning the fluorescent layer through the focus of the objective. The dots are the measured standard deviations of 1024 phase measurements. The solid line is the theoretical curve σ ϕ =1/ 2 SNR .

Fig. 5
Fig. 5

Comparison of SIFM and confocal microscopy on a three-dimensional distribution of fluorescent microspheres. (a) SIFM intensity image (100 × 100 µm). The red square marks the area that was compared to a standard confocal stack. (b) SIFM phase image. (c) Representative slice from the SIFM 3D reconstruction. (d) Corresponding slice from the confocal stack. (e) SIFM and confocal slices overlapped. SIFM data displayed in green and confocal in red. Yellow indicates the overlap of both data sets. A video that shows the overlap of the data sets for the whole volume is available online (Media1).

Fig. 6
Fig. 6

SIFM image of microvasculature in a mouse heart. The image represents a 500 x 500 x 60 µm volume of tissue, starting at 15 µm below the tissue surface. (A) The depth of the vessels is color-coded: the deepest layers are displayed in violet and the top layers are displayed in red. (B) A movie that shows a three-dimensional rendering of the data is available online (Media 2).

Equations (11)

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I sifm (k)=C I source (k)( 1 A 2 + A 2 cos( k( d+ Δ opl (δ) ) ) )
S i =( 1 d i 0 1 ), L i =( 1 0 1 f i 1 )
v i =( y i θ i ).
M=( m 0 0 1 m )
v out =M S 1 L 0 S 0 v in =( 0 m f 0 1 m f 0 δ m f 0 ) v in =( m f 0 θ in y in +δ θ in m f 0 ).
v out =( m f 0 θ in δ θ in m f 0 ).
R( δ )= mf θ in δ θ in mf = m 2 f 2 δ .
opd( y,δ )= R ( δ ) 2 + y 2 R( δ ).
opd( y,δ ) 1 2 y 2 R = 1 2 y 2 δ m 2 f 2 .
op d avg2D ( a,b,δ )= 0 2π a b opd( r;δ ) e r 2 w 2 rdrdϕ 0 2π a b e r 2 w 2 rdrdϕ ,
Δϕ= 2π λ ( op d avg2D ( ρ,,δ )op d avg2D ( 0,ρ,δ ) )

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