Perspective | Published:

Tackling standardization in fluorescence molecular imaging

Nature Photonicsvolume 12pages505515 (2018) | Download Citation

Abstract

The emerging clinical use of targeted fluorescent agents heralds a shift in intraoperative imaging practices that overcome the limitations of human vision. However, in contrast to established radiological methods, no appropriate performance specifications and standards have been established in fluorescence molecular imaging. Moreover, the dependence of fluorescence signals on many experimental parameters and the use of wavelengths ranging from the visible to short-wave infrared (400–1,700 nm) complicate quality control in fluorescence molecular imaging. Here, we discuss the experimental parameters that critically affect fluorescence molecular imaging accuracy, and introduce the concept of high-fidelity fluorescence imaging as a means for ensuring reliable reproduction of fluorescence biodistribution in tissue.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Koch, M. & Ntziachristos, V. Advancing surgical vision with fluorescence imaging. Annu. Rev. Med. 67, 153–164 (2016).

  2. 2.

    Zhang, R. R. et al. Beyond the margins: real-time detection of cancer using targeted fluorophores. Nat. Rev. Clin. Oncol. 14, 347–364 (2017).

  3. 3.

    van Dam, G. M. et al. Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-alpha targeting: first in-human results. Nat. Med. 17, 1315–1319 (2011).

  4. 4.

    Tummers, Q. R. J. G., Hoogstins, C. E. S. & Gaarenstroom, K. N. Intraoperative imaging of folate receptor alpha positive ovarian and breast cancer using the tumor specific agent EC17. Oncotarget 7, 32144–32155 (2016).

  5. 5.

    Rosenthal, E. L. et al. Safety and tumor specificity of cetuximab-IRDye800 for surgical navigation in head and neck cancer. Clin. Cancer Res. 21, 3658–3666 (2015).

  6. 6.

    Whitley, M. J. et al. A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer. Sci. Transl. Med. 8, 320ra4 (2016).

  7. 7.

    Hsiung, P.-L. et al. Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy. Nat. Med. 14, 454–458 (2008).

  8. 8.

    Atreya, R. et al. In vivo imaging using fluorescent antibodies to tumor necrosis factor predicts therapeutic response in Crohn’s disease. Nat. Med. 20, 313–318 (2014).

  9. 9.

    Glatz, J., Symvoulidis, P., Garcia-Allende, P. B. & Ntziachristos, V. Robust overlay schemes for the fusion of fluorescence and color channels in biological imaging. J. Biomed. Opt. 19, 040501 (2014).

  10. 10.

    Glatz, J. et al. Concurrent video-rate color and near-infrared fluorescence laparoscopy. J. Biomed. Opt. 18, 101302 (2013).

  11. 11.

    Hong, G. et al. Through-skull fluorescence imaging of the brain in a new near-infrared window. Nat. Photon. 8, 723–730 (2014).

  12. 12.

    Hong, G. et al. Multifunctional in vivo vascular imaging using near-infrared II fluorescence. Nat. Med. 18, 1841–1846 (2012).

  13. 13.

    Ghosh, D. et al. Deep, noninvasive imaging and surgical guidance of submillimeter tumors using targeted M13-stabilized single-walled carbon nanotubes. Proc. Natl Acad. Sci. USA 111, 13948–13953 (2014).

  14. 14.

    Carr, J. A. et al. Shortwave infrared fluorescence imaging with the clinically approved near-infrared dye indocyanine green. Proc. Natl Acad. Sci. USA 115, 4465–4470 (2018).

  15. 15.

    DSouza, A. V., Lin, H., Henderson, E. R., Samkoe, K. S. & Pogue, B. W. Review of fluorescence guided surgery systems: identification of key performance capabilities beyond indocyanine green imaging. J. Biomed. Opt. 21, 080901 (2016).

  16. 16.

    Scheuer, W., van Dam, G. M., Dobosz, M., Schwaiger, M. & Ntziachristos, V. Drug-based optical agents: infiltrating clinics at lower risk. Sci. Transl. Med. 4, 134ps11 (2012).

  17. 17.

    Marshall, M. V. et al. Near-infrared fluorescence imaging in humans with indocyanine green: a review and update. Open Surg. Oncol. J. 2, 12–25 (2012).

  18. 18.

    US National Library of Medicine. VEGF-targeted fluorescent tracer imaging in breast cancer. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01508572 (2012).

  19. 19.

    Bradley, R. S. & Thorniley, M. S. A review of attenuation correction techniques for tissue fluorescence. J. R. Soc. Interface 3, 1–13 (2006).

  20. 20.

    Themelis, G., Yoo, J. S., Soh, K.-S., Schulz, R. & Ntziachristos, V. Real-time intraoperative fluorescence imaging system using light-absorption correction. J. Biomed. Opt. 14, 064012 (2014).

  21. 21.

    Moriyama, E. H., Kim, A., Bogaards, A., Lilge, L. & Wilson, B. C. A ratiometric fluorescence imaging system for surgical guidance. Adv. Opt. Technol. 2008, 532368 (2008).

  22. 22.

    DeWerd, L. A. & Kissick, M. The Phantoms of Medical and Health Physics (Springer, New York, NY, 2014).

  23. 23.

    Zhu, B., Rasmussen, J. C., Litorja, M. & Sevick-Muraca, E. M. Determining the performance of fluorescence molecular imaging devices using traceable working standards with SI units of radiance. IEEE Trans. Med. Imaging 35, 802–811 (2016).

  24. 24.

    Ntziachristos, V. et al. Planar fluorescence imaging using normalized data. J. Biomed. Opt. 10, 064007 (2005).

  25. 25.

    Tichauer, K. M. et al. Microscopic lymph node tumor burden quantified by macroscopic dual-tracer molecular imaging. Nat. Med. 20, 1348–1353 (2014).

  26. 26.

    Valdés, P. A. et al. Quantitative, spectrally-resolved intraoperative fluorescence imaging. Sci. Rep. 2, 798 (2012).

  27. 27.

    Zhu, B., Rasmussen, J. C. & Sevick-Muraca, E. M. Non-invasive fluorescence imaging under ambient light conditions using a modulated ICCD and laser diode. Biomed. Opt. Express 5, 562–572 (2014).

  28. 28.

    Sexton, K. et al. Pulsed-light imaging for fluorescence guided surgery under normal room lighting. Opt. Lett. 38, 3249–3252 (2013).

  29. 29.

    Zonios, G. & Dimou, A. Modeling diffuse reflectance from semi-infinite turbid media: application to the study of skin optical properties. Opt. Express 14, 8661–8674 (2006).

  30. 30.

    Garcia-Allende, P. B. et al. Uniqueness in multispectral constant-wave epi-illumination imaging. Opt. Lett. 41, 3098–3101 (2016).

  31. 31.

    Saager, R. B., Cuccia, D. J., Saggese, S., Kelly, K. M. & Durkin, A. J. Quantitative fluorescence imaging of protoporphyrin IX through determination of tissue optical properties in the spatial frequency domain. J. Biomed. Opt. 16, 126013 (2011).

  32. 32.

    Yang, B. & Tunnell, J. W. Real-time absorption reduced surface fluorescence imaging. J. Biomed. Opt. 19, 090505 (2014).

  33. 33.

    Kanick, S. C. & Pogue, B. W. Why reflectance is an imperfect basis for the correction of fluorescence distortion due to optical properties. In Biomedical Optics 2014 BS3A.35 (OSA, 2014).

  34. 34.

    Bogaards, A., Sterenborg, H. J. C. M. & Wilson, B. C. In vivo quantification of fluorescent molecular markers in real-time: a review to evaluate the performance of five existing methods. Photodiagnosis Photodyn. Ther. 4, 170–178 (2007).

  35. 35.

    Yang, V. X. D., Muller, P. J., Herman, P. & Wilson, B. C. A multispectral fluorescence imaging system: design and initial clinical tests in intra-operative photofrin-photodynamic therapy of brain tumors. Lasers Surg. Med. 32, 224–232 (2003).

  36. 36.

    Minamikawa, T. et al. Simplified and optimized multispectral imaging for 5-ALA-based fluorescence diagnosis of malignant lesions. Sci. Rep. 6, 25530 (2016).

  37. 37.

    Haller, J. et al. Visualization of pulmonary inflammation using noninvasive fluorescence molecular imaging. J. Appl. Physiol. 104, 795–802 (2008).

  38. 38.

    Godavarty, A. et al. Fluorescence-enhanced optical imaging in large tissue volumes using a gain-modulated ICCD camera. Phys. Med. Biol. 48, 1701–1720 (2003).

  39. 39.

    Vervandier, J. & Gioux, S. Single snapshot imaging of optical properties. Biomed. Opt. Express 4, 2938–2944 (2013).

  40. 40.

    Niedre, M. J. et al. Early photon tomography allows fluorescence detection of lung carcinomas and disease progression in mice in vivo. Proc. Natl Acad. Sci. USA 105, 19126–19131 (2008).

  41. 41.

    Resch-Genger, U., Grabolle, M., Cavaliere-Jaricot, S., Nitschke, R. & Nann, T. Quantum dots versus organic dyes as fluorescent labels. Nat. Methods 5, 763–775 (2008).

  42. 42.

    Gao, X. et al. In vivo molecular and cellular imaging with quantum dots. Curr. Opin. Biotechnol. 16, 63–72 (2005).

  43. 43.

    Alivisatos, A. P., Gu, W. & Larabell, C. Quantum dots as cellular probes. Annu. Rev. Biomed. Eng. 7, 55–76 (2005).

  44. 44.

    Zhu, B., Tan, I.-C., Rasmussen, J. C. & Sevick-Muraca, E. M. Validating the sensitivity and performance of near-infrared fluorescence imaging and tomography devices using a novel solid phantom and measurement approach. Technol. Cancer Res. Treat. 11, 95–104 (2012).

  45. 45.

    Roy, M., Kim, A., Dadani, F. & Wilson, B. C. Homogenized tissue phantoms for quantitative evaluation of subsurface fluorescence contrast. J. Biomed. Opt. 16, 016013 (2011).

  46. 46.

    Zhu, B., Rasmussen, J. C. & Sevick-Muraca, E. M. A matter of collection and detection for intraoperative and noninvasive near-infrared fluorescence molecular imaging: to see or not to see? Med. Phys. 41, 022105 (2014).

  47. 47.

    Moffitt, T., Chen, Y.-C. & Prahl, S. A. Preparation and characterization of polyurethane optical phantoms. J. Biomed. Opt. 11, 041103 (2006).

  48. 48.

    Anastasopoulou, M. et al. Comprehensive phantom for interventional fluorescence molecular imaging. J. Biomed. Opt. 21, 091309 (2016).

  49. 49.

    Gorpas, D., Koch, M., Anastasopoulou, M., Klemm, U. & Ntziachristos, V. Benchmarking of fluorescence cameras through the use of a composite phantom. J. Biomed. Opt. 22, 016009 (2017).

Download references

Acknowledgements

We thank A. Ghazaryan for help with optoacoustic measurements. V.N. acknowledges funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 687866 (INNODERM) and from the Deutsche Forschungsgemeinschaft (DFG), Germany (Gottfried Wilhelm Leibnitz Prize 2013; NT 3/10-1).

Author information

Author notes

  1. These authors contributed equally to this work: Maximillian Koch, Panagiotis Symvoulidis.

Affiliations

  1. Chair for Biological Imaging, TranslaTUM, Technical University of Munich, Munich, Germany

    • Maximillian Koch
    • , Panagiotis Symvoulidis
    •  & Vasilis Ntziachristos
  2. Institute of Biological and Medical Imaging, Helmholtz Zentrum München, Neuherberg, Germany

    • Maximillian Koch
    • , Panagiotis Symvoulidis
    •  & Vasilis Ntziachristos

Authors

  1. Search for Maximillian Koch in:

  2. Search for Panagiotis Symvoulidis in:

  3. Search for Vasilis Ntziachristos in:

Competing interests

After the completion of the manuscript, but before the final submission, Bracco Imaging Deutschland, a company commercializing targeted fluorescence imaging, employed M.K.

Corresponding author

Correspondence to Vasilis Ntziachristos.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/s41566-018-0221-5