Development of high resolution molecular imaging methods based on fluorescent and photoacoustic contrasts.
Final Report Abstract
In many imaging applications, where biomarker distribution, disease state, or treatment efficacy need to be accurately evaluated, qualitative representation of tissue anatomy is usually insufficient. Here, quantitative mapping of volumetric distribution of a certain tissue bio-markers might become necessary. The overarching interest that has been pursued with this project was to establish new methodology for high performance deep tissue imaging using fluorescence molecular probes. From this perspective, the project’s goals have been fully achieved while, to a certain extent, the actual results have even exceeded the initial expectations, especially with respect to the actual sensitivity and other key performance characteristics of the MSOT method. From the various microscopy technologies to endoscopic, intravascular and ocular diagnostic devices, optical imaging unequivocally remains the most versatile and widely used visualization modality in clinical practice and research. However, light becomes diffuse within a few millimeters of propagation in tissues owing to elastic scattering experienced by photons when they interact with various cellular components, such as the membranes and different organelles. Diffusion results in the loss of imaging resolution. Therefore, macroscopic optical imaging techniques like fluorescence molecular tomography largely depend on spatially resolving and quantifying bulk signals from specific fluorescent entities reporting on cellular and molecular activity. The DFG project’s achievements made us believe that the optoacoustic technology is not only capable of overcoming the scattering-related limitations of optical imaging, but can truly shift the paradigm of whole-body molecular imaging towards high resolution real-time performance. These conclusions were made possible thanks to the significant theoretical achievements on the image reconstruction and quantification frontiers made during the project through high-performance imaging system development and extensive in-vivo experimentation. With the compelling advantages of optical imaging, such as highly diverse contrast mechanisms and easy and safe usability and with imaging performance characteristics that rivals ultrasound in imaging speed, MRI in spatial resolution and nuclear and optical imaging in sensitivity and specificity, the newly introduced MSOT approach is expected to play a major role in biomedical research and drug discovery applications in the years to come. This is because it brings a new standard of performance in small animal imaging and it can lead to significant niche clinical applications as well, especially in regimes that optical imaging is already an accepted modality, such as endoscopic applications, but possibly also in applications where deeper detection is required. As such, it can play a vital role, from monitoring dynamic phenomena non-invasively to accelerating the decision on potential drug candidates during invivo screening applications and toxicology animal studies. Yet, living objects present a very complex target for optoacoustic imaging due to the presence of a highly heterogeneous tissue background in the form of strong spatial variations of scattering and absorption. Extracting truly quantified information on the actual distribution of tissue chromophores and other biomarkers constitutes therefore a challenging problem. Quality of optoacoustic reconstructions is also significantly affected by various modeling imperfections, such as illumination configuration, acoustic and optical heterogeneities of the imaged object, accuracy of the inversion algorithm, spatial and frequency response of the detectors, as well as instrumentation-related parameters, such as laser source instability. Furthermore, in many realistic imaging cases, where large parts of the object are not accessible for light or its geometry is not suitable for uniform illumination, a sub-optimal partial illumination arrangement is the only method to actually perform optoacoustic imaging at the expense of reduced tomographic quality of the data. Similar issues are arising regarding the sensitivity fields of the transducers used for optoacoustic detection. Many of those factors can be efficiently accounted for by applying the model-based reconstructions that account for light propagation in the forward model of the inversion scheme, as was demonstrated here. Clearly, not all the experimental parameters are known and thus can be accurately modeled and corrected for during the reconstruction process. In summary, while some of the above challenges have been effectively addressed in the course of the current DFG project, our future research is geared toward making MSOT a true quantitative modality that can extract accurate unbiased information on the functional and physiological tissue parameters and agent bio-distribution.
Publications
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“Multi-spectral optoacoustic tomography of deep-seated fluorescent proteins in-vivo”, Nature Phot. 3(7): 412-417 (2009)
D. Razansky, M. Distel, C. Vinegoni, R. Ma, N. Perrimon, R. W. Köster, and V. Ntziachristos
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“Multispectral optoacoustic tomography (MSOT) scanner for whole-body molecular imaging“, Opt. Exp. 17(24): 21414-21426 (2009)
R. Ma, A. Taruttis, V. Ntziachristos, and D. Razansky
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“Volumetric real-time multispectral optoacoustic tomography of biomarkers”, Nature Prot. 6(8): 1121-1129 (2011)
D. Razansky, A. Buehler, and V. Ntziachristos
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“Accurate model-based inversion algorithm for three-dimensional optoacoustic tomography”, IEEE Trans. Med. Imag. 31(10): 1922-1928 (2012)
X. L. Deán-Ben, A. Buehler, V. Ntziachristos, and D. Razansky
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“Fast multispectral optoacoustic tomography (MSOT) for dynamic imaging of pharmacokinetics and biodistribution in multiple organs”, PLoS ONE 7(1): e30491 (2012)
A. Taruttis, S. Morscher, N. C. Burton, D. Razansky, and V. Ntziachristos
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“High resolution targeting of tumor apoptosis in living mice by means of multispectral optoacoustic tomography”, Eur. J. Nucl. Med. Mol. Imag. Res. 2:14 (2012)
A. Buehler, E. Herzog, A. Ale, B. A. Smith, V. Ntziachristos, and D. Razansky
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“Multi-Spectral Optoacoustic Tomography – Volumetric Color Hearing in Real Time”, IEEE J. Sel. Topics Quantum Electron. 18(3): 1234 – 1243 (2012)
D. Razansky
