Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

All-optical anatomical co-registration for molecular imaging of small animals using dynamic contrast

Abstract

Optical molecular imaging in small animals harnesses the power of highly specific and biocompatible contrast agents for drug development and disease research1,2,3,4,5,6,7. However, the widespread adoption of in vivo optical imaging has been inhibited by its inability to clearly resolve and identify targeted internal organs. Optical tomography8,9,10,11 and combined X-ray and micro-computed tomography (micro-CT)12 approaches developed to address this problem are generally expensive, complex or incapable of true anatomical co-registration. Here, we present a remarkably simple all-optical method that can generate co-registered anatomical maps of a mouse's internal organs, while also acquiring in vivo molecular imaging data. The technique uses a time series of images acquired after injection of an inert dye. Differences in the dye's in vivo biodistribution dynamics allow precise delineation and identification of major organs. Such co-registered anatomical maps permit longitudinal organ identification irrespective of repositioning or weight gain, thereby promising greatly improved accuracy and versatility for studies of orthotopic disease, diagnostics and therapies.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Dynamic imaging system.
Figure 2: In vivo anatomical maps derived using PCA of an image series following ICG injection.
Figure 3: In vivo, non-invasive anatomical mapping of nine organ-specific spatiotemporal components.

Similar content being viewed by others

References

  1. Moore, A., Grimm, J., Han, B. & Santamaria, P. Tracking the recruitment of diabetogenic CD8+ T-cells to the pancreas in real time. Diabetes 53, 1459–1466 (2004).

    Article  Google Scholar 

  2. Gao, X., Cui, Y., Levenson, R. M., Chung, L. W. K. & Nie, S. In vivo cancer targeting and imaging with semiconductor quantum dots. Nature Biotechnol. 22, 969–976 (2004).

    Article  Google Scholar 

  3. Moore, A., Medarova, Z., Potthast, A. & Dai, G. In vivo targeting of underglycosylated MUC-1 tumor antigen using a multimodal imaging probe. Cancer Res. 64, 1821–1827 (2004).

    Article  Google Scholar 

  4. Weissleder, R., Kelly, K., Sun, E. Y., Shtatland, T. & Josephson, L. Cell-specific targeting of nanoparticles by multivalent attachment of small molecules. Nature Biotechnol. 23, 1418–1423 (2005).

    Article  Google Scholar 

  5. Evgenov, N. V., Medarova, Z., Dai, G., Bonner-Weir, S. & Moore, A. In vivo imaging of islet transplantation. Nature Med. 12, 144–148 (2006).

    Article  Google Scholar 

  6. Ntziachristos, V. et al. Visualization of antitumor treatment by means of fluorescence molecular tomography with an annexin V-Cy5.5 conjugate. Proc. Natl Acad. Sci. USA 101, 12294–12299 (2004).

    Article  ADS  Google Scholar 

  7. Hsieh, C.-L. et al. A luciferase transgenic mouse model: Visualization of prostate development and its androgen responsiveness in live animals. J. Mol. Endocrinol. 35, 293–304 (2005).

    Article  Google Scholar 

  8. Dehghani, H. et al. Spectrally resolved bioluminescence optical tomography. Opt. Lett. 31, 365–367 (2006).

    Article  ADS  Google Scholar 

  9. Ntziachristos, V., Tung, C.-H., Bremer, C. & Weissleder, R. Fluorescence molecular tomography resolves protease activity in vivo. Nature Med. 8, 757–761 (2002).

    Article  Google Scholar 

  10. Hielscher, A. H. Optical tomographic imaging of small animals. Curr. Opin. Biotechnol. 16, 79–88 (2005).

    Article  Google Scholar 

  11. Patwardhan, S., Bloch, S., Achilefu, S. & Culver, J. Time-dependent whole-body fluorescence tomography of probe bio-distributions in mice. Opt. Express 13, 2564–2577 (2005).

    Article  ADS  Google Scholar 

  12. Zacharakis, G. et al. Volumetric tomography of fluorescent proteins through small animals in vivo. Proc. Natl Acad. Sci. USA 102, 18252–18257 (2005).

    Article  ADS  Google Scholar 

  13. Jenkins, D. E., Hornig, Y. S., Oei, Y., Dusich, J. & Purchio, T. Bioluminescent human breast cancer cell lines that permit rapid and sensitive in vivo detection of mammary tumors and multiple metastases in immune deficient mice. Breast Cancer Res. 7, R444–R454 (2005).

    Article  Google Scholar 

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

    Article  ADS  Google Scholar 

  15. Cui, J. H. et al. Intact tissue of gastrointestinal cancer specimen orthotopically transplanted into nude mice. Hepatogastroenterology 45, 2087–2096 (1998).

    Google Scholar 

  16. Fidler, I. J. Critical factors in the biology of human cancer metastasis: Twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res. 50, 6130–6138 (1990).

    Google Scholar 

  17. Gulsen, G., Birgul, O., Unlu, M. B., Shafiiha, R. & Nalcioglu, O. Combined diffuse optical tomography (DOT) and MRI system for cancer imaging in small animals. Technol. Cancer Res. Treat. 5, 351–364 (2006).

    Article  Google Scholar 

  18. Hintersteiner, M. et al. In vivo detection of amyloid-β deposits by near-infrared imaging using an oxazine-derivative probe. Nature Biotechnol. 23, 577–583 (2005).

    Article  Google Scholar 

  19. Zaheer, A. et al. In vivo near-infrared fluorescence imaging of osteoblastic activity. Nature Biotechnol. 19, 1148–1154 (2001).

    Article  Google Scholar 

  20. Daly, P. F., Zimmerman, J. B., Cannillo, J. A. & Wolf, G. L. MR imagetime-intensity relations in spleen and kidney: A comparative study of GdDTPA, albumin-(GdDTPA), and Gd2O3 colloid. Am. J. Physiol. Imaging 5, 119–124 (1990).

    Google Scholar 

  21. Wang, Y., Xuan, J., Srikanchana, R. & Choyke, P. L. Modeling and reconstruction of mixed functional and molecular patterns. Int. J. Biomed. Imag. 2006, 29707 (2006).

    Google Scholar 

  22. Miles, K. A., Hayball, M. & Dixon, A. K. Colour perfusion imaging: a new application of computed tomography. Lancet 337, 643–645 (1991).

    Article  Google Scholar 

  23. Weissleder, R. A clearer vision for in vivo imaging. Nature Biotechnol. 19, 316–317 (2001).

    Article  Google Scholar 

  24. Comsa, D. C., Farrell, T. J. & Patterson, M. S. Quantification of bioluminescence images of point source objects using diffusion theory models. Phys. Med. Biol. 51, 3733–3746 (2006).

    Article  Google Scholar 

  25. Salam, A. R. A., Drummond, G. B., Bauld, H. W. & Scott, D. B. Clearance of indocyanine green as an index of liver function during cyclopropane anaesthesia and induced hypotension. Br. J. Anaesth. 48, 231–238 (1976).

    Article  Google Scholar 

  26. Gurfinkel, M., Ke, S., Wang, W., Li, C. & Sevick-Muraca, E. M. Quantifying molecular specificity of αvβ3 integrin-targeted optical contrast agents with dynamic optical imaging. J. Biomed. Opt. 10, 034019 (2005).

    Article  ADS  Google Scholar 

  27. Gurfinkel, M. et al. Pharmacokinetics of ICG and HPPH-car for the detection of normal and tumor tissue using fluorescence, near-infrared reflectance imaging: A case study. Photochem. Photobiol. 72, 94–102 (2000).

    Article  Google Scholar 

  28. Cuccia, D. J. et al. In vivo quantification of optical contrast agent dynamics in rat tumors by use of diffuse optical spectroscopy with magnetic resonance imaging coregistration. Appl. Opt. 42, 2940–2950 (2003).

    Article  ADS  Google Scholar 

  29. Intes, X. et al. In vivo continuous-wave optical breast imaging enhanced with Indocyanine Green. Med. Phys. 30, 1039–1047 (2003).

    Article  Google Scholar 

  30. Barbour, R. L., Graber, H. L., Pei, Y., Zhong, S. & Schmitz, C. H. Optical tomographic imaging of dynamic features of dense-scattering media. J. Opt. Soc. Am. A 18, 3018–3036 (2001).

    Article  ADS  Google Scholar 

Download references

Acknowledgements

This work was funded by National Institutes of Health grants: 1R01DK072137, 5R01DK064850, R21DK071225 and 1U54CA126513. The authors wish to sincerely thank R. M. Levenson and X. E. Guo for helpful discussions and guidance. We also acknowledge the contributions of S. B. Raymond, B. J. Bacskai, M. Bouchard and D. A. Boas at Massachusetts General Hospital.

Author information

Authors and Affiliations

Authors

Contributions

E.M.C.H. conceived the technique, designed and performed the experiments, analysed the data and wrote the manuscript. A.M. prompted and guided development of the concept and aided in data acquisition, data interpretation and manuscript preparation.

Corresponding authors

Correspondence to Elizabeth M. C. Hillman or Anna Moore.

Ethics declarations

Competing interests

A patent application was filed on 1 June 2007 by Massachusetts General Hospital on the method described in this paper with Elizabeth M. C. Hillman as the sole inventor.

Supplementary information

Supplementary Information

Supplementary figures S1-S4 (PDF 2126 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hillman, E., Moore, A. All-optical anatomical co-registration for molecular imaging of small animals using dynamic contrast. Nature Photon 1, 526–530 (2007). https://doi.org/10.1038/nphoton.2007.146

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nphoton.2007.146

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing