US velocimetry in participants with aortoiliac occlusive disease

The accurate quantification of blood flow in aortoiliac arteries is challenging but clinically relevant because local flow patterns can influence atherosclerotic disease. To investigate the feasibility and clinical application of two-dimensional blood flow quantification using high-frame-rate contrast-enhanced US (HFR-CEUS) and particle image velocimetry (PIV), or US velocimetry, in participants with aortoiliac stenosis. In this prospective study, participants with a recently diagnosed aortoiliac stenosis underwent HFR-CEUS measurements of the pre- and poststenotic vessel segments. Two-dimensional quantification of blood flow was achieved by performing PIV analysis, which was based on pairwise cross-correlation of the HFR-CEUS images. Visual inspection of the entire data set was performed by five observers to evaluate the ability of the technique to enable adequate visualization of blood flow. The contrast-to-background ratio and average vector correlation were calculated. In two participants who showed flow disturbances, the flow complexity and vorticity were calculated. Results: 35 participants were included. Visual scoring showed that flow quantification was achieved in 41 of 42 locations. In 25 locations, one or multiple issues occurred that limited optimal flow quantification, including loss of correlation during systole, shadow regions, a short vessel segment in the image plane, and loss of contrast during diastole. In the remaining 16 locations, optimal quantification was achieved. The contrast-to-background ratio was higher during systole than during diastole, whereas the vector correlation was lower. Flow complexity and vorticity were high in regions with disturbed flow. Blood flow quantification with US velocimetry is feasible in patients with an aortoiliac stenosis, but several challenges must be overcome before implementation into clinical practice

Nonlinear dynamics of single freely-floating microbubbles under prolonged insonation

The acoustic nonlinear responses of ultrasound contrast agent microbubbles (MBs) are of great interest for both diagnostic and therapeutic applications. Previously, optical and acoustical methods were developed to characterize single bubbles floating against a rigid wall. However, there is a need to develop an efficient approach for statistical measurement of single freely-floating MBs. Here we combine simultaneous optical sizing and sensitive acoustical characterization measurement to study quantitatively the nonlinear dynamics of single freely-floating bubbles under prolonged ultrasound exposure. The nonlinearity (ε2f, ε3f) and asymmetry (i.e., compression-dominant behavior) of bubble vibrations were found to increase with increasing oscillation amplitude, and reach the maximum for bubbles at resonance. Moreover, with the same fundamental response (εf), the second harmonic response (ε2f) of bubbles smaller than the resonance size is 150% stronger than bubbles bigger than the resonance size. The data showed agreement with numerical simulations based on the shell-buckling model by Marmottant et al. The new system shows its great potential for in vitro characterization of contrast agent MB populations

Ultrasound-Mediated Drug Delivery With a Clinical Ultrasound System: In Vitro Evaluation

Chemotherapy efficacy is often reduced by insufficient drug uptake in tumor cells. The combination of ultrasound and microbubbles (USMB) has been shown to improve drug delivery and to enhance the efficacy of several drugs in vitro and in vivo, through effects collectively known as sonopermeation. However, clinical translation of USMB therapy is hampered by the large variety of (non-clinical) US set-ups and US parameters that are used in these studies, which are not easily translated to clinical practice. In order to facilitate clinical translation, the aim of this study was to prove that USMB therapy using a clinical ultrasound system (Philips iU22) in combination with clinically approved microbubbles (SonoVue) leads to efficient in vitro sonopermeation. To this end, we measured the efficacy of USMB therapy for different US probes (S5-1, C5-1 and C9-4) and US parameters in FaDu cells. The US probe with the lowest central frequency (i.e. 1.6 MHz for S5-1) showed the highest USMB-induced intracellular uptake of the fluorescent dye SYTOX™ Green (SG). These SG uptake levels were comparable to or even higher than those obtained with a custom-built US system with optimized US parameters. Moreover, USMB therapy with both the clinical and the custom-built US system increased the cytotoxicity of the hydrophilic drug bleomycin. Our results demonstrate that a clinical US system can be used to perform USMB therapy as efficiently as a single-element transducer set-up with optimized US parameters. Therefore, future trials could be based on these clinical US systems, including validated US parameters, in order to accelerate successful translation of USMB therapy.ImPhys/Medical Imagin

Time-resolved absolute radius estimation of vibrating contrast microbubbles using an acoustical camera

Ultrasound (US) contrast agents consist of microbubbles ranging from 1 to 10 μm in size. The acoustical response of individual microbubbles can be studied with high-frame-rate optics or an "acoustical camera"(AC). The AC measures the relative microbubble oscillation while the optical camera measures the absolute oscillation. In this article, the capabilities of the AC are extended to measure the absolute oscillations. In the AC setup, microbubbles are insonified with a high- (25 MHz) and low-frequency US wave (1-2.5 MHz). Other than the amplitude modulation (AM) from the relative size change of the microbubble (employed in Renaud, Bosch, van der Steen, and de Jong (2012a). "An 'acoustical camera' for in vitro characterization of contrast agent microbubble vibrations,"Appl. Phys. Lett. 100(10), 101911, the high-frequency response from individual vibrating microbubbles contains a phase modulation (PM) from the microbubble wall displacement, which is the extension described here. The ratio of PM and AM is used to determine the absolute radius, R0. To test this sizing, the size distributions of two monodisperse microbubble populations (R 0 = 2.1 and 3.5 μm) acquired with the AC were matched to the distribution acquired with a Coulter counter. As a result of measuring the absolute size of the microbubbles, this "extended AC"can capture the full radial dynamics of single freely floating microbubbles with a throughput of hundreds of microbubbles per hour. ImPhys/Medical Imagin