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1.  Optimal self-calibration of tomographic reconstruction parameters in whole-body small animal optoacoustic imaging 
Photoacoustics  2014;2(3):128-136.
In tomographic optoacoustic imaging, multiple parameters related to both light and ultrasound propagation characteristics of the medium need to be adequately selected in order to accurately recover maps of local optical absorbance. Speed of sound in the imaged object and surrounding medium is a key parameter conventionally assumed to be uniform. Mismatch between the actual and predicted speed of sound values may lead to image distortions but can be mitigated by manual or automatic optimization based on metrics of image sharpness. Although some simple approaches based on metrics of image sharpness may readily mitigate distortions in the presence of highly contrasting and sharp image features, they may not provide an adequate performance for smooth signal variations as commonly present in realistic whole-body optoacoustic images from small animals. Thus, three new hybrid methods are suggested in this work, which are shown to outperform well-established autofocusing algorithms in mouse experiments in vivo.
PMCID: PMC4244639  PMID: 25431756
Optoacoustic imaging; Speed of sound; Focus measures; Image reconstruction; In vivo imaging; Image processing
2.  Functional optoacoustic imaging of moving objects using microsecond-delay acquisition of multispectral three-dimensional tomographic data 
Scientific Reports  2014;4:5878.
The breakthrough capacity of optoacoustics for three-dimensional visualization of dynamic events in real time has been recently showcased. Yet, efficient spectral unmixing for functional imaging of entire volumetric regions is significantly challenged by motion artifacts in concurrent acquisitions at multiple wavelengths. Here, we introduce a method for simultaneous acquisition of multispectral volumetric datasets by introducing a microsecond-level delay between excitation laser pulses at different wavelengths. Robust performance is demonstrated by real-time volumetric visualization of functional blood parametrers in human vasculature with a handheld matrix array optoacoustic probe. This approach can avert image artifacts imposed by velocities greater than 2 m/s, thus, does not only facilitate imaging influenced by respiratory, cardiac or other intrinsic fast movements in living tissues, but can achieve artifact-free imaging in the presence of more significant motion, e.g. abrupt displacements during handheld-mode operation in a clinical environment.
PMCID: PMC4115207  PMID: 25073504
3.  Functional Real-Time Optoacoustic Imaging of Middle Cerebral Artery Occlusion in Mice 
PLoS ONE  2014;9(4):e96118.
Background and Purpose
Longitudinal functional imaging studies of stroke are key in identifying the disease progression and possible therapeutic interventions. Here we investigate the applicability of real-time functional optoacoustic imaging for monitoring of stroke progression in the whole brain of living animals.
Materials and Methods
The middle cerebral artery occlusion (MCAO) was used to model stroke in mice, which were imaged preoperatively and the occlusion was kept in place for 60 minutes, after which optoacoustic scans were taken at several time points.
Post ischemia an asymmetry of deoxygenated hemoglobin in the brain was observed as a region of hypoxia in the hemisphere affected by the ischemic event. Furthermore, we were able to visualize the penumbra in-vivo as a localized hemodynamically-compromised area adjacent to the region of stroke-induced perfusion deficit.
The intrinsic sensitivity of the new imaging approach to functional blood parameters, in combination with real time operation and high spatial resolution in deep living tissues, may see it become a valuable and unique tool in the development and monitoring of treatments aimed at suspending the spread of an infarct area.
PMCID: PMC4002478  PMID: 24776997
4.  Functional optoacoustic human angiography with handheld video rate three dimensional scanner☆ 
Photoacoustics  2013;1(3-4):68-73.
Optoacoustic imaging provides a unique combination of high optical contrast and excellent spatial resolution, making it ideal for simultaneous imaging of tissue anatomy as well as functional and molecular contrast in deep optically opaque tissues. We report on development of a portable clinical system for three-dimensional optoacoustic visualization of deep human tissues at video rate. Studies in human volunteers have demonstrated powerful performance in delivering high resolution volumetric multispectral optoacoustic tomography (vMSOT) images of tissue morphology and function, such as blood oxygenation parameters, in real time. Whilst most imaging modalities currently in clinical use are not able to deliver volumetric data with comparable time resolution, the presented imaging approach holds promise to attain new diagnostic and treatment monitoring value for multiple indications, such as cardiovascular and peripheral vascular disease, disorders related to the lymphatic system, breast lesions, arthritis and inflammation.
PMCID: PMC4134902  PMID: 25302151
Optoacoustic imaging; Cardiovascular diagnostics; Functional and molecular imaging
5.  Optoacoustic Imaging and Tomography: Reconstruction Approaches and Outstanding Challenges in Image Performance and Quantification 
Sensors (Basel, Switzerland)  2013;13(6):7345-7384.
This paper comprehensively reviews the emerging topic of optoacoustic imaging from the image reconstruction and quantification perspective. Optoacoustic imaging combines highly attractive features, including rich contrast and high versatility in sensing diverse biological targets, excellent spatial resolution not compromised by light scattering, and relatively low cost of implementation. Yet, living objects present a 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 quantified information on the actual distribution of tissue chromophores and other biomarkers constitutes therefore a challenging problem. Image quantification is further compromised by some frequently-used approximated inversion formulae. In this review, the currently available optoacoustic image reconstruction and quantification approaches are assessed, including back-projection and model-based inversion algorithms, sparse signal representation, wavelet-based approaches, methods for reduction of acoustic artifacts as well as multi-spectral methods for visualization of tissue bio-markers. Applicability of the different methodologies is further analyzed in the context of real-life performance in small animal and clinical in-vivo imaging scenarios.
PMCID: PMC3715274  PMID: 23736854
optoacoustic imaging; photoacoustic tomography; image reconstruction; quantification; multispectral optoacoustic tomography; inverse problem; light transport; spectroscopic imaging
6.  Fast scanning coaxial optoacoustic microscopy 
Biomedical Optics Express  2012;3(7):1724-1731.
The hybrid nature of optoacoustic imaging might impose limitations on concurrent placement of optical and ultrasonic detection components, especially in high resolution microscopic applications that require dense arrangements and miniaturization of components. This hinders optimal deployment of the optical excitation and ultrasonic detection paths, leading to reduction of imaging speed and spatial resolution performance. We suggest a compact coaxial design for optoacoustic microscopy that allows optimizing both the light illumination and ultrasonic detection parameters of the imaging system. System performance is showcased in phantoms and in vivo imaging of microvasculature, achieving real time operation in two dimensions and penetration of 6 mm into optically dense human tissues.
PMCID: PMC3395494  PMID: 22808441
(170.5120) Photoacoustic imaging; (110.6880) Three-dimensional image acquisition; (170.3880) Medical and biological imaging; (120.3890) Medical optics instrumentation
7.  Mapping Molecular Agents Distributions in Whole Mice Hearts Using Born-Normalized Optical Projection Tomography 
PLoS ONE  2012;7(4):e34427.
To date there is a lack of tools to map the spatio-temporal dynamics of diverse cells in experimental heart models. Conventional histology is labor intensive with limited coverage, whereas many imaging techniques do not have sufficiently high enough spatial resolution to map cell distributions. We have designed and built a high resolution, dual channel Born-normalized near-infrared fluorescence optical projection tomography system to quantitatively and spatially resolve molecular agents distribution within whole murine heart. We validated the use of the system in a mouse model of monocytes/macrophages recruitment during myocardial infarction. While acquired, data were processed and reconstructed in real time. Tomographic analysis and visualization of the key inflammatory components were obtained via a mathematical formalism based on left ventricular modeling. We observed extensive monocyte recruitment within and around the infarcted areas and discovered that monocytes were also extensively recruited into non-ischemic myocardium, beyond that of injured tissue, such as the septum.
PMCID: PMC3324534  PMID: 22509302
8.  High resolution tumor targeting in living mice by means of multispectral optoacoustic tomography 
EJNMMI Research  2012;2:14.
Tumor targeting is of high clinical and biological relevance, and major efforts have been made to develop molecular imaging technologies for visualization of the disease markers in tissue. Of particular interest is apoptosis which has a profound role within tumor development and has significant effect on cancer malignancy.
Herein, we report on targeting of phosphatidylserine-exposing cells within live tumor allograft models using a synthetic near infrared zinc(II)-dipicolylamine probe. Visualization of the probe biodistribution is performed with whole body multispectral optoacoustic tomography (MSOT) system and subsequently compared to results attained by planar and tomographic fluorescence imaging systems.
Compared to whole body optical visualization methods, MSOT attains remarkably better imaging capacity by delivering high-resolution scans of both disease morphology and molecular function in real time. Enhanced resolution of MSOT clearly showed that the probe mainly localizes in the vessels surrounding the tumor, suggesting that its tumor selectivity is gained by targeting the phosphatidylserine exposed on the surface of tumor vessels.
The current study demonstrates the high potential of MSOT to broadly impact the fields of tumor diagnostics and preclinical drug development.
PMCID: PMC3337810  PMID: 22464315
Optoacoustic imaging; Tumor targeting; Molecular imaging; Phosphatidylserine targeting
9.  Fast Multispectral Optoacoustic Tomography (MSOT) for Dynamic Imaging of Pharmacokinetics and Biodistribution in Multiple Organs 
PLoS ONE  2012;7(1):e30491.
The characterization of pharmacokinetic and biodistribution profiles is an essential step in the development process of new candidate drugs or imaging agents. Simultaneously, the assessment of organ function related to the uptake and clearance of drugs is of great importance. To this end, we demonstrate an imaging platform capable of high-rate characterization of the dynamics of fluorescent agents in multiple organs using multispectral optoacoustic tomography (MSOT). A spatial resolution of approximately 150 µm through mouse cross-sections allowed us to image blood vessels, the kidneys, the liver and the gall bladder. In particular, MSOT was employed to characterize the removal of indocyanine green from the systemic circulation and its time-resolved uptake in the liver and gallbladder. Furthermore, it was possible to track the uptake of a carboxylate dye in separate regions of the kidneys. The results demonstrate the acquisition of agent concentration metrics at rates of 10 samples per second at a single wavelength and 17 s per multispectral sample with 10 signal averages at each of 5 wavelengths. Overall, such imaging performance introduces previously undocumented capabilities of fast, high resolution in vivo imaging of the fate of optical agents for drug discovery and basic biological research.
PMCID: PMC3266258  PMID: 22295087
10.  Multispectral Optoacoustic Tomography of Matrix Metalloproteinase Activity in Vulnerable Human Carotid Plaques 
Molecular Imaging and Biology  2011;14(3):277-285.
Elevated expression of cathepsins, integrins and matrix metalloproteinases (MMPs) is typically associated with atherosclerotic plaque instability. While fluorescent tagging of such molecules has been amply demonstrated, no imaging method was so far shown capable of resolving these inflammation-associated tags with high fidelity and resolution beyond microscopic depths. This study is aimed at demonstrating a new method with high potential for noninvasive clinical cardiovascular diagnostics of vulnerable plaques using high-resolution deep-tissue multispectral optoacoustic tomography (MSOT) technology.
Methods and results
MMP-sensitive activatable fluorescent probe (MMPSense™ 680) was applied to human carotid plaques from symptomatic patients. Atherosclerotic activity was detected by tuning MSOT wavelengths to activation-dependent absorption changes of the molecules, structurally modified in the presence of enzymes. MSOT analysis simultaneously provided morphology along with heterogeneous MMP activity with better than 200 micron resolution throughout the intact plaque tissue. The results corresponded well with epi-fluorescence images made from thin cryosections. Elevated MMP activity was further confirmed by in situ zymography, accompanied by increased macrophage influx.
We demonstrated, for the first time to our knowledge, the ability of MSOT to provide volumetric images of activatable molecular probe distribution deep within optically diffuse tissues. High-resolution mapping of MMP activity was achieved deep in the vulnerable plaque of intact human carotid specimens. This performance directly relates to pre-clinical screening applications in animal models and to clinical decision potential as it might eventually allow for highly specific visualization and staging of plaque vulnerability thus impacting therapeutic clinical decision making.
PMCID: PMC3346936  PMID: 21720908
Atherosclerosis; Optoacoustic imaging; Carotid arteries; Plaque; Contrast media; Inflammation; Medicine & Public Health; Imaging / Radiology
11.  Born Normalization for Fluorescence Optical Projection Tomography for Whole Heart Imaging 
Optical projection tomography is a three-dimensional imaging technique that has been recently introduced as an imaging tool primarily in developmental biology and gene expression studies. The technique renders biological sample optically transparent by first dehydrating them and then placing in a mixture of benzyl alcohol and benzyl benzoate in a 2:1 ratio (BABB or Murray s Clear solution). The technique renders biological samples optically transparent by first dehydrating them in graded ethanol solutions then placing them in a mixture of benzyl alcohol and benzyl benzoate in a 2:1 ratio (BABB or Murray s Clear solution) to clear. After the clearing process the scattering contribution in the sample can be greatly reduced and made almost negligible while the absorption contribution cannot be eliminated completely. When trying to reconstruct the fluorescence distribution within the sample under investigation, this contribution affects the reconstructions and leads, inevitably, to image artifacts and quantification errors.. While absorption could be reduced further with a permanence of weeks or months in the clearing media, this will lead to progressive loss of fluorescence and to an unrealistically long sample processing time. This is true when reconstructing both exogenous contrast agents (molecular contrast agents) as well as endogenous contrast (e.g. reconstructions of genetically expressed fluorescent proteins).
PMCID: PMC2794886  PMID: 19578329
12.  Imaging of molecular probe activity with Born-normalized fluorescence optical projection tomography 
Optics letters  2010;35(7):1088-1090.
Optical projection tomography is a new ex vivo imaging technique that allows imaging of whole organs in three dimensions at high spatial resolutions. In this Letter we demonstrate its capability to tomographically visualize molecular activity in whole organs of mice. In particular, eosinophil activity in asthmatic lungs is resolved using a Born-normalized fluorescence optical projection tomography and employing a near-IR molecular probe. The possibility to achieve molecularly sensitive imaging contrast in optical projection tomography by means of targeted and activatable imaging reporter agents adds a new range of capabilities for investigating molecular signatures of pathophysiological processes and a wide variety of diseases and their development.
PMCID: PMC2900933  PMID: 20364226
13.  Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood-brain barrier: perspectives on tracking and neuroimaging 
Nanotechnology has brought a variety of new possibilities into biological discovery and clinical practice. In particular, nano-scaled carriers have revolutionalized drug delivery, allowing for therapeutic agents to be selectively targeted on an organ, tissue and cell specific level, also minimizing exposure of healthy tissue to drugs. In this review we discuss and analyze three issues, which are considered to be at the core of nano-scaled drug delivery systems, namely functionalization of nanocarriers, delivery to target organs and in vivo imaging. The latest developments on highly specific conjugation strategies that are used to attach biomolecules to the surface of nanoparticles (NP) are first reviewed. Besides drug carrying capabilities, the functionalization of nanocarriers also facilitate their transport to primary target organs. We highlight the leading advantage of nanocarriers, i.e. their ability to cross the blood-brain barrier (BBB), a tightly packed layer of endothelial cells surrounding the brain that prevents high-molecular weight molecules from entering the brain. The BBB has several transport molecules such as growth factors, insulin and transferrin that can potentially increase the efficiency and kinetics of brain-targeting nanocarriers. Potential treatments for common neurological disorders, such as stroke, tumours and Alzheimer's, are therefore a much sought-after application of nanomedicine. Likewise any other drug delivery system, a number of parameters need to be registered once functionalized NPs are administered, for instance their efficiency in organ-selective targeting, bioaccumulation and excretion. Finally, direct in vivo imaging of nanomaterials is an exciting recent field that can provide real-time tracking of those nanocarriers. We review a range of systems suitable for in vivo imaging and monitoring of drug delivery, with an emphasis on most recently introduced molecular imaging modalities based on optical and hybrid contrast, such as fluorescent protein tomography and multispectral optoacoustic tomography. Overall, great potential is foreseen for nanocarriers in medical diagnostics, therapeutics and molecular targeting. A proposed roadmap for ongoing and future research directions is therefore discussed in detail with emphasis on the development of novel approaches for functionalization, targeting and imaging of nano-based drug delivery systems, a cutting-edge technology poised to change the ways medicine is administered.
PMCID: PMC2847536  PMID: 20199661
14.  Normalized Born ratio for fluorescence optical projection tomography 
Optics letters  2009;34(3):319-321.
We present a normalized Born approach for fluorescence optical projection tomography that takes into account tissue absorption properties. This approach can be particularly useful to study fluorochrome distribution within tissue. We use the algorithm to three-dimensionally reconstruct and characterize a fluorescein isothiocyanate containing absorptive phantom and an infarcted mouse heart previously injected with a fluorescent molecular probe.
PMCID: PMC2771918  PMID: 19183644
15.  Transillumination fluorescence imaging in mice using biocompatible upconverting nanoparticles 
Optics letters  2009;34(17):2566-2568.
We report on a systematic study of upconverting fluorescence signal generation within turbid phantoms and real tissues. An accurate three-point Green's function, describing the forward model of photon propagation, is established and experimentally validated. We further demonstrate, for the first time to our knowledge, autofluorescence-free transillumination imaging of mice that have received biocompatible upconverting nanoparticles. The method holds great promise for artifact-free whole-body visualization of optical molecular probes.
PMCID: PMC2749971  PMID: 19724491
16.  Mesoscopic Fluorescence Tomography for In-vivo Imaging of Developing Drosophila 
Visualizing developing organ formation as well as progession and treatment of disease often heavily relies on the ability to optically interrogate molecular and functional changes in intact living organisms. Most existing optical imaging methods are inadequate for imaging at dimensions that lie between the penetration limits of modern optical microscopy (0.5–1mm) and the diffusion-imposed limits of optical macroscopy (>1cm) [1]. Thus, many important model organisms, e.g. insects, animal embryos or small animal extremities, remain inaccessible for in-vivo optical imaging.
Although there is increasing interest towards the development of nanometer-resolution optical imaging methods, there have not been many successful efforts in improving the imaging penetration depth. The ability to perform in-vivo imaging beyond microscopy limits is in fact met with the difficulties associated with photon scattering present in tissues. Recent efforts to image entire embryos for example [2,3] require special chemical treatment of the specimen, to clear them from scattering, a procedure that makes them suitable only for post-mortem imaging. These methods however evidence the need for imaging larger specimens than the ones usually allowed by two-photon or confocal microscopy, especially in developmental biology and in drug discovery.
We have developed a new optical imaging technique named Mesoscopic Fluorescence Tomography [4], which appropriate for non-invasive in-vivo imaging at dimensions of 1mm–5mm. The method exchanges resolution for penetration depth, but offers unprecedented tomographic imaging performance and it has been developed to add time as a new dimension in developmental biology observations (and possibly other areas of biological research) by imparting the ability to image the evolution of fluorescence-tagged responses over time. As such it can accelerate studies of morphological or functional dependencies on gene mutations or external stimuli, and can importantly, capture the complete picture of development or tissue function by allowing longitudinal time-lapse visualization of the same, developing organism.
The technique utilizes a modified laboratory microscope and multi-projection illumination to collect data at 360-degree projections. It applies the Fermi simplification to Fokker-Plank solution of the photon transport equation, combined with geometrical optics principles in order to build a realistic inversion scheme suitable for mesoscopic range. This allows in-vivo whole-body visualization of non-transparent three-dimensional structures in samples up to several millimeters in size.
We have demonstrated the in-vivo performance of the technique by imaging three-dimensional structures of developing Drosophila tissues in-vivo and by following the morphogenesis of the wings in the opaque Drosophila pupae in real time over six consecutive hours.
PMCID: PMC2736679  PMID: 19696720
17.  Acoustic Inversion in Optoacoustic Tomography: A Review 
Current Medical Imaging Reviews  2013;9(4):318-336.
Optoacoustic tomography enables volumetric imaging with optical contrast in biological tissue at depths beyond the optical mean free path by the use of optical excitation and acoustic detection. The hybrid nature of optoacoustic tomography gives rise to two distinct inverse problems: The optical inverse problem, related to the propagation of the excitation light in tissue, and the acoustic inverse problem, which deals with the propagation and detection of the generated acoustic waves. Since the two inverse problems have different physical underpinnings and are governed by different types of equations, they are often treated independently as unrelated problems. From an imaging standpoint, the acoustic inverse problem relates to forming an image from the measured acoustic data, whereas the optical inverse problem relates to quantifying the formed image. This review focuses on the acoustic aspects of optoacoustic tomography, specifically acoustic reconstruction algorithms and imaging-system practicalities. As these two aspects are intimately linked, and no silver bullet exists in the path towards high-performance imaging, we adopt a holistic approach in our review and discuss the many links between the two aspects. Four classes of reconstruction algorithms are reviewed: time-domain (so called back-projection) formulae, frequency-domain formulae, time-reversal algorithms, and model-based algorithms. These algorithms are discussed in the context of the various acoustic detectors and detection surfaces which are commonly used in experimental studies. We further discuss the effects of non-ideal imaging scenarios on the quality of reconstruction and review methods that can mitigate these effects. Namely, we consider the cases of finite detector aperture, limited-view tomography, spatial under-sampling of the acoustic signals, and acoustic heterogeneities and losses.
PMCID: PMC3996917  PMID: 24772060
Optoacoustic imaging; photoacoustic imaging; tomography; inverse problems; ultrasound detectors; algorithms; acoustic waves.

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