Abstract

The sensitivity and resolution of fluorescence-based imaging in vivo is often limited by autofluorescence and other background noise. To overcome these limitations, we have developed a wide-field background-free imaging technique based on magnetic modulation of fluorescent nanodiamond emission. Fluorescent nanodiamonds are bright, photo-stable, biocompatible nanoparticles that are promising probes for a wide range of in vitro and in vivo imaging applications. Our readily applied background-free imaging technique improves the signal-to-background ratio for in vivo imaging up to 100-fold. This technique has the potential to significantly improve and extend fluorescent nanodiamond imaging capabilities on diverse fluorescence imaging platforms.

© 2014 Optical Society of America

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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
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    [CrossRef]
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    [CrossRef]
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  33. H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. A. Regino, Y. Urano, and P. L. Choyke, “Simultaneous multicolor imaging of five different lymphatic basins using quantum dots,” Nano Lett.7(6), 1711–1716 (2007).
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2013

M. W. Doherty, N. B. Manson, P. Delaney, F. Jelezko, J. Wrachtrup, and L. C. L. Hollenberg, “The nitrogen-vacancy colour centre in diamond,” Phys. Rep.528(1), 1–45 (2013).
[CrossRef]

S. T. Proulx and M. Detmar, “Molecular mechanisms and imaging of lymphatic metastasis,” Exp. Cell Res.319(11), 1611–1617 (2013).
[CrossRef] [PubMed]

A. Bumb, S. K. Sarkar, N. Billington, M. W. Brechbiel, and K. C. Neuman, “Silica encapsulation of fluorescent nanodiamonds for colloidal stability and facile surface functionalization,” J. Am. Chem. Soc.135(21), 7815–7818 (2013).
[CrossRef] [PubMed]

A. Hegyi and E. Yablonovitch, “Molecular imaging by optically detected electron spin resonance of nitrogen-vacancies in nanodiamonds,” Nano Lett.13(3), 1173–1178 (2013).
[CrossRef] [PubMed]

R. Chapman and T. Plakhoitnik, “Background-free imaging of luminescent nanodiamonds using external magnetic field for contrast enhancement,” Opt. Lett.38(11), 1847–1849 (2013).
[CrossRef] [PubMed]

2012

R. Igarashi, Y. Yoshinari, H. Yokota, T. Sugi, F. Sugihara, K. Ikeda, H. Sumiya, S. Tsuji, I. Mori, H. Tochio, Y. Harada, and M. Shirakawa, “Real-time background-free selective imaging of fluorescent nanodiamonds in vivo,” Nano Lett.12(11), 5726–5732 (2012).
[CrossRef] [PubMed]

A. Jarmola, V. M. Acosta, K. Jensen, S. Chemerisov, and D. Budker, “Temperature- and magnetic-field-dependent longitudinal spin relaxation in nitrogen-vacancy ensembles in diamond,” Phys. Rev. Lett.108(19), 197601 (2012).
[CrossRef] [PubMed]

V. Vaijayanthimala, P. Y. Cheng, S. H. Yeh, K. K. Liu, C. H. Hsiao, J. I. Chao, and H. C. Chang, “The long-term stability and biocompatibility of fluorescent nanodiamond as an in vivo contrast agent,” Biomaterials33(31), 7794–7802 (2012).
[CrossRef] [PubMed]

2011

E. K. Chow, X. Q. Zhang, M. Chen, R. Lam, E. Robinson, H. J. Huang, D. Schaffer, E. Osawa, A. Goga, and D. Ho, “Nanodiamond therapeutic delivery agents mediate enhanced chemoresistant tumor treatment,” Sci. Transl. Med.3(73), 73ra21 (2011).
[CrossRef] [PubMed]

L. M. Pham, D. L. Sage, P. L. Stanwix, T. K. Yeung, D. Glenn, A. Trifonov, P. Cappellaro, P. R. Hemmer, M. D. Lukin, H. Park, A. Yacoby, and R. L. Walsworth, “Magnetic field imaging with nitrogen-vacancy ensembles,” New J. Phys.13, 045021 (2011).

A. Bumb, C. A. Regino, J. G. Egen, M. Bernardo, P. J. Dobson, R. N. Germain, P. L. Choyke, and M. W. Brechbiel, “Trafficking of a dual-modality magnetic resonance and fluorescence imaging superparamagnetic iron oxide-based nanoprobe to lymph nodes,” Mol. Imaging Biol.13(6), 1163–1172 (2011).
[CrossRef] [PubMed]

J. Maze, A. Gali, E. Togan, Y. Chu, A. Trifonov, E. Kaxiras, and M. Lukin, “Properties of nitrogen-vacancy centers in diamond: the group theoretic approach,” New J. Phys.13(2), 025025 (2011).
[CrossRef]

2010

V. M. Acosta, A. Jarmola, E. Bauch, and D. Budker, “Optical properties of the nitrogen-vacancy singlet levels in diamond,” Phys. Rev. B82(20), 201202 (2010).
[CrossRef]

N. Mohan, C. S. Chen, H. H. Hsieh, Y. C. Wu, and H. C. Chang, “In Vivo Imaging and Toxicity Assessments of Fluorescent Nanodiamonds in Caenorhabditis elegans,” Nano Lett.10(9), 3692–3699 (2010).
[CrossRef] [PubMed]

2009

A. M. Smith, M. C. Mancini, and S. Nie, “Bioimaging: second window for in vivo imaging,” Nat. Nanotechnol.4(11), 710–711 (2009).
[CrossRef] [PubMed]

H. Xu and B. W. Rice, “In-vivo fluorescence imaging with a multivariate curve resolution spectral unmixing technique,” J. Biomed. Opt.14, 064011 (2009).

N. D. Lai, D. Zheng, F. Jelezko, F. Treussart, and J.-F. Roch, “Influence of a static magnetic field on the photoluminescence of an ensemble of nitrogen-vacancy color centers in a diamond single-crystal,” Appl. Phys. Lett.95(13), 133101 (2009).
[CrossRef]

C. I. Richards, J. C. Hsiang, D. Senapati, S. Patel, J. Yu, T. Vosch, and R. M. Dickson, “Optically modulated fluorophores for selective fluorescence signal recovery,” J. Am. Chem. Soc.131(13), 4619–4621 (2009).
[CrossRef] [PubMed]

N. Kosaka, M. Ogawa, N. Sato, P. L. Choyke, and H. Kobayashi, “In vivo real-time, multicolor, quantum dot lymphatic imaging,” J. Invest. Dermatol.129(12), 2818–2822 (2009).
[CrossRef] [PubMed]

2008

G. Marriott, S. Mao, T. Sakata, J. Ran, D. K. Jackson, C. Petchprayoon, T. J. Gomez, E. Warp, O. Tulyathan, H. L. Aaron, E. Y. Isacoff, and Y. Yan, “Optical lock-in detection imaging microscopy for contrast-enhanced imaging in living cells,” Proc. Natl. Acad. Sci. U.S.A.105(46), 17789–17794 (2008).
[CrossRef] [PubMed]

Y. R. Chang, H. Y. Lee, K. Chen, C. C. Chang, D. S. Tsai, C. C. Fu, T. S. Lim, Y. K. Tzeng, C. Y. Fang, C. C. Han, H. C. Chang, and W. Fann, “Mass production and dynamic imaging of fluorescent nanodiamonds,” Nat. Nanotechnol.3(5), 284–288 (2008).
[CrossRef] [PubMed]

2007

C.-C. Fu, H.-Y. Lee, K. Chen, T.-S. Lim, H.-Y. Wu, P.-K. Lin, P.-K. Wei, P.-H. Tsao, H.-C. Chang, and W. Fann, “Characterization and application of single fluorescent nanodiamonds as cellular biomarkers,” Proc. Natl. Acad. Sci. U.S.A.104(3), 727–732 (2007).
[CrossRef] [PubMed]

A. M. Schrand, H. J. Huang, C. Carlson, J. J. Schlager, E. Omacr Sawa, S. M. Hussain, and L. M. Dai, “Are diamond nanoparticles cytotoxic?” J. Phys. Chem. B111(1), 2–7 (2007).
[CrossRef] [PubMed]

H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. A. Regino, Y. Urano, and P. L. Choyke, “Simultaneous multicolor imaging of five different lymphatic basins using quantum dots,” Nano Lett.7(6), 1711–1716 (2007).
[CrossRef] [PubMed]

2006

F. Jelezko and J. Wrachtrup, “Single defect centres in diamond: A review,” Phys. Status Solidi203(13), 3207–3225 (2006).
[CrossRef]

2005

S.-J. Yu, M.-W. Kang, H.-C. Chang, K.-M. Chen, and Y.-C. Yu, “Bright fluorescent nanodiamonds: no photobleaching and low cytotoxicity,” J. Am. Chem. Soc.127(50), 17604–17605 (2005).
[CrossRef] [PubMed]

J. R. Mansfield, K. W. Gossage, C. C. Hoyt, and R. M. Levenson, “Autofluorescence removal, multiplexing, and automated analysis methods for in-vivo fluorescence imaging,” J. Biomed. Opt.10, 041207 (2005).

2003

J. V. Frangioni, “In vivo near-infrared fluorescence imaging,” Curr. Opin. Chem. Biol.7(5), 626–634 (2003).
[CrossRef] [PubMed]

J. N. Anker and R. Kopelman, “Magnetically modulated optical nanoprobes,” Appl. Phys. Lett.82(7), 1102–1104 (2003).
[CrossRef]

2002

G. Hermosillo, C. Chefd’Hotel, and O. Faugeras, “Variational methods for multimodal image matching,” Int. J. Comput. Vis.50(3), 329–343 (2002).
[CrossRef]

1994

J. H. Scofield, “Frequency-domain description of a lock-in amplifier,” Am. J. Phys.62(2), 129–132 (1994).
[CrossRef]

1992

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, K. W. Berndt, and M. Johnson, “Fluorescence lifetime imaging,” Anal. Biochem.202(2), 316–330 (1992).
[CrossRef] [PubMed]

1946

R. H. Dicke, “The measurement of thermal radiation at microwave frequencies,” Rev. Sci. Instrum.17(7), 268–275 (1946).
[CrossRef] [PubMed]

Aaron, H. L.

G. Marriott, S. Mao, T. Sakata, J. Ran, D. K. Jackson, C. Petchprayoon, T. J. Gomez, E. Warp, O. Tulyathan, H. L. Aaron, E. Y. Isacoff, and Y. Yan, “Optical lock-in detection imaging microscopy for contrast-enhanced imaging in living cells,” Proc. Natl. Acad. Sci. U.S.A.105(46), 17789–17794 (2008).
[CrossRef] [PubMed]

Acosta, V. M.

A. Jarmola, V. M. Acosta, K. Jensen, S. Chemerisov, and D. Budker, “Temperature- and magnetic-field-dependent longitudinal spin relaxation in nitrogen-vacancy ensembles in diamond,” Phys. Rev. Lett.108(19), 197601 (2012).
[CrossRef] [PubMed]

V. M. Acosta, A. Jarmola, E. Bauch, and D. Budker, “Optical properties of the nitrogen-vacancy singlet levels in diamond,” Phys. Rev. B82(20), 201202 (2010).
[CrossRef]

Anker, J. N.

J. N. Anker and R. Kopelman, “Magnetically modulated optical nanoprobes,” Appl. Phys. Lett.82(7), 1102–1104 (2003).
[CrossRef]

Barrett, T.

H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. A. Regino, Y. Urano, and P. L. Choyke, “Simultaneous multicolor imaging of five different lymphatic basins using quantum dots,” Nano Lett.7(6), 1711–1716 (2007).
[CrossRef] [PubMed]

Bauch, E.

V. M. Acosta, A. Jarmola, E. Bauch, and D. Budker, “Optical properties of the nitrogen-vacancy singlet levels in diamond,” Phys. Rev. B82(20), 201202 (2010).
[CrossRef]

Bernardo, M.

A. Bumb, C. A. Regino, J. G. Egen, M. Bernardo, P. J. Dobson, R. N. Germain, P. L. Choyke, and M. W. Brechbiel, “Trafficking of a dual-modality magnetic resonance and fluorescence imaging superparamagnetic iron oxide-based nanoprobe to lymph nodes,” Mol. Imaging Biol.13(6), 1163–1172 (2011).
[CrossRef] [PubMed]

Berndt, K. W.

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, K. W. Berndt, and M. Johnson, “Fluorescence lifetime imaging,” Anal. Biochem.202(2), 316–330 (1992).
[CrossRef] [PubMed]

Billington, N.

A. Bumb, S. K. Sarkar, N. Billington, M. W. Brechbiel, and K. C. Neuman, “Silica encapsulation of fluorescent nanodiamonds for colloidal stability and facile surface functionalization,” J. Am. Chem. Soc.135(21), 7815–7818 (2013).
[CrossRef] [PubMed]

Brechbiel, M. W.

A. Bumb, S. K. Sarkar, N. Billington, M. W. Brechbiel, and K. C. Neuman, “Silica encapsulation of fluorescent nanodiamonds for colloidal stability and facile surface functionalization,” J. Am. Chem. Soc.135(21), 7815–7818 (2013).
[CrossRef] [PubMed]

A. Bumb, C. A. Regino, J. G. Egen, M. Bernardo, P. J. Dobson, R. N. Germain, P. L. Choyke, and M. W. Brechbiel, “Trafficking of a dual-modality magnetic resonance and fluorescence imaging superparamagnetic iron oxide-based nanoprobe to lymph nodes,” Mol. Imaging Biol.13(6), 1163–1172 (2011).
[CrossRef] [PubMed]

Budker, D.

A. Jarmola, V. M. Acosta, K. Jensen, S. Chemerisov, and D. Budker, “Temperature- and magnetic-field-dependent longitudinal spin relaxation in nitrogen-vacancy ensembles in diamond,” Phys. Rev. Lett.108(19), 197601 (2012).
[CrossRef] [PubMed]

V. M. Acosta, A. Jarmola, E. Bauch, and D. Budker, “Optical properties of the nitrogen-vacancy singlet levels in diamond,” Phys. Rev. B82(20), 201202 (2010).
[CrossRef]

Bumb, A.

A. Bumb, S. K. Sarkar, N. Billington, M. W. Brechbiel, and K. C. Neuman, “Silica encapsulation of fluorescent nanodiamonds for colloidal stability and facile surface functionalization,” J. Am. Chem. Soc.135(21), 7815–7818 (2013).
[CrossRef] [PubMed]

A. Bumb, C. A. Regino, J. G. Egen, M. Bernardo, P. J. Dobson, R. N. Germain, P. L. Choyke, and M. W. Brechbiel, “Trafficking of a dual-modality magnetic resonance and fluorescence imaging superparamagnetic iron oxide-based nanoprobe to lymph nodes,” Mol. Imaging Biol.13(6), 1163–1172 (2011).
[CrossRef] [PubMed]

Cappellaro, P.

L. M. Pham, D. L. Sage, P. L. Stanwix, T. K. Yeung, D. Glenn, A. Trifonov, P. Cappellaro, P. R. Hemmer, M. D. Lukin, H. Park, A. Yacoby, and R. L. Walsworth, “Magnetic field imaging with nitrogen-vacancy ensembles,” New J. Phys.13, 045021 (2011).

Carlson, C.

A. M. Schrand, H. J. Huang, C. Carlson, J. J. Schlager, E. Omacr Sawa, S. M. Hussain, and L. M. Dai, “Are diamond nanoparticles cytotoxic?” J. Phys. Chem. B111(1), 2–7 (2007).
[CrossRef] [PubMed]

Chang, C. C.

Y. R. Chang, H. Y. Lee, K. Chen, C. C. Chang, D. S. Tsai, C. C. Fu, T. S. Lim, Y. K. Tzeng, C. Y. Fang, C. C. Han, H. C. Chang, and W. Fann, “Mass production and dynamic imaging of fluorescent nanodiamonds,” Nat. Nanotechnol.3(5), 284–288 (2008).
[CrossRef] [PubMed]

Chang, H. C.

V. Vaijayanthimala, P. Y. Cheng, S. H. Yeh, K. K. Liu, C. H. Hsiao, J. I. Chao, and H. C. Chang, “The long-term stability and biocompatibility of fluorescent nanodiamond as an in vivo contrast agent,” Biomaterials33(31), 7794–7802 (2012).
[CrossRef] [PubMed]

N. Mohan, C. S. Chen, H. H. Hsieh, Y. C. Wu, and H. C. Chang, “In Vivo Imaging and Toxicity Assessments of Fluorescent Nanodiamonds in Caenorhabditis elegans,” Nano Lett.10(9), 3692–3699 (2010).
[CrossRef] [PubMed]

Y. R. Chang, H. Y. Lee, K. Chen, C. C. Chang, D. S. Tsai, C. C. Fu, T. S. Lim, Y. K. Tzeng, C. Y. Fang, C. C. Han, H. C. Chang, and W. Fann, “Mass production and dynamic imaging of fluorescent nanodiamonds,” Nat. Nanotechnol.3(5), 284–288 (2008).
[CrossRef] [PubMed]

Chang, H.-C.

C.-C. Fu, H.-Y. Lee, K. Chen, T.-S. Lim, H.-Y. Wu, P.-K. Lin, P.-K. Wei, P.-H. Tsao, H.-C. Chang, and W. Fann, “Characterization and application of single fluorescent nanodiamonds as cellular biomarkers,” Proc. Natl. Acad. Sci. U.S.A.104(3), 727–732 (2007).
[CrossRef] [PubMed]

S.-J. Yu, M.-W. Kang, H.-C. Chang, K.-M. Chen, and Y.-C. Yu, “Bright fluorescent nanodiamonds: no photobleaching and low cytotoxicity,” J. Am. Chem. Soc.127(50), 17604–17605 (2005).
[CrossRef] [PubMed]

Chang, Y. R.

Y. R. Chang, H. Y. Lee, K. Chen, C. C. Chang, D. S. Tsai, C. C. Fu, T. S. Lim, Y. K. Tzeng, C. Y. Fang, C. C. Han, H. C. Chang, and W. Fann, “Mass production and dynamic imaging of fluorescent nanodiamonds,” Nat. Nanotechnol.3(5), 284–288 (2008).
[CrossRef] [PubMed]

Chao, J. I.

V. Vaijayanthimala, P. Y. Cheng, S. H. Yeh, K. K. Liu, C. H. Hsiao, J. I. Chao, and H. C. Chang, “The long-term stability and biocompatibility of fluorescent nanodiamond as an in vivo contrast agent,” Biomaterials33(31), 7794–7802 (2012).
[CrossRef] [PubMed]

Chapman, R.

Chefd’Hotel, C.

G. Hermosillo, C. Chefd’Hotel, and O. Faugeras, “Variational methods for multimodal image matching,” Int. J. Comput. Vis.50(3), 329–343 (2002).
[CrossRef]

Chemerisov, S.

A. Jarmola, V. M. Acosta, K. Jensen, S. Chemerisov, and D. Budker, “Temperature- and magnetic-field-dependent longitudinal spin relaxation in nitrogen-vacancy ensembles in diamond,” Phys. Rev. Lett.108(19), 197601 (2012).
[CrossRef] [PubMed]

Chen, C. S.

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G. Hermosillo, C. Chefd’Hotel, and O. Faugeras, “Variational methods for multimodal image matching,” Int. J. Comput. Vis.50(3), 329–343 (2002).
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E. K. Chow, X. Q. Zhang, M. Chen, R. Lam, E. Robinson, H. J. Huang, D. Schaffer, E. Osawa, A. Goga, and D. Ho, “Nanodiamond therapeutic delivery agents mediate enhanced chemoresistant tumor treatment,” Sci. Transl. Med.3(73), 73ra21 (2011).
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M. W. Doherty, N. B. Manson, P. Delaney, F. Jelezko, J. Wrachtrup, and L. C. L. Hollenberg, “The nitrogen-vacancy colour centre in diamond,” Phys. Rep.528(1), 1–45 (2013).
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J. R. Mansfield, K. W. Gossage, C. C. Hoyt, and R. M. Levenson, “Autofluorescence removal, multiplexing, and automated analysis methods for in-vivo fluorescence imaging,” J. Biomed. Opt.10, 041207 (2005).

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C. I. Richards, J. C. Hsiang, D. Senapati, S. Patel, J. Yu, T. Vosch, and R. M. Dickson, “Optically modulated fluorophores for selective fluorescence signal recovery,” J. Am. Chem. Soc.131(13), 4619–4621 (2009).
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N. Mohan, C. S. Chen, H. H. Hsieh, Y. C. Wu, and H. C. Chang, “In Vivo Imaging and Toxicity Assessments of Fluorescent Nanodiamonds in Caenorhabditis elegans,” Nano Lett.10(9), 3692–3699 (2010).
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J. Maze, A. Gali, E. Togan, Y. Chu, A. Trifonov, E. Kaxiras, and M. Lukin, “Properties of nitrogen-vacancy centers in diamond: the group theoretic approach,” New J. Phys.13(2), 025025 (2011).
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N. Kosaka, M. Ogawa, N. Sato, P. L. Choyke, and H. Kobayashi, “In vivo real-time, multicolor, quantum dot lymphatic imaging,” J. Invest. Dermatol.129(12), 2818–2822 (2009).
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H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. A. Regino, Y. Urano, and P. L. Choyke, “Simultaneous multicolor imaging of five different lymphatic basins using quantum dots,” Nano Lett.7(6), 1711–1716 (2007).
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H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. A. Regino, Y. Urano, and P. L. Choyke, “Simultaneous multicolor imaging of five different lymphatic basins using quantum dots,” Nano Lett.7(6), 1711–1716 (2007).
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Y. R. Chang, H. Y. Lee, K. Chen, C. C. Chang, D. S. Tsai, C. C. Fu, T. S. Lim, Y. K. Tzeng, C. Y. Fang, C. C. Han, H. C. Chang, and W. Fann, “Mass production and dynamic imaging of fluorescent nanodiamonds,” Nat. Nanotechnol.3(5), 284–288 (2008).
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C.-C. Fu, H.-Y. Lee, K. Chen, T.-S. Lim, H.-Y. Wu, P.-K. Lin, P.-K. Wei, P.-H. Tsao, H.-C. Chang, and W. Fann, “Characterization and application of single fluorescent nanodiamonds as cellular biomarkers,” Proc. Natl. Acad. Sci. U.S.A.104(3), 727–732 (2007).
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J. R. Mansfield, K. W. Gossage, C. C. Hoyt, and R. M. Levenson, “Autofluorescence removal, multiplexing, and automated analysis methods for in-vivo fluorescence imaging,” J. Biomed. Opt.10, 041207 (2005).

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Y. R. Chang, H. Y. Lee, K. Chen, C. C. Chang, D. S. Tsai, C. C. Fu, T. S. Lim, Y. K. Tzeng, C. Y. Fang, C. C. Han, H. C. Chang, and W. Fann, “Mass production and dynamic imaging of fluorescent nanodiamonds,” Nat. Nanotechnol.3(5), 284–288 (2008).
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C.-C. Fu, H.-Y. Lee, K. Chen, T.-S. Lim, H.-Y. Wu, P.-K. Lin, P.-K. Wei, P.-H. Tsao, H.-C. Chang, and W. Fann, “Characterization and application of single fluorescent nanodiamonds as cellular biomarkers,” Proc. Natl. Acad. Sci. U.S.A.104(3), 727–732 (2007).
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M. W. Doherty, N. B. Manson, P. Delaney, F. Jelezko, J. Wrachtrup, and L. C. L. Hollenberg, “The nitrogen-vacancy colour centre in diamond,” Phys. Rep.528(1), 1–45 (2013).
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G. Marriott, S. Mao, T. Sakata, J. Ran, D. K. Jackson, C. Petchprayoon, T. J. Gomez, E. Warp, O. Tulyathan, H. L. Aaron, E. Y. Isacoff, and Y. Yan, “Optical lock-in detection imaging microscopy for contrast-enhanced imaging in living cells,” Proc. Natl. Acad. Sci. U.S.A.105(46), 17789–17794 (2008).
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J. Maze, A. Gali, E. Togan, Y. Chu, A. Trifonov, E. Kaxiras, and M. Lukin, “Properties of nitrogen-vacancy centers in diamond: the group theoretic approach,” New J. Phys.13(2), 025025 (2011).
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A. M. Schrand, H. J. Huang, C. Carlson, J. J. Schlager, E. Omacr Sawa, S. M. Hussain, and L. M. Dai, “Are diamond nanoparticles cytotoxic?” J. Phys. Chem. B111(1), 2–7 (2007).
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G. Marriott, S. Mao, T. Sakata, J. Ran, D. K. Jackson, C. Petchprayoon, T. J. Gomez, E. Warp, O. Tulyathan, H. L. Aaron, E. Y. Isacoff, and Y. Yan, “Optical lock-in detection imaging microscopy for contrast-enhanced imaging in living cells,” Proc. Natl. Acad. Sci. U.S.A.105(46), 17789–17794 (2008).
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Figures (4)

Fig. 1
Fig. 1

Magnetic modulation of FND emission. (a) Energy level diagram of NV¯ centers in diamond showing spin-triplet (ms = 0 and ms = ± 1) ground and excited states as well as the pair of singlet metastable states [1, 31]. NV¯ centers can be optically excited over a broad range of wavelengths (450-650 nm) as long as the Δms = 0 condition is satisfied between the two states (green arrows). NV¯ centers in the ms = ± 1 sublevels of the excited states have a higher probability to decay via the metastable states [31] (grey dashed arrows) than to the ms = ± 1 sublevels of the ground state. From the metastable state pathway, NV¯ centers predominantly transition to the ms = 0 sublevel of the ground state without emitting visible light. Therefore, in the absence of a magnetic field, NV¯ centers are rapidly pumped into the ms = 0 sublevel of the ground state when excited. This results in an initial increase in fluorescence emission intensity as steady state is reached. In the presence of a magnetic field, the ms = 0 and ms = ± 1 states are mixed, making the decay pathway through the metastable singlet state accessible and therefore decreasing the fluorescence emission intensity. (b) A scanning confocal image of FNDs with an average diameter of 40 nm containing ~15 NV¯ excited with ~100 W/cm2 at 532 nm. (c) Intensity modulation of the FND enclosed in the box in Fig. 1(b) from application of a ~100 G magnetic field with 0.1 Hz square wave (0-100 G amplitude) modulation.

Fig. 2
Fig. 2

Background-free imaging via magnetic modulation of FND emission. (a) A field of view with ~40 nm FNDs each containing ~15 NV¯ imaged as in Fig. 1(b). (b) Image of the same field of view after introducing ~1 µM Alexa647 dye solution into the flow cell. (c) Image of the same field of view after processing images in the presence of the Alexa647 background signal (as in part b). The difference between pairs of images collected with and without the magnetic field was computed and 1000 of these difference images were averaged together to generate the processed image. Through this processing, images of the diamonds shown in Fig. 2(a) are recovered from images like Fig. 2(b) with high background.

Fig. 3
Fig. 3

Background-free imaging using wide-field lock-in detection. (a) One frame of a 1000 frame movie recorded at 0.25 s per frame with a scanning confocal microscope. A ~100 G magnetic field modulated at 0.1 Hz was applied during acquisition of the movie. (b) Time series of the pixel values corresponding to a FND (Red arrow in a) shows fluorescence modulation. (c) Time series of the pixel values corresponding to background (blue arrow in a) shows no fluorescence modulation. (d) Magnitude as a function of frequency of the fast Fourier transform (FFT) of the pixel value time series in b. Note the peaks at 0.1 and 0.3 Hz. (e) The magnitude as a function of frequency of the FFT of the pixel value time series in d. (f) FFT magnitude of the pixel value time series in b multiplied by a reference sine wave, 1 + sin(2π·0.1·t). Note the prominent peak at 0.2 Hz, corresponding to twice the modulation frequency. (g) FFT magnitude of the pixel value time series in C multiplied by a reference sine wave, 1 + sin(2π·0.1·t). Grey vertical lines at 0.2 Hz indicate the values at twice the reference frequency. This process was repeated by multiplying the pixel values by a reference cosine, 1 + cos(2π·0.1·t). The mean of three points around 0.2 Hz in the sine and cosine FFT amplitudes was calculated for each pixel and added in quadrature, i.e., I = √(I2sin + I2cos). (h) The resulting wide-field background-free image. Means of the pixel values over 1000 frames before applying the lock-in algorithm are 173 and 18 for the pixels corresponding to b and c respectively, corresponding to a signal-to-background ratio of ~10. Means of the FFT amplitudes for three points around 0.2 Hz are 21.42 and 0.28 for the pixels corresponding to b and c after applying the lock-in algorithm corresponding to a signal-to-background ratio of ~77.

Fig. 4
Fig. 4

In vivo imaging of sentinel lymph nodes. (a) FNDs were injected into the front footpad of a mouse and imaged using spectral unmixing methods to separate the emission of the FNDs (top right, red in overlay) from background fluorescence (top left, white in overlay). For comparison, a raw unprocessed image from the Maestro imager is shown in the inset in the overlay. FNDs were not detected through the skin in the draining axillary lymph node. (b) The same mouse imaged by averaging 475 images obtained by pairwise subtracting images with and without the magnetic field. The processed image (top right inset, red in overlay) was overlaid on an unprocessed image obtained with the magnetic field off (top left inset, white in overlay). The white arrows point to the injection site in the footpad and the location of the auxiliary lymph node. Signal from the FNDs in the lymph node is clearly detected. (c) Lock-in detection of emission from FNDs from the same images used to generate Fig. 4(b) using the lock-in algorithm described in Fig. 3 (top right inset, red in overlay) overlaid on the unprocessed image obtained with the magnetic field off (top left inset, white in overlay). (d) Magnetic modulation image of the same mouse's open chest cavity by averaging images obtained by pairwise subtracting images with and without the magnetic field. The processed image (bottom inset, red in overlay) was overlaid on an unprocessed image obtained with the magnetic field off (top inset, white in overlay). The white arrows point to the injection site in the front footpad and the location of the auxiliary lymph node. (e) Lock-in detection of emission from FNDs from the same images used to generate Fig. 4(d). The lock-in signal (bottom inset, red in overlay) is overlaid on the unprocessed image obtained with the magnetic field off (top inset from panel d, white in overlay). The top inset is a contrast enhanced version of the unprocessed image in panel d. The gross anatomy of the mouse (front footpad on the right) and open chest cavity can be discerned. In the partially dissected mouse, localization of the FNDs to the lymph node can be clearly seen. (f) The pixel values as a function time corresponding to the selected points in b and d. The pixels selected were over 1) the axillary lymph node and 2) a negative control on the skin in Fig. b; 3) the axillary lymph node and 4) a negative control on a rib in Fig. d. Signal modulation as a result of the applied magnetic field is clearly visible in the lymph node through the skin, as well as when the chest cavity was opened. Meanwhile, the skin and rib showed random signal as expected for the negative control.

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