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Abstract Ultrasound-based shear wave elastography is a promising technique to non-invasively assess the dynamic stiffness variations of the heart. The technique is based on tracking the propagation of acoustically induced shear waves in the myocardium of which the propagation speed is linked to tissue stiffness. This measurement is repeated multiple times across the cardiac cycle to assess the natural variations in wave propagation speed. The interpretation of these measurements remains however complex, as factors such as loading and contractility affect wave propagation. We therefore applied transthoracic shear wave elastography in 13 pigs to investigate the dependencies of wave speed on pressure–volume derived indices of loading, myocardial stiffness, and contractility, while altering loading and inducing myocardial ischemia/reperfusion injury. Our results show that diastolic wave speed correlates to a pressure–volume derived index of operational myocardial stiffness (R = 0.75, p

Abstract Background Echo-Particle Image Velocimetry (echoPIV) tracks speckle patterns from ultrasound contrast agent(UCA), being less angle-sensitive than colour Doppler. High frame rate (HFR) echoPIV enables tracking of high velocity flow in the left ventricle (LV). We aimed to demonstrate the potential clinical use of HFR echoPIV and investigate the feasibility and accuracy in patients. Methods Nineteen patients admitted for heart failure were included. HFR contrast images were acquired from an apical long axis view (ALAX), using a fully-programmable ultrasound system. A clinical UCA was continuously infused with a dedicated pump. Additionally, echocardiographic images were obtained using a clinical system, including LV contrast-enhanced images and pulsed-wave (PW) Doppler of the LV inflow and outflow in ALAX. 11 patients underwent CMR and 4 cardiac CT as clinically indicated. These CMR and CT images were used as reference. In 10 patients with good echoPIV tracking and reference imaging, the intracavitary flow was compared between echoPIV, conventional and UCA echocardiography. Results EchoPIV tracking quality was good in 12/19 (63%), moderate in 2/19 (10%) and poor in 5/19 (26%) subjects. EchoPIV could determine inflow velocity in 17/19 (89%), and outflow in 14/19 (74%) patients. The correlation of echoPIV and PW Doppler was good for the inflow (R2 = 0.77 to PW peak; R2 = 0.80 PW mean velocity) and moderate for the outflow (R2 = 0.54 to PW peak; R2 = 0.44 to PW mean velocity), with a tendency for echoPIV to underestimate PW velocities. In selected patients, echoPIV was able in a single acquisition to demonstrate flow patterns which required multiple interrogations with classical echocardiography. Those flow patterns could also be linked to anatomical abnormalities as seen in CMR or CT. Conclusion HFR echoPIV tracks multidirectional and complex flow patterns which are unapparent with conventional echocardiography, while having comparable feasibility. EchoPIV tends to underestimate flow velocities as compared to PW Doppler. It has the potential to provide in one acquisition all the functional information obtained by conventional imaging, overcoming the angle dependency of Doppler and low frame rate of classical contrast imaging.

In photoacoustic tomography (PAT) systems, the tangential resolution decreases due to the finite size of the transducer as the off-center distance increases. To address this problem, we propose a multi-angle detection approach in which the transducer used for data acquisition rotates around its center (with specific angles) as well as around the scanning center. The angles are calculated based on the central frequency and diameter of the transducer and the radius of the region-of-interest (ROI). Simulations with point-like absorbers (for point-spread-function evaluation) and a vasculature phantom (for quality assessment), and experiments with ten 0.5 mm-diameter pencil leads and a leaf skeleton phantom are used for evaluation of the proposed approach. The results show that a location-independent tangential resolution is achieved with 150 spatial sampling and central rotations with angles of ±8°/±16°. With further developments, the proposed detection strategy can replace the conventional detection (rotating a transducer around ROI) in PAT.

Skeletal muscles generate force, enabling movement through a series of fast electro-mechanical activations coordinated by the central nervous system. Understanding the underlying mechanism of such fast muscle dynamics is essential in neuromuscular diagnostics, rehabilitation medicine and sports biomechanics. The unique combination of electromyography (EMG) and ultrafast ultrasound imaging (UUI) provides valuable insights into both electrical and mechanical activity of muscle fibers simultaneously, the excitation-contraction (E-C) coupling. In this feasibility study we propose a novel non-invasive method to simultaneously track the propagation of both electrical and mechanical waves in muscles using high-density electromyography and ultrafast ultrasound imaging (5000 fps). Mechanical waves were extracted from the data through an axial tissue velocity estimator based on one-lag autocorrelation. The E-C coupling in electrically evoked twitch contractions of the Biceps Brachii in healthy participants could successfully be tracked. The excitation wave (i.e. action potential) had a velocity of 3.9±0.5ms−1 and the subsequent mechanical (i.e. contraction) wave had a velocity of 3.5±0.9ms−1. The experiment showed evidence that contracting sarcomeres that were already activated by the action potential (AP) pull on sarcomeres that were not yet reached by the AP, which was corroborated by simulated contractions of a newly developed multisegmental muscle fiber model, consisting of 500 sarcomeres in series. In conclusion, our method can track the electromechanical muscle dynamics with high spatio-temporal resolution. Ultimately, characterizing E-C coupling in patients with neuromuscular diseases (e.g. Duchenne or Becker muscular dystrophy) may assess contraction efficiency, monitor the progression of the disease, and determine the efficacy of new treatment options.

Abstract Background Shear waves are generated by the closure of the heart valves. Significant differences in shear wave velocity have been found recently between normal myocardium and disease models of diffusely increased muscle stiffness. In this study we correlate in vivo myocardial shear wave imaging (SWI) with presence of scarred tissue, as model for local increase of stiffness. Stiffness variation is hypothesized to appear as velocity variation. Methods Ten healthy volunteers (group 1), 10 hypertrophic cardiomyopathy (HCM) patients without any cardiac intervention (group 2), and 10 HCM patients with prior septal reduction therapy (group 3) underwent high frame rate tissue Doppler echocardiography. The SW in the interventricular septum after aortic valve closure was mapped along two M-mode lines, in the inner and outer layer. Results We compared SWI to 3D echocardiography and strain imaging. In groups 1 and 2, no change in velocity was detected. In group 3, 8/10 patients showed a variation in SW velocity. All three patients having transmural scar showed a simultaneous velocity variation in both layers. Out of six patients with endocardial scar, five showed variations in the inner layer. Conclusion Local variations in stiffness, with myocardial remodeling post septal reduction therapy as model, can be detected by a local variation in the propagation velocity of naturally occurring shear waves.

High frame rate three-dimensional (3D) ultrasound imaging would offer excellent possibilities for the accurate assessment of carotid artery diseases. This calls for a matrix transducer with a large aperture and a vast number of elements. Such a matrix transducer should be interfaced with an application-specific integrated circuit (ASIC) for channel reduction. However, the fabrication of such a transducer integrated with one very large ASIC is very challenging and expensive. In this study, we develop a prototype matrix transducer mounted on top of multiple identical ASICs in a tiled configuration. The matrix was designed to have 7680 piezoelectric elements with a pitch of 300 μm × 150 μm integrated with an array of 8 × 1 tiled ASICs. The performance of the prototype is characterized by a series of measurements. The transducer exhibits a uniform behavior with the majority of the elements working within the −6 dB sensitivity range. In transmit, the individual elements show a center frequency of 7.5 MHz, a −6 dB bandwidth of 45%, and a transmit efficiency of 30 Pa/V at 200 mm. In receive, the dynamic range is 81 dB, and the minimum detectable pressure is 60 Pa per element. To demonstrate the imaging capabilities, we acquired 3D images using a commercial wire phantom.

While transcranial ultrasound imaging is a promising diagnostic modality, it is still hindered due to phase aberration and multiple scattering caused by the skull. In this paper, we compare near-field phase-screen modeling (PS) to a geometry-based phase aberration correction technique (GB) when an ultrafast imaging sequence (five plane waves tilted from −15 to +15 degrees in the cutaneous tissue layer) is used for data acquisition. With simulation data, the aberration profile (AP) of two aberrator models (flat and realistic temporal bone) was estimated in five isoplanatic patches, while the wave-speed of the brain tissue surrounding the point targets was either modeled homogeneously (ideal) or slightly heterogeneously to generate speckle (for mimicking a more realistic brain tissue). For the experiment, a phased array P4-1 transducer was used to image a wire phantom; a 4.2-mm-thick bone-mimicking plate was placed in front of the probe. The AP of the plate was estimated in three isoplanatic patches. The numerical results indicate that, while all the scatterers are detectable in the image reconstructed by the GB method, many scatterers are not detected with the PS method when the dataset used for AP estimation is generated with a realistic bone model and heterogeneous brain tissue. The experimental results show that the GB method increases the signal-to-clutter ratio (SCR) by 7.5 dB and 6.5 dB compared to the PS and conventional reconstruction methods, respectively. The GB method reduces the axial/lateral localization error by 1.97/0.66 mm and 2.08/0.7 mm compared to the PS method and conventional reconstruction, respectively. The lateral spatial resolution (full-width-half-maximum) is also improved by 0.1 mm and 1.06 mm compared to the PS method and conventional reconstruction, respectively. Our comparison study suggests that GB aberration correction outperforms the PS method when an ultrafast multi-angle plane wave sequence is used for transcranial imaging with a single transducer.

Background and Aim: Newborns needing major surgical intervention are at risk of brain injury and impaired neurodevelopment later in life. Disturbance of cerebral perfusion might be an underlying factor. This study investigates the feasibility of serial transfontanellar ultrasound measurements of the pial arteries during neonatal surgery, and whether perioperative changes in cerebral perfusion can be observed and related to changes in the perioperative management.Methods: In this prospective, observational feasibility study, neonates with congenital diaphragmatic hernia and esophageal atresia scheduled for surgical treatment within the first 28 days of life were eligible for inclusion. We performed transfontanellar directional power Doppler and pulsed wave Doppler ultrasound during major high-risk non-cardiac neonatal surgery. Pial arteries were of interest for the measurements. Extracted Doppler ultrasound parameters were: peak systolic velocity, end diastolic velocity, the resistivity index and pulsatility index.Results: In 10 out of 14 patients it was possible to perform perioperative measurements; the others failed for logistic and technical reasons. In 6 out of 10 patients, it was feasible to perform serial intraoperative transfontanellar ultrasound measurements with directional power Doppler and pulsed wave Doppler of the same pial artery during neonatal surgery. Median peak systolic velocity was ranging between 5.7 and 7.0 cm s−1 and end diastolic velocity between 1.9 and 3.2 cm s−1. In patients with a vasoactive-inotropic score below 12 the trend of peak systolic velocity and end diastolic velocity corresponded with the mean arterial blood pressure trend.Conclusion: Perioperative transfontanellar ultrasound Doppler measurements of the pial arteries are feasible and provide new longitudinal data about perioperative cortical cerebral blood flow velocity.Trial Registration:https://www.trialregister.nl/trial/6972, identifier: NL6972.

Bacteria encased in a biofilm poses significant challenges to successful treatment, since both the immune system and antibiotics are ineffective. Sonobactericide, which uses ultrasound and microbubbles, is a potential new strategy for increasing antimicrobial effectiveness or directly killing bacteria. Several studies suggest that sonobactericide can lead to bacterial dispersion or sonoporation (i.e., cell membrane permeabilization); however, real-time observations distinguishing individual bacteria during and directly after insonification are missing. Therefore, in this study, we investigated, in real-time and at high-resolution, the effects of ultrasound-induced microbubble oscillation on Staphylococcus aureus biofilms, without or with an antibiotic (oxacillin, 1 μg/mL). Biofilms were exposed to ultrasound (2 MHz, 100–400 kPa, 100–1000 cycles, every second for 30 s) during time-lapse confocal microscopy recordings of 10 min. Bacterial responses were quantified using post hoc image analysis with particle counting. Bacterial dispersion was observed as the dominant effect over sonoporation, resulting from oscillating microbubbles. Increasing pressure and cycles both led to significantly more dispersion, with the highest pressure leading to the most biofilm removal (up to 83.7%). Antibiotic presence led to more variable treatment responses, yet did not significantly impact the therapeutic efficacy of sonobactericide, suggesting synergism is not an immediate effect. These findings elucidate the direct effects induced by sonobactericide to best utilize its potential as a biofilm treatment strategy.

Phospholipid-coated targeted microbubbles are used for ultrasound molecular imaging and locally enhanced drug delivery, with the binding efficacy being an important trait. The use of organic solvent in microbubble production makes the difference between a heterogeneous or homogeneous ligand distribution. This study demonstrates the effect of ligand distribution on the binding efficacy of phospholipid-coated ανβ3-targeted microbubbles in vitro using a monolayer of human umbilical-vein endothelial cells and in vivo using chicken embryos. Microbubbles with a homogeneous ligand distribution had a higher binding efficacy than those with a heterogeneous ligand distribution both in vitro and in vivo. In vitro, 1.55× more microbubbles with a homogeneous ligand distribution bound under static conditions, while this was 1.49× more under flow with 1.25 dyn/cm2, 1.56× more under flow with 2.22 dyn/cm2, and 1.25× more in vivo. The in vitro dissociation rate of bound microbubbles with homogeneous ligand distribution was lower at low shear stresses (1–5 dyn/cm2). The internalized depth of bound microbubbles was influenced by microbubble size, not by ligand distribution. In conclusion, for optimal binding the use of organic solvent in targeted microbubble production is preferable over directly dispersing phospholipids in aqueous medium.

Phospholipid-coated microbubbles are ultrasound contrast agents that can be employed for ultrasound molecular imaging and drug delivery. For safe and effective implementation, microbubbles must respond uniformly and predictably to ultrasound. Therefore, we investigated how lipid handling and phase distribution affected the variability in the acoustic behavior of microbubbles. Cholesterol was used to modify the lateral molecular packing of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)-based microbubbles. To assess the effect of lipid handling, microbubbles were produced by a direct method, i.e., lipids directly dispersed in an aqueous medium or indirect method, i.e., lipids first dissolved in an organic solvent. The lipid phase and ligand distribution in the microbubble coating were investigated using confocal microscopy, and the acoustic response was recorded with the Brandaris 128 ultra-high-speed camera. In microbubbles with 12 mol% cholesterol, the lipids were miscible and all in the same phase, which resulted in more buckle formation, lower shell elasticity and higher shell viscosity. Indirect DSPC microbubbles had a more uniform response to ultrasound than direct DSPC and indirect DSPC-cholesterol microbubbles. The difference in lipid handling between direct and indirect DSPC microbubbles significantly affected the acoustic behavior. Indirect DSPC microbubbles are the most promising candidate for ultrasound molecular imaging and drug delivery applications.

This paper presents an ultrasound transceiver application-specific integrated circuit (ASIC) directly integrated with an array of 12 × 80 piezoelectric transducer elements to enable next-generation ultrasound probes for 3D carotid artery imaging. The ASIC, implemented in a 0.18 µm high-voltage Bipolar-CMOS-DMOS (HV BCD) process, adopted a programmable switch matrix that allowed selected transducer elements in each row to be connected to a transmit and receive channel of an imaging system. This made the probe operate like an electronically translatable linear array, allowing large-aperture matrix arrays to be interfaced with a manageable number of system channels. This paper presents a second-generation ASIC that employed an improved switch design to minimize clock feedthrough and charge-injection effects of high-voltage metal–oxide–semiconductor field-effect transistors (HV MOSFETs), which in the first-generation ASIC caused parasitic transmissions and associated imaging artifacts. The proposed switch controller, implemented with cascaded non-overlapping clock generators, generated control signals with improved timing to mitigate the effects of these non-idealities. Both simulation results and electrical measurements showed a 20 dB reduction of the switching artifacts. In addition, an acoustic pulse-echo measurement successfully demonstrated a 20 dB reduction of imaging artifacts.

Recently, we realized a prototype matrix transducer consisting of 48 rows of 80 elements on top of a tiled set of Application Specific Integrated Circuits (ASICs) implementing a row-level control connecting one transmit/receive channel to an arbitrary subset of elements per row. A fully sampled array data acquisition is implemented by a column-by-column (CBC) imaging scheme (80 transmit-receive shots) which achieves 250 volumes/second (V/s) at a pulse repetition frequency of 20 kHz. However, for several clinical applications such as carotid pulse wave imaging (CPWI), a volume rate of 1000 per second is needed. This allows only 20 transmit-receive shots per 3D image. In this study, we propose a shifting aperture scheme and investigate the effects of receive/transmit aperture size and aperture shifting step in the elevation direction. The row-level circuit is used to interconnect elements of a receive aperture in the elevation (row) direction. An angular weighting method is used to suppress the grating lobes caused by the enlargement of the effective elevation pitch of the array, as a result of element interconnection in the elevation direction. The effective aperture size, level of grating lobes, and resolution/sidelobes are used to select suitable reception/transmission parameters. Based on our assessment, the proposed imaging sequence is a full transmission (all 80 elements excited at the same time), a receive aperture size of 5 and an aperture shifting step of 3. Numerical results obtained at depths of 10, 15, and 20 mm show that, compared to the fully sampled array, the 1000 V/s is achieved at the expense of, on average, about two times wider point spread function and 4 dB higher clutter level. The resulting grating lobes were at −27 dB. The proposed imaging sequence can be used for carotid pulse wave imaging to generate an informative 3D arterial stiffness map, for cardiovascular disease assessment.

In vivo cell tracking of therapeutic, tumor, and endothelial cells is an emerging field and a promising technique for imaging cardiovascular disease and cancer development. Site-specific labeling of endothelial cells with the MRI contrast agent superparamagnetic iron oxide (SPIO) in the absence of toxic agents is challenging. Therefore, the aim of this in vitro study was to find optimal parameters for efficient and safe SPIO-labeling of endothelial cells using ultrasound-activated CD31-targeted microbubbles for future MRI tracking. Ultrasound at a frequency of 1 MHz (10,000 cycles, repetition rate of 20 Hz) was used for varying applied peak negative pressures (10-160 kPa, i.e. low mechanical index (MI) of 0.01-0.16), treatment durations (0-30 s), time of SPIO addition (-5 min- 15 min with respect to the start of the ultrasound), and incubation time after SPIO addition (5 min- 3 h). Iron specific Prussian Blue staining in combination with calcein-AM based cell viability assays were applied to define the most efficient and safe conditions for SPIO-labeling. Optimal SPIO labeling was observed when the ultrasound parameters were 40 kPa peak negative pressure (MI 0.04), applied for 30 s just before SPIO addition (0 min). Compared to the control, this resulted in an approximate 12 times increase of SPIO uptake in endothelial cells in vitro with 85% cell viability. Therefore, ultrasound-activated targeted ultrasound contrast agents show great potential for effective and safe labeling of endothelial cells with SPIO.

Acoustic behavior of lipid-coated microbubbles has been widely studied, which has led to several numerical microbubble dynamics models that incorporate lipid coating behavior, such as buckling and rupture. In this study we investigated the relationship between microbubble acoustic and lipid coating behavior on a nanosecond scale by using fluorescently labeled lipids. It is hypothesized that a local increased concentration of lipids, appearing as a focal area of increased fluorescence intensity (hot spot) in the fluorescence image, is related to buckling and folding of the lipid layer thereby highly influencing the microbubble acoustic behavior. To test this hypothesis, the lipid microbubble coating was fluorescently labeled. The vibration of the microbubble (n = 177; 2.3-10.3 μm in diameter) upon insonification at an ultrasound frequency of 0.5 or 1 MHz at 25 or 50 kPa acoustic pressure was recorded with the UPMC Cam, an ultra-high-speed fluorescence camera, operated at ~4-5 million frames per second. During short tone-burst excitation, hot spots on the microbubble coating occurred at relative vibration amplitudes > 0.3 irrespective of frequency and acoustic pressure. Around resonance, the majority of the microbubbles formed hot spots. When the microbubble also deflated acoustically, hot spot formation was likely irreversible. Although compression-only behavior (defined as substantially more microbubble compression than expansion) and subharmonic responses were observed in those microbubbles that formed hot spots, both phenomena were also found in microbubbles that did not form hot spots during insonification. In conclusion, this study reveals hot spot formation of the lipid monolayer in the microbubble's compression phase. However, our experimental results show that there is no direct relationship between hot spot formation of the lipid coating and microbubble acoustic behaviors such as compression-only and the generation of a subharmonic response. Hence, our hypothesis that hot spots are related to acoustic buckling could not be verified.

Photoacoustic imaging (PAI) is an emerging label-free and non-invasive modality for imaging biological tissues. PAI has been implemented in different configurations, one of which is photoacoustic computed tomography (PACT) with a potential wide range of applications, including brain and breast imaging. Hemispherical Array PACT (HA-PACT) is a variation of PACT that has solved the limited detection-view problem. Here, we designed an HA-PACT system consisting of 50 single element transducers. For implementation, we initially performed a simulation study, with parameters close to those in practice, to determine the relationship between the number of transducers and the quality of the reconstructed image. We then used the greatest number of transducers possible on the hemisphere and imaged copper wire phantoms coated with a light absorbing material to evaluate the performance of the system. Several practical issues such as light illumination, arrangement of the transducers, and an image reconstruction algorithm have been comprehensively studied.