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.

  • Article
  • Published:

FMT-XCT: in vivo animal studies with hybrid fluorescence molecular tomography–X-ray computed tomography

Abstract

The development of hybrid optical tomography methods to improve imaging performance has been suggested over a decade ago and has been experimentally demonstrated in animals and humans. Here we examined in vivo performance of a camera-based hybrid fluorescence molecular tomography (FMT) system for 360° imaging combined with X-ray computed tomography (XCT). Offering an accurately co-registered, information-rich hybrid data set, FMT-XCT has new imaging possibilities compared to stand-alone FMT and XCT. We applied FMT-XCT to a subcutaneous 4T1 tumor mouse model, an Aga2 osteogenesis imperfecta model and a Kras lung cancer mouse model, using XCT information during FMT inversion. We validated in vivo imaging results against post-mortem planar fluorescence images of cryoslices and histology data. Besides offering concurrent anatomical and functional information, FMT-XCT resulted in the most accurate FMT performance to date. These findings indicate that addition of FMT optics into the XCT gantry may be a potent upgrade for small-animal XCT systems.

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: Neck tumor study using nude mouse with subcutaneous 4T1 tumor.
Figure 2: Bone growth and remodeling study using Aga2 osteogenesis imperfecta mouse model.
Figure 3: Lung tumor study using Kras mouse model.
Figure 4: Lung tumor imaging over time using Kras mouse model.
Figure 5: Cross-area analysis for FMT-XCT reconstruction and cryoslices.

Similar content being viewed by others

References

  1. Ntziachristos, V. Going deeper than microscopy: the optical imaging frontier in biology. Nat. Methods 7, 603–614 (2010).

    Article  CAS  Google Scholar 

  2. Ntziachristos, V., Ripoll, J., Wang, L.H.V. & Weissleder, R. Looking and listening to light: the evolution of whole-body photonic imaging. Nat. Biotechnol. 23, 313–320 (2005).

    Article  CAS  Google Scholar 

  3. Arridge, S.R. Optical tomography in medical imaging. Inverse Probl. 15, R41–R93 (1999).

    Article  Google Scholar 

  4. Leblond, F., Davis, S.C., Valdes, P.A. & Pogue, B.W. Pre-clinical whole-body fluorescence imaging: Review of instruments, methods and applications. J. Photochem. Photobiol. B 98, 77–94 (2010).

    Article  CAS  Google Scholar 

  5. Ntziachristos, V., Tung, C.H., Bremer, C. & Weissleder, R. Fluorescence molecular tomography resolves protease activity in vivo. Nat. Med. 8, 757–760 (2002).

    Article  CAS  Google Scholar 

  6. Kepshire, D.S. et al. Imaging of glioma tumor with endogenous fluorescence tomography. J. Biomed. Opt. 14, 030501 (2009).

    Article  Google Scholar 

  7. Milstein, A.B. et al. Fluorescence optical diffusion tomography. Appl. Opt. 42, 3081–3094 (2003).

    Article  Google Scholar 

  8. Hyde, D., Schulz, R., Brooks, D., Miller, E. & Ntziachristos, V. Performance dependence of hybrid X-ray computed tomography/fluorescence molecular tomography on the optical forward problem. J. Opt. Soc. Am. A Opt. Image Sci. Vis. 26, 919–923 (2009).

    Article  CAS  Google Scholar 

  9. Jacques, S.L. & Pogue, B.W. Tutorial on diffuse light transport. J. Biomed. Opt. 13, 041302 (2008).

    Article  Google Scholar 

  10. Soubret, A., Ripoll, J. & Ntziachristos, V. Accuracy of fluorescent tomography in the presence of heterogeneities: study of the normalized born ratio. IEEE Trans. Med. Imaging 24, 1377–1386 (2005).

    Article  Google Scholar 

  11. Cherry, S.R. Multimodality imaging: beyond PET/CT and SPECT/CT. Semin. Nucl. Med. 39, 348–353 (2009).

    Article  Google Scholar 

  12. Kinahan, P.E., Hasegawa, B.H. & Beyer, T. X-ray-based attenuation correction for positron emission tomography/computed tomography scanners. Semin. Nucl. Med. 33, 166–179 (2003).

    Article  Google Scholar 

  13. Levine, M. & Julian, J. Imaging: PET-CT imaging in non-small-cell lung cancer. Nat. Rev. Clin. Oncol. 6, 619–620 (2009).

    Article  Google Scholar 

  14. Nahrendorf, M. et al. Nanoparticle PET-CT imaging of macrophages in inflammatory atherosclerosis. Circulation 117, 379–387 (2008).

    Article  CAS  Google Scholar 

  15. Riklund, K.A. PET/CT: nuclear medicine imaging in the future. Radiat. Prot. Dosimetry 139, 8–11 (2010).

    Article  Google Scholar 

  16. Judenhofer, M.S. et al. Simultaneous PET-MRI: a new approach for functional and morphological imaging. Nat. Med. 14, 459–465 (2008).

    Article  CAS  Google Scholar 

  17. O′Leary, M.A., Boas, D.A., Li, X.D., Chance, B. & Yodh, A.G. Fluorescence lifetime imaging in turbid media. Opt. Lett. 21, 158–160 (1996).

    Article  Google Scholar 

  18. Yalavarthy, P.K., Pogue, B.W., Dehghani, H. & Paulsen, K.D. Weight-matrix structured regularization provides optimal generalized least-squares estimate in diffuse optical tomography. Med. Phys. 34, 2085–2098 (2007).

    Article  Google Scholar 

  19. Ntziachristos, V., Yodh, A.G., Schnall, M. & Chance, B. Concurrent MRI and diffuse optical tomography of breast after indocyanine green enhancement. Proc. Natl. Acad. Sci. USA 97, 2767–2772 (2000).

    Article  CAS  Google Scholar 

  20. Zhang, Q. et al. Coregistered tomographic X-ray and optical breast imaging: initial results. J. Biomed. Opt. 10, 024033 (2005).

    Article  Google Scholar 

  21. Davis, S.C. et al. Magnetic resonance-coupled fluorescence tomography scanner for molecular imaging of tissue. Rev. Sci. Instrum. 79, 064302 (2008).

    Article  Google Scholar 

  22. Schulz, R.B. et al. Hybrid system for simultaneous fluorescence and X-ray computed tomography. IEEE Trans. Med. Imaging 29, 465–473 (2010).

    Article  Google Scholar 

  23. Hyde, D. et al. Hybrid FMT-CT imaging of amyloid-beta plaques in a murine Alzheimer′s disease model. Neuroimage 44, 1304–1311 (2009).

    Article  Google Scholar 

  24. Hyde, D., Miller, E.L., Brooks, D.H. & Ntziachristos, V. Data specific spatially varying regularization for multimodal fluorescence molecular tomography. IEEE Trans. Med. Imaging 29, 365–374 (2010).

    Article  Google Scholar 

  25. Lisse, T.S. et al. ER stress-mediated apoptosis in a new mouse model of osteogenesis imperfecta. PLoS Genet. 4, e7 (2008).

    Article  Google Scholar 

  26. Johnson, L. et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410, 1111–1116 (2001).

    Article  CAS  Google Scholar 

  27. Deliolanis, N.C. et al. Performance of the red-shifted fluorescent proteins in deep-tissue molecular imaging applications. J. Biomed. Opt. 13, 044008 (2008).

    Article  Google Scholar 

  28. Graham, K.C. et al. Contrast-enhanced microcomputed tomography using intraperitoneal contrast injection for the assessment of tumor-burden in liver metastasis models. Invest. Radiol. 43, 488–495 (2008).

    Article  Google Scholar 

  29. Arnoldi, E. et al. CT detection of myocardial blood volume deficits: dual-energy CT compared with single-energy CT spectra. Circulation 120, S375 (2009).

    Google Scholar 

  30. Pfeiffer, F., Kottler, C., Bunk, O. & David, C. Hard X-ray phase tomography with low-brilliance sources. Phys. Rev. Lett. 98, 108105 (2007).

    Article  CAS  Google Scholar 

  31. Davis, S.C. et al. Image-guided diffuse optical fluorescence tomography implemented with Laplacian-type regularization. Opt. Express 15, 4066–4082 (2007).

    Article  Google Scholar 

  32. Guven, M., Yazici, B., Intes, X. & Chance, B. Diffuse optical tomography with a priori anatomical information. Phys. Med. Biol. 50, 2837–2858 (2005).

    Article  Google Scholar 

  33. Intes, X., Maloux, C., Guven, M., Yazici, B. & Chance, B. Diffuse optical tomography with physiological and spatial a priori constraints. Phys. Med. Biol. 49, N155–N163 (2004).

    Article  Google Scholar 

  34. Barber, W.C. et al. Combined fluorescence and X-ray tomography for quantitative in vivo detection of fluorophore. Technol. Cancer Res. Treat. 9, 45–52 (2010).

    Article  CAS  Google Scholar 

  35. Lin, Y.T. et al. Quantitative fluorescence tomography using a combined tri-modality FT/DOT/XCT system. Opt. Express 18, 7835–7850 (2010).

    Article  CAS  Google Scholar 

  36. Freyer, M. et al. Fast automatic segmentation of anatomical structures in X-ray computed tomography images to improve fluorescence molecular tomography reconstruction. J. Biomed. Opt. 15, 036006 (2010).

    Article  Google Scholar 

  37. Niedre, M.J., Turner, G.M. & Ntziachristos, V. Time-resolved imaging of optical coefficients through murine chest cavities. J. Biomed. Opt. 11, 064017 (2006).

    Article  Google Scholar 

  38. Sarantopoulos, A., Themelis, G. & Ntziachristos, V. Imaging the bio-distribution of fluorescent probes using multispectral epi-illumination cryoslicing imaging. Mol. Imaging Biol. 13, 874–885 (2011).

    Article  Google Scholar 

Download references

Acknowledgements

We thank A. Sarantopoulos, R. Schulz and M.W. Koch for help with cryoslicer and FMT-XCT measurements. V.N., A.A and V.E. acknowledge support from the EU Framework Program 7 FMT-XCT grant agreement 201792.

Author information

Authors and Affiliations

Authors

Contributions

V.N. designed and supervised the project and wrote the paper. A.A. wrote the paper, worked on method development, performed the FMT-XCT experiments, carried out data reconstructions and analyzed the results. V.E. performed Kras and osteogenesis imperfecta experiments. M.H.d.A. supervised C.C. E.H. performed neck tumor experiments. C.C. prepared the mouse model for osteogenesis imperfecta experiments.

Corresponding author

Correspondence to Vasilis Ntziachristos.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–2, Supplementary Table 1, Supplementary Notes 1–2 (PDF 560 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ale, A., Ermolayev, V., Herzog, E. et al. FMT-XCT: in vivo animal studies with hybrid fluorescence molecular tomography–X-ray computed tomography. Nat Methods 9, 615–620 (2012). https://doi.org/10.1038/nmeth.2014

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nmeth.2014

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