Vasilis Ntziachristos

Helmholtz Zentrum München, München, Bavaria, Germany

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Publications (526)1758.86 Total impact

  • Teresa Correia · Maximilian Koch · Angelique Ale · Vasilis Ntziachristos · Simon Arridge
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    ABSTRACT: Fluorescence diffuse optical tomography (fDOT) provides 3D images of fluorescence distributions in biological tissue, which represent molecular and cellular processes. The image reconstruction problem is highly ill-posed and requires regularisation techniques to stabilise and find meaningful solutions. Quadratic regularisation tends to either oversmooth or generate very noisy reconstructions, depending on the regularisation strength. Edge preserving methods, such as anisotropic diffusion regularisation (AD), can preserve important features in the fluorescence image and smooth out noise. However, AD has limited ability to distinguish an edge from noise. We propose a patch-based anisotropic diffusion regularisation (PAD), where regularisation strength is determined by a weighted average according to the similarity between patches around voxels within a search window, instead of a simple local neighbourhood strategy. However, this method has higher computational complexity and, hence, we wavelet compress the patches (PAD-WT) to speed it up, while simultaneously taking advantage of the denoising properties of wavelet thresholding. Furthermore, structural information can be incorporated into the image reconstruction with PAD-WT to improve image quality and resolution. In this case, the weights used to average voxels in the image are calculated using the structural image, instead of the fluorescence image. The regularisation strength depends on both structural and fluorescence images, which guarantees that the method can preserve fluorescence information even when it is not structurally visible in the anatomical images. In part 1, we tested the method using a denoising problem. Here, we use simulated and in vivo mouse fDOT data to assess the algorithm performance. Our results show that the proposed PAD-WT method provides high quality and noise free images, superior to those obtained using AD.
    No preview · Article · Jan 2016 · Physics in Medicine and Biology

  • No preview · Article · Jan 2016 · Journal of Biomedical Optics
  • Maximilian Koch · Vasilis Ntziachristos
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    ABSTRACT: Surgical success depends on the accuracy with which disease and vital tissue can be intraoperatively detected. However, the dominant visualization approach, i.e., human vision, does not see under the tissue surface and operates on low contrast between sites of disease, such as cancer, and the surrounding tissue. Intraoperative fluorescence imaging is emerging as a highly effective method to improve surgical vision and offers the potential to be intergrated seamlessly into the normal workflow of the operating room without causing disruption or undue delay. We review and compare two critical fluorescence imaging directions: one that uses nonspecific fluorescence dyes, addressing tissue perfusion and viability, and one that uses targeted agents, interrogating pathophysiological features of disease. These two approaches present detection sensitivity challenges that may differ by orders of magnitude and require different detection strategies. Nevertheless, fluorescence imaging provides the surgeon with previously unavailable real-time feedback that improves surgical precision and can become essential for interventional decision-making.
    No preview · Article · Jan 2016 · Annual Review of Medicine
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    ABSTRACT: A handheld approach to optoacoustic imaging is essential for the clinical translation. The first 2- and 3-dimensional handheld multispectral optoacoustic tomography (MSOT) probes featuring real-time unmixing have recently been developed. Imaging performance of both probes was determined in vitro and in a brain melanoma metastasis mouse model in vivo. T1-weighted MR images were acquired for anatomical reference. The limit of detection of melanoma cells in vitro was significantly lower using the 2D than the 3D probe. The signal decrease was more profound in relation to depth with the 3D versus the 2D probe. Both approaches were capable of imaging the melanoma tumors qualitatively at all time points. Quantitatively, the 2D approach enabled closer anatomical resemblance of the tumor compared to the 3D probe, particularly at depths beyond 3mm. The 3D probe was shown to be superior for rapid 3D imaging and, thus, holds promise for more superficial target structures.
    Full-text · Article · Jan 2016 · Photoacoustics
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    Yiyong Han · Vasilis Ntziachristos · Amir Rosenthal

    Full-text · Article · Jan 2016 · Journal of Biomedical Optics
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    ABSTRACT: Methods: VEGF-A and EGFR expression was determined by immunohistochemistry on a large subset of human colorectal tissue samples: 48 sessile serrated adenomas/polyps (SSA/P), 70 sporadic high-grade dysplastic (HGD) adenomas, 19 hyperplastic polyps (HP) and tissue derived from patients with Lynch syndrome (LS): 78 low-grade dysplastic (LGD) adenomas, 57 HGD adenomas and 31 colon cancer samples. To perform an ex vivo colonoscopy procedure, 14 mice with small intraperitoneal EGFR-positive HCT116luc tumors received intravenously bevacizumab-800CW (anti-VEGF-A), cetuximab-800CW (anti-EGFR), control tracer IgG-800CW or sodium chloride. Three days later, 8 resected HCT116luc tumors (2-5 mm) were stitched into one freshly resected human colon specimen and followed by an ex vivo molecular-guided colonoscopy procedure. Results: Immunohistochemistry showed high VEGF-A expression in 79-96% and high EGFR expression in 51-69% of the colorectal lesions. Both targets were significantly overexpressed in the colorectal lesions compared to the adjacent normal colon crypts. During ex vivo molecular-guided endoscopy all tumors could clearly be delineated for both bevacizumab-800CW and cetuximab-800CW tracers. Specific tumor uptake was confirmed with fluorescent microscopy showing respectively stromal and cell membrane fluorescence. Conclusion: VEGF-A is a promising target for molecular-guided fluorescence endoscopy as it showed a high protein expression, especially in SSA/P and LS. We demonstrate the feasibility to visualize small tumors real-time during colonoscopy using a NIR fluorescence endoscopy platform, providing the endoscopist a wide-field 'red-flag' technique for adenoma detection. Clinical studies are currently being performed in order to provide in-human evaluation of our approach.
    Full-text · Article · Dec 2015 · Journal of Nuclear Medicine
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    ABSTRACT: Light propagating in tissue attains a spectrum that varies with location due to wavelength-dependent fluence attenuation by tissue optical properties, an effect that causes spectral corruption. Predictions of the spectral variations of light fluence in tissue are challenging since the spatial distribution of optical properties in tissue cannot be resolved in high resolution or with high accuracy by current methods. Spectral corruption has fundamentally limited the quantification accuracy of optical and optoacoustic methods and impeded the long sought-after goal of imaging blood oxygen saturation (sO2) deep in tissues; a critical but still unattainable target for the assessment of oxygenation in physiological processes and disease. We discover a new principle underlying light fluence in tissues, which describes the wavelength dependence of light fluence as an affine function of a few reference base spectra, independently of the specific distribution of tissue optical properties. This finding enables the introduction of a previously undocumented concept termed eigenspectra Multispectral Optoacoustic Tomography (eMSOT) that can effectively account for wavelength dependent light attenuation without explicit knowledge of the tissue optical properties. We validate eMSOT in more than 2000 simulations and with phantom and animal measurements. We find that eMSOT can quantitatively image tissue sO2 reaching in many occasions a better than 10-fold improved accuracy over conventional spectral optoacoustic methods. Then, we show that eMSOT can spatially resolve sO2 in muscle and tumor; revealing so far unattainable tissue physiology patterns. Last, we related eMSOT readings to cancer hypoxia and found congruence between eMSOT tumor sO2 images and tissue perfusion and hypoxia maps obtained by correlative histological analysis.
    Full-text · Article · Nov 2015
  • Mathias Schwarz · Andreas Buehler · Juan Aguirre · Vasilis Ntziachristos
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    ABSTRACT: Optical imaging plays a major role in disease detection in dermatology. However, current optical methods are limited by lack of three-dimensional detection of pathophysiological parameters within skin. It was recently shown that single-wavelength optoacoustic (photoacoustic) mesoscopy resolves skin morphology, i.e. melanin and blood vessels within epidermis and dermis. In this work we employed illumination at multiple wavelengths for enabling three-dimensional multispectral optoacoustic mesoscopy (MSOM) of natural chromophores in human skin in vivo operating at 15-125 MHz. We employ a per-pulse tunable laser to inherently co-register spectral datasets, and reveal previously undisclosed insights of melanin, and blood oxygenation in human skin. We further reveal broadband absorption spectra of specific skin compartments. We discuss the potential of MSOM for label-free visualization of physiological biomarkers in skin in vivo. Cross-sectional optoacoustic image of human skin in vivo. The epidermal layer is characterized by melanin absorption. A vascular network runs through the dermal layer, exhibiting blood oxygenation values of 50-90%. All scale bars: 250 µm.
    No preview · Article · Nov 2015 · Journal of Biophotonics
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    ABSTRACT: High fidelity optoacoustic (photoacoustic) tomography requires dense spatial sampling of optoacoustic signals using point acoustic detectors. However, in practice, spatial resolution of the images is often limited by limited sampling either due to coarse multi-element arrays or time in raster scan measurements. Herein, we investigate a method that integrates information from multiple optoacoustic images acquired at sub-diffraction steps into one high resolution image by means of an iterative registration algorithm. Experimental validations performed in target phantoms and ex-vivo tissue samples confirm that the suggested approach renders significant improvements in terms of optoacoustic image resolution and quality without introducing significant alterations into the signal acquisition hardware or inversion algorithms.
    Full-text · Article · Oct 2015 · IEEE Transactions on Medical Imaging
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    ABSTRACT: Quantification of tumor necrosis in cancer patients is of diagnostic value as the amount of necrosis is correlated with disease prognosis and it could also be used to predict early efficacy of anti-cancer treatments. In the present study, we identified two near infrared fluorescent (NIRF) carboxylated cyanines, HQ5 and IRDye 800CW (800CW), which possess strong necrosis avidity. In vitro studies showed that both dyes selectively bind to cytoplasmic proteins of dead cells that have lost membrane integrity. Affinity for cytoplasmic proteins was confirmed using quantitative structure activity relations modeling. In vivo results, using NIRF and optoacoustic imaging, confirmed the necrosis avid properties of HQ5 and 800CW in a mouse 4T1 breast cancer tumor model of spontaneous necrosis. Finally, in a mouse EL4 lymphoma tumor model, already 24 h post chemotherapy, a significant increase in 800CW fluorescence intensity was observed in treated compared to untreated tumors. In conclusion, we show, for the first time, that the NIRF carboxylated cyanines HQ5 and 800CW possess strong necrosis avid properties in vitro and in vivo. When translated to the clinic, these dyes may be used for diagnostic or prognostic purposes and for monitoring in vivo tumor response early after the start of treatment.
    Full-text · Article · Oct 2015 · Oncotarget
  • Hailong He · Andreas Buehler · Vasilis Ntziachristos
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    ABSTRACT: The optoacoustic (photoacoustic) technique has been shown to resolve anatomical, functional, and molecular features at depths that go beyond the reach of epi-illumination optical microscopy, offering new opportunities for endoscopic imaging. In this Letter, we investigate the merits of optoacoustic endoscopy implemented by translating a sound detector in linear or curved geometries. The linear and curved detection geometries are achieved by employing an intravascular ultrasound transducer within a plastic guide shaped to a line or a curve. This concept could be used together with optical endoscopes to yield hybrid optical and optoacoustic imaging.
    No preview · Article · Oct 2015 · Optics Letters
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    ABSTRACT: The concept of sparsity is extensively exploited in the fields of data acquisition and image processing, contributing to better signal-to-noise and spatio-temporal performance of the various imaging methods. In the field of optoacoustic tomography, the image reconstruction problem is often characterized by computationally extensive inversion of very large datasets, for instance when acquiring volumetric multispectral data with high temporal resolution. In this article we seek to accelerate accurate model-based optoacoustic inversions by identifying various sources of sparsity in the forward and inverse models as well as in the single- and multi-frame representation of the projection data. These sources of sparsity are revealed through appropriate transformations in the signal, model and image domains and are subsequently exploited for expediting image reconstruction. The sparsity-based inversion scheme was tested with experimental data, offering reconstruction speed enhancement by a factor of 40 to 700 times as compared with the conventional iterative model-based inversions while preserving similar image quality. The demonstrated results pave the way for achieving real-time performance of model-based reconstruction in multi-dimensional optoacoustic imaging.
    Full-text · Article · Oct 2015
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    ABSTRACT: Discerning the accurate distribution of chromophores and biomarkers by means of optoacoustic imaging is commonly challenged by the highly heterogeneous excitation light patterns resulting from strong spatial variations of tissue scattering and absorption. Here we used the light-fluence dependent switching kinetics of reversibly switchable fluorescent proteins (RSFPs), in combination with real-time acquisition of volumetric multi-spectral optoacoustic data to correct for the light fluence distribution deep in scattering media. The new approach allows for dynamic fluence correction in time-resolved imaging, e.g., of moving organs, and can be extended to work with a large palette of available synthetic and genetically encoded photochromic substances for multiplexed wavelength-specific fluence normalization.
    Full-text · Article · Oct 2015 · Optics Letters
  • J. Ripoll · B. Koberstein-Schwarz · V. Ntziachristos
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    ABSTRACT: The past decade marked an optical revolution in biology: an unprecedented number of optical techniques were developed and adopted for biological exploration, demonstrating increasing interest in optical imaging and in vivo interrogations. Optical methods have become faster and have reached nanoscale resolution, and are now complemented by optoacoustic (photoacoustic) methods capable of imaging whole specimens in vivo. Never before were so many optical imaging barriers broken in such a short time-frame: with new approaches to optical microscopy and mesoscopy came an increased ability to image biology at unprecedented speed, resolution, and depth. This review covers the most relevant techniques for imaging in developmental biology, and offers an outlook on the next steps for these technologies and their applications.
    No preview · Article · Oct 2015 · Trends in Biotechnology
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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.
    Full-text · Article · Sep 2015 · Mechanisms of development
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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.
    Full-text · Article · Sep 2015 · European Radiology
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    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.
    Full-text · Article · Sep 2015 · Medical Physics
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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.
    Full-text · Article · Sep 2015 · Chemical Communications
  • 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.
    No preview · Article · Sep 2015
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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.
    Full-text · Article · Sep 2015 · Biomedical Optics Express

Publication Stats

17k Citations
1,758.86 Total Impact Points


  • 2008-2016
    • 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
  • 2002-2015
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2001-2014
    • Harvard Medical School
      • • Department of Medicine
      • • Department of Radiology
      Boston, Massachusetts, United States
  • 2011
    • University Hospital München
      München, Bavaria, Germany
  • 2007-2009
    • Northeastern University
      • Department of Electrical and Computer Engineering
      Boston, MA, United States
  • 2002-2008
    • Massachusetts General Hospital
      • • Center for Molecular Imaging Research
      • • Molecular Biology Laboratory
      Boston, Massachusetts, United States
  • 2005
    • Inje University
      • Department of Computer Engineering
      Kŭmhae, Gyeongsangnam-do, South Korea
  • 2004-2005
    • Foundation for Research and Technology - Hellas
      • Institute of Electronic Structure and Laser (IESL)
      Megalokastro, Crete, Greece
  • 1998-2003
    • University of Pennsylvania
      • • Department of Biochemistry and Biophysics
      • • Department of Physics and Astronomy
      • • Department of Radiology
      Philadelphia, PA, United States