Vasilis Ntziachristos

Helmholtz Zentrum München, München, Bavaria, Germany

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Publications (500)1676.19 Total impact

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    ABSTRACT: Unveiling mechanisms driving specification, recruitment and regeneration of melanophores is the key to understanding melanin-related disorders. This study reports on the applicability of a hybrid focus opto-acoustic microscope (HFOAM) for volumetric tracking of migratory melanophores in developing zebrafish. The excellent contrast from highly-absorbing melanin provided by the method is shown to be ideal for label-free dynamic visualization of melanophores in their unperturbed living environment. We established safe laser energy levels that enable high-contrast longitudinal tracking of the cells over an extended period of developmental time without causing cell toxicity or pigment bleaching. Owing to its hybrid optical and acoustic resolution, the new imaging technique can be seamlessly applied for non-invasive studies of both optically-transparent larval as well as adult stages of the zebrafish model organism, which is not possible using other optical microscopy methods.
    Mechanisms of development 09/2015; DOI:10.1016/j.mod.2015.09.001 · 2.44 Impact Factor
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    ABSTRACT: Intravital imaging within heterogenic solid tumours is important for understanding blood perfusion profiles responsible for establishment of multiple parameters within the tumour mass, such as hypoxic and nutrition gradients, cell viability, proliferation and drug response potentials. Herein, we developed a method based on a volumetric multispectral optoacoustic tomography (vMSOT) for cancer imaging in preclinical models and explored its capacity for three-dimensional imaging of anatomic, vascular and functional tumour profiles in real time. In contrast to methods based on cross-sectional (2D) image acquisition as a basis for 3D rendering, vMSOT has attained concurrent observations from the entire tumour volume at 10 volumetric frames per second. This truly four dimensional imaging performance has enabled here the simultaneous assessment of blood oxygenation gradients and vascularization in solid breast tumours and revealed different types of blood perfusion profiles in-vivo. The newly introduced capacity for high-resolution three-dimensional tracking of fast tumour perfusion suggests vMSOT as a powerful method in preclinical cancer research and theranostics. As the imaging setup can be equally operated in both stationary and handheld mode, the solution is readily translatable for perfusion monitoring in a clinical setting. • vMSOT visualizes 3D anatomic, vascular and functional tumour profiles in real time. • Three types of blood perfusion profiles are revealed in breast tumour model. • The method is readily adaptable to operate in a handheld clinical mode.
    European Radiology 09/2015; DOI:10.1007/s00330-015-3980-0 · 4.01 Impact Factor
  • Yiyong Han · Stratis Tzoumas · Antonio Nunes · Vasilis Ntziachristos · Amir Rosenthal
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    ABSTRACT: Purpose: With recent advancement in hardware of optoacoustic imaging systems, highly detailed cross-sectional images may be acquired at a single laser shot, thus eliminating motion artifacts. Nonetheless, other sources of artifacts remain due to signal distortion or out-of-plane signals. The purpose of image reconstruction algorithms is to obtain the most accurate images from noisy, distorted projection data. Methods: In this paper, the authors use the model-based approach for acoustic inversion, combined with a sparsity-based inversion procedure. Specifically, a cost function is used that includes the L1 norm of the image in sparse representation and a total variation (TV) term. The optimization problem is solved by a numerically efficient implementation of a nonlinear gradient descent algorithm. TV-L1 model-based inversion is tested in the cross section geometry for numerically generated data as well as for in vivo experimental data from an adult mouse. Results: In all cases, model-based TV-L1 inversion showed a better performance over the conventional Tikhonov regularization, TV inversion, and L1 inversion. In the numerical examples, the images reconstructed with TV-L1 inversion were quantitatively more similar to the originating images. In the experimental examples, TV-L1 inversion yielded sharper images and weaker streak artifact. Conclusions: The results herein show that TV-L1 inversion is capable of improving the quality of highly detailed, multiscale optoacoustic images obtained in vivo using cross-sectional imaging systems. As a result of its high fidelity, model-based TV-L1 inversion may be considered as the new standard for image reconstruction in cross-sectional imaging.
    Medical Physics 09/2015; 42(9):5444. DOI:10.1118/1.4928596 · 2.64 Impact Factor
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    ABSTRACT: The cellular localisation and binding specificity of two NMDAR-targeted near-IR imaging probes has been examined by microscopy, followed by exemplification of MSOT to monitor simulated glutamate bursts in cellulo and a preliminary study in mice observing the signal in the brain.
    Chemical Communications 09/2015; DOI:10.1039/c5cc06277b · 6.83 Impact Factor
  • Pouyan Mohajerani · Vasilis Ntziachristos
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    ABSTRACT: The imaging performance of fluorescence molecular tomography (FMT) improves when information from the underlying anatomy is incorporated into the inversion scheme, in the form of priors. The requirement for incorporation of priors has recently driven the development of hybrid FMT systems coupled to other modalities, such as X-ray CT and MRI. A critical methodological aspect in this case relates to the particular method selected to incorporate prior information obtained from the anatomical imaging modality into the FMT inversion. We propose herein a new approach for utilizing prior information, which preferentially minimizes residual errors associated with measurements that better describe the anatomical segments considered. This preferential minimization was realized using a weighted least square (WLS) approach, where the weights were optimized using a Mamdani-type fuzzy inference system. The method of priors introduced herein was deployed as a two-step structured regularization approach and was verified with experimental measurements from phantoms as well as ex vivo and in vivo animal studies. The results demonstrate accurate performance and minimization of reconstruction bias, without requiring user input for setting the regularization parameters. As such, the proposed method offers significant progress in incorporation of anatomical priors in FMT and, as a result, in realization of the full potential of hybrid FMT.
    09/2015; DOI:10.1109/TMI.2015.2475356
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    Ara Ghazaryan · Murad Omar · George J Tserevelakis · Vasilis Ntziachristos
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    ABSTRACT: Oxidative-based diseases including diabetes, chronic renal failure, cardiovascular diseases and neurological disorders are accompanied by accumulation of advanced glycation endproducts (AGE). Therefore, AGE-associated changes in tissue optical properties could yield a viable pathological indicator for disease diagnostics and monitoring. We investigated whether skin glycation could be detected based on absorption changes associated with AGE accumulation using spectral optoacoustic measurements and interrogated the optimal spectral band for skin glycation determination. Glycated and non-glycated skin was optoacoustically measured at multiple wavelengths in the visible region. The detected signals were spectrally processed and compared to measurements of skin auto-fluorescence and to second harmonic generation multiphoton microscopy images. Optoacoustic measurements are shown to be capable of detecting skin glycolysis based on AGE detection. A linear dependence was observed between optoacoustic intensity and the progression of skin glycation. The findings where corroborated by autofluorescence observations. Detection sensitivity is enhanced by observing normalised tissue spectra. This result points to a ratiometric method for skin glycation detection, specifically at 540 nm and 620 nm. We demonstrate that optoacoustic spectroscopy could be employed to detect AGE accumulation, and possibly can be employed as a non-invasive quick method for monitoring tissue glycation.
    Biomedical Optics Express 09/2015; 6(9):3149-3156. DOI:10.1364/BOE.6.003149 · 3.65 Impact Factor
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    ABSTRACT: Intravital imaging of large specimens is intrinsically challenging for postembryonic studies. Selective plane illumination microscopy (SPIM) has been introduced to volumetrically visualize organisms used in developmental biology and experimental genetics. Ideally suited for imaging transparent samples, SPIM can offer high frame rate imaging with optical microscopy resolutions and low phototoxicity. However, its performance quickly deteriorates when applied to opaque tissues. To overcome this limitation, SPIM optics were merged with optical and optoacoustic (photoacoustic) readouts. The performance of this hybrid imaging system was characterized using various phantoms and by imaging a highly scattering ex vivo juvenile zebrafish. The results revealed the system’s enhanced capability over that of conventional SPIM for high-resolution imaging over extended depths of scattering content. The approach described here may enable future visualization of organisms throughout their entire development, encompassing regimes in which the tissue may become opaque.
    Laser & Photonics Review 09/2015; 9(5):L29-L34. DOI:10.1002/lpor.201500120 · 8.01 Impact Factor
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    Dominik Soliman · George J Tserevelakis · Murad Omar · Vasilis Ntziachristos
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    ABSTRACT: Biology requires observations at multiple geometrical scales, a feature that is not typically offered by a single imaging modality. We developed a hybrid optical system that not only provides different contrast modes but also offers imaging at different geometrical scales, achieving uniquely broad resolution and a 1000-fold volume sampling increase compared to volumes scanned by optical microscopy. The system combines optoacoustic mesoscopy, optoacoustic microscopy and two-photon microscopy, the latter integrating second and third harmonic generation modes. Label-free imaging of a mouse ear and zebrafish larva ex-vivo demonstrates the contrast and scale complementarity provided by the hybrid system. We showcase the superior anatomical orientation offered by the label-free capacity and hybrid operation, over fluorescence microscopy, and the dynamic selection between field of view and resolution achieved, leading to new possibilities in biological visualization.
    Scientific Reports 08/2015; 5. DOI:10.1038/srep12902 · 5.58 Impact Factor
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    ABSTRACT: The inversion accuracy in optoacoustic tomography depends on a number of parameters, including the number of detectors employed, discrete sampling issues or imperfectness of the forward model. These parameters result in ambiguities on the reconstructed image. A common ambiguity is the appearance of negative values, which have no physical meaning since optical absorption can only be higher or equal than zero. We investigate herein algorithms that impose non-negative constraints in model-based optoacoustic inversion. Several state-of-the-art non-negative constrained algorithms are analyzed. Furthermore, an algorithm based on the conjugate gradient method is introduced in this work. We are particularly interested in investigating whether positive restrictions lead to accurate solutions or drive the appearance of errors and artifacts. It is shown that the computational performance of non-negative constrained inversion is higher for the introduced algorithm than for the other algorithms, while yielding equivalent results. The experimental performance of this inversion procedure is then tested in phantoms and small animals, showing an improvement in image quality and quantitativeness with respect to the unconstrained approach. The study performed validates the use of non-negative constraints for improving image accuracy compared to unconstrained methods, while maintaining computational efficiency.
    Physics in Medicine and Biology 08/2015; 60(17):6733-6750. DOI:10.1088/0031-9155/60/17/6733 · 2.76 Impact Factor
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    ABSTRACT: Optical mesoscopy extends the capabilities of biological visualization beyond the limited penetration depth achieved by microscopy. However, imaging of opaque organisms or tissues larger than a few hundred micrometers requires invasive tissue sectioning or chemical treatment of the specimen for clearing photon scattering, an invasive process that is regardless limited with depth. We developed previously unreported broadband optoacoustic mesoscopy as a tomographic modality to enable imaging of optical contrast through several millimeters of tissue, without the need for chemical treatment of tissues. We show that the unique combination of three-dimensional projections over a broad 500 kHz–40 MHz frequency range combined with multi-wavelength illumination is necessary to render broadband multispectral optoacoustic mesoscopy (2B-MSOM) superior to previous optical or optoacoustic mesoscopy implementations.
    Biomedical Optics Express 07/2015; 6(9). DOI:10.1364/BOE.6.003134 · 3.65 Impact Factor
  • Dominik Soliman · George Tserevelakis · Murad Omar · Vasilis Ntziachristos
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    ABSTRACT: Many biological applications require a simultaneous observation of different anatomical features. However, unless potentially harmful staining of the specimens is employed, individual microscopy techniques do generally not provide multi-contrast capabilities. We present a hybrid microscope integrating optoacoustic microscopy and multiphoton microscopy, including second-harmonic generation, into a single device. This combined multiphoton and optoacoustic microscope (MPOM) offers visualization of a broad range of structures by employing different contrast mechanisms and at the same time enables pure label-free imaging of biological systems. We investigate the relative performance of the two microscopy modalities and demonstrate their multi-contrast abilities through the label-free imaging of a zebrafish larva ex vivo, simultaneously visualizing muscles and pigments. This hybrid microscopy application bears great potential for developmental biology studies, enabling more comprehensive information to be obtained from biological specimens without the necessity of staining. © (2015) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only.
    ECBO 2015, Opto-Acoustic Methods and Applications in Biophotonics II; 07/2015
  • Murad Omar · Dominik Soliman · Jérôme Gateau · Vasilis Ntziachristos
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    ABSTRACT: We have developed an epi-illumination raster-scan optoacoustic mesoscopy system (RSOM), the new system is capable of imaging model organisms, and vasculature. The newly developed system is based on a custom designed; spherically focused detector with a Characterization of the system shows an isotropic lateral resolution of 18 μm, and an axial resolution of 4 μm. The scan times are on the order of 8 minutes for a field of view of 10×10 mm2. The achieved resolution is slightly degraded up to a depth of 5 mm. After characterizing the system we showcase it’s performance on a zebrafish ex vivo, and an excised mouse ear. Additionally, to improve the visibility of small structures we have reconstructed the high frequencies, and the low frequencies separately, and at the end overplayed the two reconstructions using different colors, this way the high frequencies are not masked by the low frequencies which have a higher signal to noise ratio. © (2015) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only.
    ECBO 2015, Opto-Acoustic Methods and Applications in Biophotonics II; 07/2015
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    ABSTRACT: There is growing interest in genetically expressed reporters for in vivo studies of bacterial colonization in the context of infectious disease research, studies of the bacterial microbiome or cancer imaging and treatment. To empower non-invasive high-resolution bacterial tracking with deep tissue penetration, we herein use the genetically controlled biosynthesis of the deep-purple pigment Violacein as a photobleaching-resistant chromophore label for in vivo optoacoustic (photoacoustic) imaging in the near-infrared range. We demonstrate that Violacein-producing bacteria can be imaged with high contrast-to-noise in strongly vascularized xenografted murine tumors and further observe that Violacein shows anti-tumoral activity. Our experiments thus identify Violacein as a robust bacterial label for non-invasive optoacoustic imaging with high potential for basic research and future theranostic applications in bacterial tumor targeting.
    Scientific Reports 06/2015; 5:11048. DOI:10.1038/srep11048 · 5.58 Impact Factor
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    ABSTRACT: We reported earlier the diagnostic potential of a melanogenic vaccinia virus based system in magnetic resonance (MRI) and optoacoustic deep tissue imaging (MSOT). Since melanin overproduction lead to attenuated virus replication, we constructed a novel recombinant vaccinia virus strain (rVACV), GLV-1h462, which expressed the key enzyme of melanogenesis (tyrosinase) under the control of an inducible promoter-system. In this study melanin production was detected after exogenous addition of doxycycline in two different tumor xenograft mouse models. Furthermore , it was confirmed that this novel vaccinia virus strain still facilitated signal enhancement as detected by MRI and optoacoustic tomography. At the same time we demonstrated an enhanced oncolytic potential compared to the constitutively melanin synthesizing rVACV system.
    Theranostics 06/2015; 5(10). DOI:10.7150/thno.12533 · 8.02 Impact Factor
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    ABSTRACT: Nanosized contrast agents for molecular imaging have attracted widespread interest for diagnostic applications with high resolution in medicine. However, many solid nanoparticles exhibit a great potential to induce toxicity, hindering their use for clinical applications. On the other hand, near-infrared (NIR) dyes have also been used for extensive biological applications, but show some limitations due to their poor aqueous stability, tendency to aggregation and rapid elimination from the body. An alternative proposed in this work to overcome these limitations is the use of NIR dye-loaded nanoparticles. Here we introduce nanoparticles constructed with poly(D,L-lactide-co-glycolic acid) (PLGA), a biodegradable and biocompatible polymer widely used for biomedical applications, attached to the polycation polyethyleneimine (PEI) to obtain positively charged nanoparticles. The in vivo biodistribution of the cationic PEI-PLGA nanoparticles was investigated after administration through three different routes (intravenous, intraperitoneal and subcutaneous) using multispectral optoacoustic tomography (MSOT). The prepared nanoparticles exhibited good colloidal stability and adequate optical properties for optoacoustic imaging. The in vivo biodistribution assays indicated a strong accumulation of the particles in the liver and spleen, and retention in these organs for at least 24 h. Therefore, these nanoparticles could find promising applications in MSOT due to a sharp and characteristic optoacoustic spectrum and high optoacoustic signal generation, and become a promising building block for theranostic strategies. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
    Contrast Media & Molecular Imaging 05/2015; DOI:10.1002/cmmi.1644 · 2.92 Impact Factor
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    ABSTRACT: This study introduces a novel noninvasive differential photoacoustic method, Wavelength Modulated Differential Photoacoustic Spectroscopy (WM-DPAS), for noninvasive early cancer detection and continuous hypoxia monitoring through ultrasensitive measurements of hemoglobin oxygenation levels (StO2 ). Unlike conventional photoacoustic spectroscopy, WM-DPAS measures simultaneously two signals induced from square-wave modulated laser beams at two different wavelengths where the absorption difference between maximum deoxy- and oxy-hemoglobin is 680 nm, and minimum (zero) 808 nm (the isosbestic point). The two-wavelength measurement efficiently suppresses background, greatly enhances the signal to noise ratio and thus enables WM-DPAS to detect very small changes in total hemoglobin concentration (CHb ) and oxygenation levels, thereby identifying pre-malignant tumors before they are anatomically apparent. The non-invasive nature also makes WM-DPAS the best candidate for ICU bedside hypoxia monitoring in stroke patients. Sensitivity tunability is another special feature of the technology: WM-DPAS can be tuned for different applications such as quick cancer screening and accurate StO2 quantification by selecting a pair of parameters, signal amplitude ratio and phase shift. The WM-DPAS theory has been validated with sheep blood phantom measurements. Sensitivity comparison between conventional single-ended signal and differential signal. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Journal of Biophotonics 05/2015; DOI:10.1002/jbio.201500131 · 4.45 Impact Factor
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    ABSTRACT: While acute myocardial infarction mortality declines, patients continue to face reinfarction and/or heart failure. The immune system, which intimately interacts with healthy and diseased tissues through resident and recruited leukocytes, is a central interface for a global host response to ischemia. Pathways that enhance the systemic leukocyte supply may be potential therapeutic targets. Pre-clinically, imaging helps to identify immunity's decision nodes, which may serve as such targets. In translating the rapidly-expanding pre-clinical data on immune activity, the difficulty of obtaining multiple clinical tissue samples from involved organs is an obstacle that whole-body imaging can help overcome. In patients, molecular and cellular imaging can be integrated with blood-based diagnostics to assess the translatability of discoveries, including the activation of hematopoietic tissues after myocardial infarction, and serve as an endpoint in clinical trials. In this review, we discuss these concepts while focusing on imaging immune activity in organs involved in ischemic heart disease. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
    Journal of the American College of Cardiology 04/2015; 65(15):1583-1591. DOI:10.1016/j.jacc.2015.02.034 · 16.50 Impact Factor
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    ABSTRACT: Wide-field targeted fluorescence evolves as a promising approach for interventional guidance. We present an overview of the key developments from our laboratory and discuss their potential to shift the surgical and endoscopic imaging paradigm.
  • Adrian Taruttis · Gooitzen M van Dam · Vasilis Ntziachristos
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    ABSTRACT: Optoacoustic imaging combines the rich contrast of optical methods with the resolution of ultrasound imaging. It can therefore deliver optical visualization of cancer far deeper in tissue than optical microscopy and other conventional optical imaging methods. Technological progress and novel contrast media have resulted in optoacoustic imaging being propagated to basic cancer research and in clinical translation projects. We briefly review recent technological advances, showcase the ability to resolve unique cancer biomarkers based on spectral features at different imaging scales, and highlight the imaging performance achieved in preclinical and clinical imaging applications. Cancer Res; 75(8); 1-12. ©2015 AACR. ©2015 American Association for Cancer Research.
    Cancer Research 04/2015; 75(8). DOI:10.1158/0008-5472.CAN-14-2522 · 9.33 Impact Factor
  • Gael Diot · Alexander Dima · Vasilis Ntziachristos
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    ABSTRACT: Unlike near-infrared spectroscopy, multispectral opto-acoustic tomography (MSOT) has the potential to offer high-resolution imaging assessment of hemodynamics and blood saturation levels in muscle. However motion artifacts impede the real-time applications of the technique. We developed fast-MSOT with motion tracking that reduces motion artifacts. We used this algorithm to follow blood oxygenation level changes associated with muscle exercise in the muscle and the skin of healthy volunteers.
    Optics Letters 04/2015; 40(7):1496-9. · 3.29 Impact Factor

Publication Stats

15k Citations
1,676.19 Total Impact Points


  • 2008–2015
    • Helmholtz Zentrum München
      • Institute for Biological and Medical Imaging
      München, Bavaria, Germany
  • 2007–2015
    • Technische Universität München
      • Institute for Biological and Medical Imaging (IBMI)
      München, Bavaria, Germany
  • 2001–2014
    • Harvard Medical School
      • • Department of Medicine
      • • Department of Radiology
      Boston, Massachusetts, United States
  • 2013
    • The International Society for Optics and Photonics
      International Falls, Minnesota, United States
  • 2011
    • University Hospital München
      München, Bavaria, Germany
  • 2002–2010
    • Massachusetts General Hospital
      • • Cardiovascular Research Center
      • • Center for Systems Biology
      • • Center for Molecular Imaging Research
      • • Molecular Biology Laboratory
      Boston, MA, United States
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2006–2009
    • Northeastern University
      • Department of Electrical and Computer Engineering
      Boston, MA, United States
  • 2004–2006
    • Foundation for Research and Technology - Hellas
      • Institute of Electronic Structure and Laser (IESL)
      Megalokastro, Crete, Greece
  • 2005
    • Inje University
      • Department of Computer Engineering
      Kŭmhae, Gyeongsangnam-do, South Korea
  • 1998–2003
    • University of Pennsylvania
      • • Department of Biochemistry and Biophysics
      • • Department of Physics and Astronomy
      • • Department of Radiology
      Philadelphia, PA, United States