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Volumetric, multimodal imaging with precise spatial and temporal coregistration can provide valuable and complementary information for diagnosis and monitoring. Considerable research has sought to combine 3-D photoacoustic (PA) and ultrasound (US) imaging in clinically translatable configurations; however, technical compromises currently result in poor image quality either for PA or ultrasonic modes. This work aims to provide translatable, high-quality, simultaneously coregistered dual-mode PA/US 3-D tomography. Volumetric imaging based on a synthetic aperture approach was implemented by interlacing PA and US acquisitions during a rotate-translate scan with a 5-MHz linear array (12 angles and 30-mm translation to image a 21-mm diameter, 19 mm long cylindrical volume within 21 s). For coregistration, an original calibration method using a specifically designed thread phantom was developed to estimate six geometrical parameters and one temporal offset through global optimization of the reconstructed sharpness and superposition of calibration phantom structures. Phantom design and cost function metrics were selected based on analysis of a numerical phantom and resulted in a high estimation accuracy for the seven parameters. Experimental estimations validated the calibration repeatability. The estimated parameters were used for the bimodal reconstruction of additional phantoms with either identical or distinct spatial distributions of US and PA contrasts. The superposition distance of the two modes was within < 10% of the acoustic wavelength, and a wavelength-order uniform spatial resolution was obtained. This dual-mode PA/US tomography should contribute to more sensitive and robust detection and follow-up of biological changes or the monitoring of slower-kinetic phenomena in living systems such as the accumulation of nanoagents.

Multispectral optoacoustic tomography (MSOT) uniquely enables spatial mapping in high resolution of oxygen saturation (SO2), with potential applications in studying pathological complications and therapy efficacy. MSOT offers seamless integration with ultrasonography, by using a common ultrasound (US) detector array. However, MSOT relies on multiple successive acquisitions of optoacoustic (OA) images at different optical wavelengths and the low frame rate of OA imaging makes the MSOT acquisition sensitive to body/respiratory motion. Moreover, the estimation of SO2 is highly sensitive to noise, and artifacts related to the respiratory motion of the animal were identified as the primary source of noise in MSOT. In this work, we propose a two-step image processing method for SO2 estimation in deep tissues. First, to mitigate motion artifacts, we propose a method of selection of OA images acquired only during the respiratory pause of the animal, using ultrafast ultrasound (US) images acquired immediately after each OA acquisition (US image acquisition duration of 1.4 ms and a total delay of 7 ms). We show that gating is more effective using US images than OA images at different optical wavelengths. Second, we propose a novel method that can estimate directly the SO2 value of a pixel and at the same time evaluate the amount of noise present in that pixel. Hence, the method can efficiently eliminate the pixels dominated by noise from the final SO2 map. Our postprocessing method is shown to outperform conventional methods for SO2 estimation, and the method was validated by in vivo oxygen challenge experiments.

Biomedical photothermal therapy with optical nanoparticles is based on the conversion of optical energy into heat through three steps: optical absorption, thermal conversion of the absorbed energy and heat transfer to the surrounding medium. The light-to-heat conversion efficiency (LHCE) has become one of the main metrics to quantitatively characterize the last two steps and evaluate the merit of nanoparticules for photothermal therapy. The estimation of the LHCE is mostly performed by monitoring the temperature evolution of a solution under laser irradiation. However, this estimation strongly depends on the experimental set-up and the heat balance model used. We demonstrate here, theoretically and experimentally, that the LHCE at multiple wavelengths can be efficiently and directly determined, without the use of models, by calibrated photoacoustic spectroscopy. The method was validated using already characterized colloidal suspensions of silver sulfide nanoparticles and maghemite nanoflowers and an uncertainty of 3 to 7% was estimated for the LHCE determination. Photoacoustic spectroscopy provides a new, precise and robust method of analysis of the photothermal capabilities of aqueous solutions of nanoagents.

Smart microgels (μGels) made of polymeric particles doped with inorganic nanoparticles have emerged recently as promising multifunctional materials for nanomedicine applications. However, the synthesis of these hybrid materials is still a challenging task with the necessity to control several features, such as particle sizes and doping levels, in order to tailor their final properties in relation to the targeted application. We report herein an innovative modular strategy to achieve the rational design of well-defined and densely filled hybrid particles. It is based on the assembly of the different building blocks, i.e., μGels, dyes, and small gold nanoparticles (<4 nm), and the tuning of nanoparticle loading within the polymer matrix through successive incubation steps. The characterization of the final hybrid networks using UV-vis absorption, fluorescence, transmission electron microscopy, dynamic light scattering, and small-angle X-ray scattering revealed that they uniquely combine the properties of hydrogel particles, including high loading capacity and stimuli-responsive behavior, the photoluminescent properties of dyes (rhodamine 6G, methylene blue and cyanine 7.5), and the features of gold nanoparticle assembly. Interestingly, in response to pH and temperature stimuli, the smart hybrid μGels can shrink, leading to the aggregation of the gold nanoparticles trapped inside the polymer matrix. This stimuli-responsive behavior results in plasmon band broadening and red shift toward the near-infrared region (NIR), opening promising prospects in biomedical science. Particularly, the potential of these smart hybrid nanoplatforms for photoactivated hyperthermia, photoacoustic imaging, cellular internalization, intracellular imaging, and photothermal therapy was assessed, demonstrating well controlled multimodal opportunities for theranostics.

We have designed a new Bodipy scaffold for efficient in vivo photoacoustic (PA) imaging of nanoparticles commonly used as drug nanovectors. The new dye has an optimized absorption band in the near-infrared window in biological tissue and a low fluorescence quantum yield that leads to a good photoacoustic generation efficiency. After Bodipy-initiated ring-opening polymerization of lactide, the polylactide-Bodipy was formulated into PEGylated nanoparticles (NPs) by mixing with PLA-PEG at different concentrations. Formulated NPs around 100 nm exhibit excellent PA properties: an absorption band at 760 nm and a molar absorption coefficient in between that of molecular PA absorbers and gold NPs. Highly improved photostability compared to cyanine-labeled PLA NPs as well as innocuity in cultured macrophages were demonstrated. After intravenous injection in healthy animals, NPs were easily detected using a commercial PA imaging system and spectral unmixing, opening the way to their use as theranostic agents.

Photoacoustic (PA) imaging systems are spreading in the biomedical community, and the development of new PA contrast agents is an active area of research. However, PA contrast agents are usually characterized with spectrophotometry or uncalibrated PA imaging systems, leading to partial assessment of their PA efficiency. To enable quantitative PA spectroscopy of contrast agents in vitro with conventional PA imaging systems, we have developed an adapted calibration method. Contrast agents in solution are injected in a dedicated non-scattering tube phantom imaged at different optical wavelengths. The calibration method uses a reference solution of cupric sulfate to simultaneously correct for the spectral energy distribution of excitation light at the tube location and perform a conversion of the tube amplitude in the image from arbitrary to spectroscopic units. The method does not require any precise alignment and provides quantitative PA spectra, even with non-uniform illumination and ultrasound sensitivity. It was implemented on a conventional imaging setup based on a tunable laser operating between 680 nm and 980 nm and a 5 MHz clinical ultrasound array. We demonstrated robust calibrated PA spectroscopy with sample volumes as low as 15 μL of known chromophores and commonly used contrast agents. The validated method will be an essential and accessible tool for the development of new and efficient PA contrast agents by improving their quantitative characterization.

This article proposes a dynamical system modeling approach for the analysis of longitudinal data of self-regulated homeostatic systems experiencing multiple excitations. It focuses on the evolution of a signal (e.g., heart rate) before, during, and after excitations taking the system out of its equilibrium (e.g., physical effort during cardiac stress testing). Such approach can be applied to a broad range of outcomes such as physiological processes in medicine and psychosocial processes in social sciences, and it allows to extract simple characteristics of the signal studied. The model is based on a first order linear differential equation with constant coefficients defined by three main parameters corresponding to the initial equilibrium value, the dynamic characteristic time, and the reaction to the excitation. Assuming the presence of interindividual variability (random effects) on these three parameters, we propose a two-step procedure to estimate them. We then compare the results of this analysis to several other estimation procedures in a simulation study that clarifies under which conditions parameters are accurately estimated. Finally, applications of this model are illustrated using cardiology data recorded during effort tests.

Light can be used to modify and control properties of media, as in the case of electromagnetically induced transparency or, more recently, for the generation of slow light or bright coherent XUV and X-ray radiation. Particularly unusual states of matter can be created by light fields with strengths comparable to the Coulomb field that binds valence electrons in atoms, leading to nearly-free electrons oscillating in the laser field and yet still loosely bound to the core [1,2]. These are known as Kramers-Henneberger states [3], a specific example of laser-dressed states [2]. Here, we demonstrate that these states arise not only in isolated atoms [4,5], but also in rare gases, at and above atmospheric pressure, where they can act as a gain medium during laser filamentation. Using shaped laser pulses, gain in these states is achieved within just a few cycles of the guided field. The corresponding lasing emission is a signature of population inversion in these states and of their stability against ionization. Our work demonstrates that these unusual states of neutral atoms can be exploited to create a general ultrafast gain mechanism during laser filamentation., Competing Interests: Competing financial interests The authors declare no competing financial interests.

We present a novel non-contact system for monitoring the heart rate on human subjects with clothes. Our approach is based on vibrocardiography, and measures locally skin displacements. Vibrocardiography with a laser Doppler vibrometer already allows monitoring of this vital sign, but can only be used on bare skin and requires an expensive piece of equipment. We propose here to use an airborne pulse-Doppler ultrasound system operating in the 20-60 kHz range, and comprised of an emitter focusing the ultrasound pulses on skin and a microphone recording the reflected waves. Our implementation was validated in vitro and on two healthy human subjects, using simultaneously laser vibrocardiography and electrocardiography as references. Accurate measurements of the heart rate on clothed skin suggest that our non-contact ultrasonic method could be implemented both inside and outside the clinical environment, and therefore benefit both medical and safety applications., (Copyright © 2017 IPEM. Published by Elsevier Ltd. All rights reserved.)

Intensity maxima and zeros of speckle patterns obtained behind a diffuser are experimentally interchanged by applying a spiral phase delay of charge ±1 to the impinging coherent beam. This transform arises from the expectation that tightly focused beams, which have a planar wave front around the focus, are so changed into vortex beams and vice versa. The statistics of extrema locations and the intensity distribution of the so-generated "complementary" patterns are characterized by numerical simulations. It is demonstrated experimentally that the incoherent superposition of the three "complementary speckle patterns" yield a synthetic speckle grain size enlarged by a factor of sqrt[3]. A cyclic permutation of optical vortices and intensity maxima is unexpectedly observed and discussed.

Whole-body optical imaging of post-embryonic stage model organisms is a challenging and long sought-after goal. It requires a combination of high-resolution performance and high-penetration depth. Optoacoustic (photoacoustic) mesoscopy holds great promise, as it penetrates deeper than optical and optoacoustic microscopy while providing high-spatial resolution. However, optoacoustic mesoscopic techniques only offer partial visibility of oriented structures, such as blood vessels, due to a limited angular detection aperture or the use of ultrasound frequencies that yield insufficient resolution. We introduce 360° multi orientation (multi-projection) raster scan optoacoustic mesoscopy (MORSOM) based on detecting an ultra-wide frequency bandwidth (up to 160 MHz) and weighted deconvolution to synthetically enlarge the angular aperture. We report unprecedented isotropic in-plane resolution at the 9-17 μm range and improved signal to noise ratio in phantoms and opaque 21-day-old Zebrafish. We find that MORSOM performance defines a new operational specification for optoacoustic mesoscopy of adult organisms, with possible applications in the developmental biology of adulthood and aging., Competing Interests: VN has a financial interest in iThera Medical GmbH, which did not support this work. KW, TSM and TM work for the ZEISS group, which is a manufacturer of optical microscopes.

Diversity of the design and alignment of illumination and ultrasonic transducers empower the fine scalability and versatility of optoacoustic imaging. In this study, we implement an innovative high-resolution optoacoustic mesoscopy for imaging the vasculature and tissue oxygenation within subcutaneous and orthotopic cancerous implants of mice in vivo through acquisition of tomographic projections over 180° at a central frequency of 24 MHz. High-resolution volumetric imaging was combined with multispectral functional measurements to resolve the exquisite inner structure and vascularization of the entire tumor mass using endogenous and exogenous optoacoustic contrast. Evidence is presented for constitutive hypoxemia within the carcinogenic tissue through analysis of the hemoglobin absorption spectra and distribution. Morphometric readouts obtained with optoacoustic mesoscopy have been verified with high-resolution ultramicroscopic studies. The findings described herein greatly extend the applications of optoacoustic mesoscopy toward structural and multispectral functional measurements of the vascularization and hemodynamics within solid tumors in vivo and are of major relevance to basic and preclinical oncological studies in small animal models., (Copyright © 2016. Published by Elsevier Inc.)

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.

Photoacoustic imaging can achieve high-resolution three-dimensional (3-D) visualization of optical absorbers at penetration depths of ∼1 cm in biological tissues by detecting optically induced high ultrasound frequencies. Tomographic acquisition with ultrasound linear arrays offers an easy implementation of single-side access, parallelized, and high-frequency detection, but usually comes with an image quality impaired by the directionality of the detectors. Indeed, a simple translation of the array perpendicular to its median imaging plane is often used, but results both in a poor resolution in the translation direction and strong limited-view artifacts.To improve the spatial resolution and the visibility of complex structures while retaining a planar detection geometry, we introduce, in this paper, a rotate-translate scanning scheme and investigate the performance ofa scanner implemented at 15 MHz center frequency. The developed system achieved a quasi-isotropic uniform 3-D resolution of ∼170 μm over a cubic volume of side length 8.5 mm, i.e., an improvement in the resolution in the translation direction by almost one order of magnitude. Dual-wavelength imaging was also demonstrated with ultrafast wavelength shifting. The validity of our approach was shown in vitro. We discuss the ability to enable in vivo imaging for preclinical and clinical studies.

In this work, we experimentally investigate thermal-based nonlinear photoacoustic generation as a mean to discriminate between different types of absorbing particles. The photoacoustic generation from solutions of dye molecules and gold nanospheres (same optical densities) was detected using a high frequency ultrasound transducer (20 MHz). Photoacoustic emission was observed with gold nanospheres at low fluence for an equilibrium temperature around 4 °C, where the linear photoacoustic effect in water vanishes, highlighting the nonlinear emission from the solution of nanospheres. The photoacoustic amplitude was also studied as a function of the equilibrium temperature from 2 °C to 20 °C. While the photoacoustic amplitude from the dye molecules vanished around 4 °C, the photoacoustic amplitude from the gold nanospheres remained significant over the whole temperature range. Our preliminary results suggest that in the context of high frequency photoacoustic imaging, nanoparticles may be discriminated from molecular absorbers based on nanoscale temperature rises.

We study the potential of photoacoustic guidance for light focusing through scattering samples via wavefront-shaping and iterative optimization. We experimentally demonstrate that the focusing efficiency on an extended absorber can be improved by iterative optimization of the high frequency components of the broadband photoacoustic signal detected with a spherically focused transducer. We demonstrate more than 12-fold increase in the photoacoustic signal generated by a 30 μm wire using a narrow frequency band around 60 MHz. By monitoring the speckle pattern evolution during the optimization process with a CCD camera, we experimentally confirm that such optimization leads to a smaller optical focus than what would be obtained by optimizing lower frequencies of the photoacoustic feedback.

We developed a reflection-mode optoacoustic mesoscopy system, based on raster-scanning of a custom designed spherically focused ultrasound detector, enabling seamless epi-illumination of the volume imaged. We study the performance of acoustic-resolution mesoscopy operating at an ultrawideband bandwidth of 20-180 MHz. i.e., a frequency band spreading over virtually an order of magnitude. Using tomographic reconstruction we showcase previously unreported, to our knowledge, axial resolutions of 4 μm and transverse resolutions of 18 μm reaching depths of up to 5 mm. We further investigate the frequency-dependence of features seen on the images to understand the implications of ultrawideband measurements. We show the overall imaging performance and the frequency ranges that contribute to observable resolution improvements from phantoms and animals.

We implement the photoacoustic transmission matrix approach on a two-dimensional photoacoustic imaging system, using a 15 MHz linear ultrasound array. Using a black leaf skeleton as a complex absorbing structure, we demonstrate that the photoacoustic transmission matrix approach allows to reveal structural features that are invisible in conventional photoacoustic images, as well as to selectively control light focusing on absorbing targets, leading to a local enhancement of the photoacoustic signal.

Image quality in 3-D optoacoustic (photoacoustic) tomography is greatly influenced by both the measurement system, in particular the number and spatial arrangement of ultrasound sensors, and the ability to account for the spatio-temporal response of the sensor element(s) in the reconstruction algorithm. Herein we present a reconstruction procedure based on the inversion of a time-domain forward model incorporating the spatial impulse response due to the shape of the transducer, which is subsequently applied in a tomographic system based on a translation-rotation scan of a linear detector array. The proposed method was also adapted to cope with the data-intensive requirements of high-resolution volumetric optoacoustic imaging. The processing of 2 · 10 (4) individual signals resulted in well-resolved images of both ~ 200 μm absorbers in phantoms and complex vascular structures in biological tissue. The results reported herein demonstrate that the introduced model-based methodology exhibits a better contrast and resolution than standard back-projection and model-based algorithms that assume point detectors. Moreover, the capability of handling large datasets anticipates that model-based methods incorporating the sensor properties can become standard practice in volumetric opto acoustic image formation.

Optoacoustic (photoacoustic) imaging uniquely visualizes optical contrast in high resolution and comes with very attractive characteristics for clinical imaging applications. In this paper, we showcase the performance of a scanner based on a 24 MHz center-frequency 128 element array, developed for applications in dermatology. We perform system characterization to examine the imaging performance achieved. We then showcase its imaging ability on healthy tissue and cancer. Finally, we image burns and human lesions in vivo and gain insights on the benefits and challenges of this approach as it is considered for diagnostic and treatment follow-up applications in dermatology and beyond.

In high-frequency photoacoustic imaging with uniform illumination, homogeneous photoabsorbing structures may be invisible because of their large size or limited-view issues. Here we show that, by exploiting dynamic speckle illumination, it is possible to reveal features that are normally invisible with a photoacoustic system comprised of a 20 MHz linear ultrasound array. We demonstrate imaging of a ∅5 mm absorbing cylinder and a 30 μm black thread arranged in a complex shape. The hidden structures are directly retrieved from photoacoustic images recorded for different random speckle illuminations of the phantoms by assessing the variation in the value of each pixel over the illumination patterns.

Broadband optoacoustic waves generated by biological tissues excited with nanosecond laser pulses carry information corresponding to a wide range of geometrical scales. Typically, the frequency content present in the signals generated during optoacoustic imaging is much larger compared to the frequency band captured by common ultrasonic detectors, the latter typically acting as bandpass filters. To image optical absorption within structures ranging from entire organs to microvasculature in three dimensions, we implemented optoacoustic tomography with two ultrasound linear arrays featuring a center frequency of 6 and 24 MHz, respectively. In the present work, we show that complementary information on anatomical features could be retrieved and provide a better understanding on the localization of structures in the general anatomy by analyzing multi-bandwidth datasets acquired on a freshly excised kidney.

Bubbles can form in biological tissues through ultrasonic activation of natural gas nuclei. The damaging aftereffects raise safety concerns. However, the population of nuclei is currently unknown, and bubble nucleation is stochastic and thus unpredictable. This study investigates the statistical behavior of bubble nucleation experimentally and introduces a model-based analysis to determine the distribution of nuclei in biological samples-two pig blood samples in vitro. Combined ultra-fast passive and active cavitation detection with a linear array was used to detect nucleation from pulsed ultrasound excitations at 660 kHz. Single nucleation events were detected at peak rarefaction pressures from -3.6 to -24 MPa, and the nucleation probability over the range 0 to 1 was estimated from more than 330 independent acquisitions per sample. Model fitting of the experimental probability revealed that the distribution of nuclei is most likely continuous, and nuclei are rare in comparison to blood cells., (2013 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved)

Optoacoustic (photoacoustic) mesoscopy aims at high-resolution optical imaging of anatomical, functional, and cellular parameters at depths that go well beyond those of optical-resolution optical or optoacoustic microscopy i.e., reaching several millimeters in depth. The approach utilizes tomography to achieve ultrasonic-diffraction resolution and operates at high-ultrasound frequencies (20 to 200 MHz) induced by few-nanosecond laser pulse excitation of tissues. We investigated here the performance of optoacoustic mesoscopy implemented at 24 MHz center frequency and its ability to resolve optical absorption contrast in the mouse kidney ex vivo. The developed system achieved better than 30 μm in-plane resolution and 110 μm elevation resolution over a cylindrical volume of 9-mm diameter and 9-mm height. This unprecedented combination of resolution and depth was achieved by implementing a translate-rotate detection geometry and by tomographic reconstruction. The approach yielded images of optically absorbing structures with a level of detail never-before visualized in an intact mouse kidney and allows insights into their unperturbed architecture. We discuss the ability to offer multispectral acquisitions and enable in vivo imaging.

We developed a raster-scan acoustic resolution broadband optoacoustic mesoscopy system and investigated the imaging performance using ultrasonic frequencies up to 125 MHz. The developed system achieves 7 μm axial resolution and transverse resolution of 30 μm reaching depths of at least 5 mm. This unprecedented performance is achieved by operating at out-of-focus ultrasonic detection and tomographic reconstruction. We demonstrate the limits reached due to the width of the laser pulse employed and showcase the technique on drosophila fly and drosophila pupae ex vivo.

Reliably assessing tissue viability during surgery is of major importance in surgical procedures. The most basic requirement for viability is sufficient oxygen supply to the tissue. Therefore it is highly desirable to visualize in real-time the dynamic process of blood perfusion up to and within the microvasculature. A modality sensitive to structures in the range of few hundred micrometers and offering high contrast to the embedding tissue is then needed. To this end, a number of methods have been developed, but have had no significant impact on the clinical routine due to various deficiencies. In this paper we demonstrate the applicability of optoacoustic imaging, which combines ultrasonic resolution with strong optical contrast. A method for optoacoustic perfusion assessment, based on a local and repeatable injection of saline, was proposed and assessed ex-vivo on large pig bowels and in-vivo in mouse tails. The obtained dynamic perfusion images highlight the method's potential to enable immediate and quantitative assessment of tissue viability during surgery., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: Optoacoustic imaging relies on the detection of ultrasonic waves induced by laser pulse excitations to map optical absorption in biological tissue. A tomographic geometry employing a conventional ultrasound linear detector array for volumetric optoacoustic imaging is reported. The geometry is based on a translate-rotate scanning motion of the detector array, and capitalizes on the geometrical characteristics of the transducer assembly to provide a large solid angular detection aperture. A system for three-dimensional whole-body optoacoustic tomography of small animals is implemented., Methods: The detection geometry was tested using a 128-element linear array (5.0∕7.0 MHz, Acuson L7, Siemens), moved by steps with a rotation∕translation stage assembly. Translation and rotation range of 13.5 mm and 180°, respectively, were implemented. Optoacoustic emissions were induced in tissue-mimicking phantoms and ex vivo mice using a pulsed laser operating in the near-IR spectral range at 760 nm. Volumetric images were formed using a filtered backprojection algorithm., Results: The resolution of the optoacoustic tomography system was measured to be better than 130 μm in-plane and 330 μm in elevation (full width half maximum), and to be homogenous along a 15 mm diameter cross section due to the translate-rotate scanning geometry. Whole-body volumetric optoacoustic images of mice were performed ex vivo, and imaged organs and blood vessels through the intact abdominal and head regions were correlated to the mouse anatomy., Conclusions: Overall, the feasibility of three-dimensional and high-resolution whole-body optoacoustic imaging of small animal using a conventional linear array was demonstrated. Furthermore, the scanning geometry may be used for other linear arrays and is therefore expected to be of great interest for optoacoustic tomography at macroscopic and mesoscopic scale. Specifically, conventional detector arrays with higher central frequencies may be investigated.

Optoacoustic (photoacoustic) mesoscopic and microscopic imaging is often implemented by linearly scanning a spherically focused ultrasound transducer. In this case, the resolution and sensitivity along the scan direction are limited by diffraction and therefore degrade rapidly for imaging depths away from the focal point. Partial restoration of the lost resolution can be achieved by using data-processing techniques, such as the virtual detector delay-and-sum method. However, these techniques are based on an approximate description of the detector properties, which limits the improvement in image quality they achieve. Herein we propose a reconstruction method based on an exact model of the optoacoustic generation and propagation that incorporates the spatial response of the sensor. The proposed method shows superior imaging performance over previously considered techniques.

Gas nuclei exist naturally in living bodies. Their activation initiates cavitation activity, and is possible using short ultrasonic excitations of high amplitude. However, little is known about the nuclei population in vivo, and therefore about the rarefaction pressure required to form bubbles in tissue. A novel method dedicated to in vivo investigations was used here that combines passive and active cavitation detection with a multi-element linear ultrasound probe (4-7 MHz). Experiments were performed in vivo on the brain of trepanated sheep. Bubble nucleation was induced using a focused single-element transducer (central frequency 660 kHz, f-number = 1) driven by a high power (up to 5 kW) electric burst of two cycles. Successive passive recording and ultrafast active imaging were shown to allow detection of a single nucleation event in brain tissue in vivo. Experiments carried out on eight sheep allowed statistical studies of the bubble nucleation process. The nucleation probability was evaluated as a function of the peak negative pressure. No nucleation event could be detected with a peak negative pressure weaker than -12.7 MPa, i.e. one order of magnitude higher than the recommendations based on the mechanical index. Below this threshold, bubble nucleation in vivo in brain tissues is a random phenomenon.

The activation of natural gas nuclei to induce larger bubbles is possible using short ultrasonic excitations of high amplitude, and is required for ultrasound cavitation therapies. However, little is known about the distribution of nuclei in tissues. Therefore, the acoustic pressure level necessary to generate bubbles in a targeted zone and their exact location are currently difficult to predict. To monitor the initiation of cavitation activity, a novel all-ultrasound technique sensitive to single nucleation events is presented here. It is based on combined passive detection and ultrafast active imaging over a large volume using the same multi-element probe. Bubble nucleation was induced using a focused transducer (660 kHz, f-number = 1) driven by a high-power electric burst (up to 300 W) of one to two cycles. Detection was performed with a linear array (4 to 7 MHz) aligned with the single-element focal point. In vitro experiments in gelatin gel and muscular tissue are presented. The synchronized passive detection enabled radio-frequency data to be recorded, comprising high-frequency coherent wave fronts as signatures of the acoustic emissions linked to the activation of the nuclei. Active change detection images were obtained by subtracting echoes collected in the unnucleated medium. These indicated the appearance of stable cavitating regions. Because of the ultrafast frame rate, active detection occurred as quickly as 330 μs after the high-amplitude excitation and the dynamics of the induced regions were studied individually.