Ultrasound Contrast Agent Microbubbles Research Articles

Contrast-Enhanced Ultrasound of the Indeterminate Renal Mass, From the AJR "How We Do It" Special Series.

Contrast-enhanced ultrasound (CEUS) is distinguished from CT and MRI by the use of microbubble ultrasound contrast agents (UCAs) with intravascular blood pool distribution. When performing CEUS, low-intensity ultrasound allows real-time tissue subtraction imaging, whereas high-intensity ultrasound leads to microbubble destruction, enabling visualization of the contrast inflow pattern. CEUS has exceptional contrast resolution that enables the detection of even minimal blood flow, achieving very high NPV for ruling out vascular perfusion and providing high frame rates in the evaluation of tissue perfusion dynamics. UCAs undergo hepatic metabolism and pulmonary clearance, ensuring safety in patients with renal impairment. CEUS excels in distinguishing solid from cystic renal masses, with higher sensitivity than CT or MRI for detection of lesion enhancement. CEUS can aid the further characterization of both solid and cystic lesions and may have particular applications in the surveillance of cystic masses and surveillance after renal cell carcinoma ablation. This review describes the use of CEUS to help characterize indeterminate renal masses, based on the authors' institutional experience. The article highlights key differences between CEUS and CT or MRI, and provides practical insights for performing and interpreting CEUS of renal masses.

Portal Vein Pressure Estimation and Portal Hypertension Discrimination Based on Subharmonic Scattering of Ultrasound Contrast Agent Microbubbles.

The acquisition of real-time portal vein pressure (PVP) is important for portal hypertension (PH) discrimination to monitor disease progress and select treatment options. To date, the PVP evaluation approaches are either invasive or noninvasive but with less stability and sensitivity. We customized an open ultrasound scanner to explore in vitro and in vivo the ultrasound contrast agent SonoVue microbubbles' subharmonic characteristics with acoustic pressure and local ambient pressure, and obtained promising results of PVP measurements in canine models with induced PH by ligation or embolization of portal vein. In in vitro experiments, the highest correlations between the subharmonic amplitude of SonoVue microbubbles and ambient pressure were observed at acoustic pressures of 523 kPa and 563 kPa (r = -0.993, -0.993, P<0.05, respectively). The correlation coefficients between absolute subharmonic amplitudes and PVP (10.7-35.4 mmHg) were the highest among existing studies using microbubbles as pressure sensors (r values ranged from -0.819 to -0.918). The PH (>16 mmHg) diagnostic capacity also achieved a high level (563 kPa, sensitivity = 93.3%, specificity = 91.7%, accuracy = 92.6%). This study proposes a promising measurement for PVP with the highest accuracy, sensitivity, and specificity in an in vivo model compared to existing studies. Future investigations are planned to assess the feasibility of this technique in clinical practice. This is the first study that comprehensively investigates the role of the subharmonic scattering signals from SonoVue microbubbles in evaluating PVP in vivo. It represents a promising alternative to invasive measurements for portal pressure.

Subharmonic resonance of phospholipid coated ultrasound contrast agent microbubbles

Phospholipid encapsulated ultrasound contrast agents have proven to be a powerful addition in diagnostic imaging and show emerging applications in targeted therapy due to their resonant and nonlinear scattering. Microbubble response is affected by their intrinsic (e.g. bubble size, encapsulation physics) and extrinsic (e.g. boundaries) factors. One of the major intrinsic factors at play affecting microbubble vibration dynamics is the initial phospholipid packing of the lipid encapsulation. Here, we examine how the initial phospholipid packing affects the subharmonic response of either individual or a system of two closely-placed microbubbles. We employ a finite element model to investigate the change in subharmonic resonance under ‘small’ and ‘large’ radial excursions. For microbubbles ranging between 1.5 and 2.5 µm in diameter and in its elastic state (σ0 = 0.01 N/m), we demonstrate up to a 10 % shift towards lower frequencies in the peak subharmonic response as the radial excursion increases. However, for a bubble initially in its buckled state (σ0 = 0 N/m), we observe a maximum shift of 8 % towards higher frequencies as the radial excursion increases over the same range of bubble sizes – the opposite trend. We studied the same scenario for a system of two individual microbubbles for which we saw similar results. For microbubbles that are initially in their elastic state, in both cases of a) two identically sized bubbles and b) a bubble in proximity to a smaller bubble, we observed a 6 % and 9 % shift towards lower frequencies respectively; while in the case of a neighboring larger bubble no change in subharmonic resonance frequency was observed. Microbubbles that are initially in a buckled state exert no change, 5 % and 19 % shift towards higher frequencies, in two-bubble systems consisting of a) same-size, b) smaller, and c) larger neighboring bubble respectively. Furthermore, we examined the effect of two adjacent bubbles with non-equal initial phospholipid states. The results presented here have important implications in ultrasound contrast agent applications.

[Experimental study on high-frequency subharmonic scattering characteristics of ultrasound contrast agent microbubbles under low ambient pressure].

Correlation between nonlinear subharmonic scattering of ultrasound contrast agent microbubbles and ambient pressure is expected to be used for local brain tissue pressure monitoring. Although high-frequency ultrasound has achieved high-resolution imaging of intracranial microvessels, the research on high-frequency subharmonic scattering characteristics of microbubbles is insufficient at present, which restricts the research progress of estimating local brain tissue pressure based on high-frequency subharmonic scattering of microbubbles. Therefore, under the excitation of 10 MHz high-frequency ultrasound, the effects of different acoustic pressures and ambient pressures on the high-frequency subharmonic scattering characteristics of three different ultrasound contrast agents including SonoVue, Sonazoid and Huashengxian were investigated in this in vitro study. Results showed that the subharmonic scattering amplitudes of the three microbubbles increased with the increase of ambient pressure at the peak negative acoustic pressures of 696, 766 and 817 kPa, and there was a favorable linear correlation between subharmonic amplitude and ambient pressure. Under the above three acoustic pressures, the highest correlation coefficient of SonoVue was 0.948 ( P = 0.03), the highest sensitivity of pressure measurement was 0.248 dB/mm Hg and the minimum root mean square error (RMSE) was 2.64 mm Hg. Sonazoid's highest correlation coefficient was 0.982 ( P < 0.01), the highest sensitivity of pressure measurement was 0.052 dB/mm Hg and the minimum RMSE was 1.51 mm Hg. The highest correlation coefficient of Huashengxian was 0.969 ( P = 0.02), the highest sensitivity of pressure measurement was 0.098 dB/mm Hg and the minimum RMSE was 2.00 mm Hg. The above in vitro experimental results indicate that by selecting ultrasound contrast agent microbubbles and optimizing acoustic pressure, the correlation between high-frequency subharmonic scattering of microbubbles and ambient pressure can be improved, the sensitivity of pressure measurement can be upgraded, and the measurement error can be reduced to meet the clinical demand for local brain tissue pressure measurement, which provided an important experimental basis for subsequent research in vivo.

Enhanced thrombolytic effect induced by acoustic cavitation generated from nitrogen-doped annealed nanodiamond particles

In biomedical research, ultrasonic cavitation, especially inertial cavitation (IC) has attracted extensive attentions due to its ability to induce mechanical, chemical and thermal effects. Like ultrasound contrast agent (UCA) microbubbles or droplets, acoustic cavitation can be effectively triggered beyond a certain pressure threshold through the interaction between ultrasound and nucleation particles, leading to an enhanced thrombolytic effect. As a newly developed nanocarbon material, nitrogen-doped annealed nanodiamond (N-AND) has shown promising catalytic performance. To further explore its effects on ultrasonic cavitation, N-AND was synthesized at the temperature of 1000 °C. After systematic material characterization, the potential of N-AND to induce enhanced IC activity was assessed for the first time by using passive cavitation detection (PCD). Based on experiments performed at varied material suspension concentration and cycle number, N-AND demonstrated a strong capability to generate significant cavitation characteristics, indicating the formation of stable bubbles from the surface of the materials. Furthermore, N-AND was applied in the in vitro thrombolysis experiments to verify its contribution to ultrasound thrombolysis. The influence of surface hydrophobicity on the cavitation potentials of ND and N-AND was innovatively discussed in combination with the theory of mote-induced nucleation. It is found that the cavitation stability of N-AND was better than that of the commercial UCA microbubbles. This study would provide better understanding of the potential of novel carbonous nanomaterials as cavitation nuclei and is expected to provide guidance for their future biomedical and industrial applications.

Controlled Hyperthermia With High-Intensity Focused Ultrasound and Ultrasound Contrast Agent Microbubbles in Porcine Liver.

The objective of this work was to study microbubble-enhanced temperature elevation with high-intensity focused ultrasound (HIFU) at different acoustic pressures and under image guidance. The microbubbles were administered with either local or vascular injections (that mimic systemic injections) in perfused and non-perfused ex vivo porcine liver under ultrasound image guidance. Porcine liver was insonified for 30 s with a single-element HIFU transducer (0.9 MHz, 0.413 ms, 82% duty cycle, focal pressures of 0.6-3.5 MPa). Contrast microbubbles were injected either locally or through the vasculature. A needle thermocouple at the focus measured temperature elevation. Diagnostic ultrasound (Philips iU22, C5-1 probe) guided placement of the thermocouple and delivery of microbubbles and monitored the procedure in real time. At lower acoustic pressures (0.6 and 1.2 MPa) in non-perfused liver, inertial cavitation of the injected microbubbles led to greater temperatures at the focus compared with HIFU-only treatments. At higher pressures (2.4 and 3.5 MPa) native inertial cavitation in the tissue (without injecting microbubbles) resulted in temperature elevations similar to those after injecting microbubbles. The heated area was larger when using microbubbles at all pressures. In the presence of perfusion, only local injections provided a sufficiently high concentration of microbubbles necessary for significant temperature enhancement. Local injections of microbubbles provide a higher concentration of microbubbles in a smaller area, avoiding acoustic shadowing, and can lead to higher temperature elevation at lower pressures and increase the size of the heated area at all pressures.

Screening of the best time window for MSC transplantation to treat acute myocardial infarction with SDF-1α antibody-loaded targeted ultrasonic microbubbles: An in vivo study in miniswine.

The present study aimed to screen the best time window for the transplantation of bone marrow mesenchymal stem cells (MSCs) after acute myocardial infarction (MI) through targeted ultrasound microbubbles loaded with SDF-1α antibody. Thirty-six MI miniswine were randomly divided into six experimental groups according to the duration after infarction (1 day, 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks after infarction). MSCs were labeled with BrdU and then injected through the coronary artery in the stem cell transplantation group to detect the number of transplanted MSCs at different time points after MI. Three miniswine were randomly selected as the control group (sham operation: open chest without ligation of the coronary artery). All SDF-1α groups and control groups were injected with a targeted microbubble ultrasound contrast agent. The values of the myocardial perfusion parameters (A, β, and A × β) were determined. A T, β T, and (A × β)T varied with time and peaked 1 week after MI (P < 0.05). The number of transplanted stem cells in the myocardium through coronary injection of MSCs at 1 week was the greatest and consistent with the changing tendency of A T, β T, and (A × β)T (r = 0.658, 0.778, 0.777, P < 0.05). β T(X), (A × β)T(X), and the number of transplanted stem cells was used to establish the regression equation as follows: Y = 36.11 + 17.601X; Y = 50.023 + 3.348X (R 2 = 0.605, 0.604, P < 0.05). The best time window for transplanting stem cells was 1 week after MI. The myocardial perfusion parameters of the SDF-1α targeted contrast agent can be used to predict the number of transplanted stem cells in the myocardial tissue.

Biomechanical characteristics in the carotid artery: Noninvasive assessment using subharmonic emissions from microbubbles.

Stroke is closely related to carotid atherosclerotic plaques, which tend to occur in specific parts of the arteries, especially at the bifurcations, and are considered to be caused by biomechanical factors. Quantitative analysis of hemodynamic stress characteristics of the carotid sinus in vivo provides a mechanical basis for the development of atherosclerotic plaque in the carotid sinus. Previous studies found that ultrasound (US) contrast agent microbubbles would vibrate nonlinearly under the excitation of sound pressure, generating subharmonics (transmission fundamental frequency, i.e., f0 and subharmonic frequency at f0 /2), which have the highest sensitivity to pressure changes and exhibit an inverse linear relationship with environmental pressure. This study employed subharmonic aided pressure estimation (SHAPE) technology to reflect carotid artery hydrodynamic characteristics in the carotid lumen. From May 2021 to December 2021, this prospective study reviewed a total of 26 normal carotid arteries of 13 participants, all of whom received bilateral carotid artery routine US and SHAPE US examinations. During this study, the lumen of the bilateral distal segment of the common carotid artery (Distal-CCA), carotid artery bifurcation (CAB), and carotid bulb (CB) were scanned section by section from bottom to top in longitudinal and transverse sections. Subsequently, the subharmonic amplitudes in the lumen of normal carotid arteries were collected and analyzed. This study found that the amplitude of subharmonic amplitude in the carotid was distributed unevenly, with the amplitudes of subharmonic at the CAB being higher. Specifically, the subharmonic gradient of the carotid artery bifurcation apex plane was maximum (9.72±4.31dB), while the average subharmonic amplitude of the outer lateral layer of the carotid artery was higher (-56.40±6.31dB) (p<0.001). The SHAPE technique is capable of indirectly reflecting the pressure changes of vascular system tissues, which may provide a new monitoring method for evaluating mechanical characteristics obviating invasion.

Microbubble contrast agent as a minimally invasive pressure sensor at body temperature and reduced concentrations in an ultrasound flow phantom

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): MRC. Background Cardiac catheterisation is the gold standard for assessing cardiac pressures. However, this is an invasive and costly procedure. A minimally invasive alternative may be to use the subharmonic signal of microbubble ultrasound contrast agents to estimate pressure using echocardiography (Sub-Harmonic Assisted Pressure Estimation: SHAPE). Purpose The aim of this work was to investigate the ability of SHAPE to track dynamic diastolic pressures in a flow phantom at body temperature and at reduced microbubble concentrations. Methods A priming dose of 0.4 mL/L of sulphur hexafluoride microbubbles was circulated through a silicone tube using a peristaltic pump at a flow rate of 375 mL/min (generating 376 pressure cycles/min and maximum pressure gradient of 1.9 mmHg/ms; Fig. 1). The ULtrasound Advanced Open Platform (ULA-OP) was used with a cardiac phased array transducer to transmit a pulse-inversion sequence at 2.1 MHz. Radiofrequency data were recorded at five acoustic pressures (71–228 kPa peak-negative). To investigate the effects of temperature, the subharmonic-pressure relationship was measured over 60 min at both room and body temperature (37°C). Microbubble concentration was maintained by regular top-up (0.15 mL/L every 3–5 min). To investigate the effect of lower concentrations on the subharmonic-pressure relationship, a priming dose of 0.4, 0.3 or 0.2 mL/L was administered before a single acquisition was made. The system was immediately purged before testing the next concentration. The subharmonic (1.05 MHz) amplitude of the microbubbles was calculated over a 40% bandwidth. A solid-state catheter recorded ground-truth pressures. Correlation coefficient (r) and sensitivity (dB/mmHg) of the subharmonic signal to the pressure values were calculated. Results The mean correlation coefficient (r = 0.91 ± 0.04; Fig. 2) and sensitivity (0.20 ± 0.04 dB/mmHg) at body temperature (n = 20) were significantly greater than those for the same batch of microbubbles at room temperature (r = 0.81 ± 0.07 and 0.14 ± 0.02; n = 18; p &amp;lt; 0.05) at the optimal acoustic pressure (Fig. 2). No significant differences in the subharmonic-pressure relationship were observed between the three different microbubble concentrations (Correlation: r = 0.96 ± 0.00, 0.96 ± 0.01, 0.97 ± 0.01. Sensitivity: 0.26 ± 0.02, 0.26 ± 0.03, 0.28 ± 0.02 mmHg/dB for 0.4, 0.3 and 0.2 mL/L, respectively; n = 3) at the optimal acoustic pressure. Conclusions SHAPE can accurately track diastolic pressures five times faster than the average resting heart rate at body temperature and with reduced microbubble concentrations. SHAPE is a potential method for assessing cardiac diastolic pressures using ultrasound in a minimally invasive fashion, being suitable for use in patients with faster microbubble clearance or in the event of delayed acquisition. The use of SHAPE fits into routine clinical procedures and has the potential to improve the diagnosis and monitoring of cardiovascular diseases.

Noninvasive Estimation of Tumor Interstitial Fluid Pressure from Subharmonic Scattering of Ultrasound Contrast Microbubbles

The noninvasive estimation of interstitial fluid pressure (IFP) using ultrasound contrast agent (UCA) microbubbles as pressure sensors will provide tumor treatments and efficacy assessments with a promising tool. This study aimed to verify the efficacy of the optimal acoustic pressure in vitro in the prediction of tumor IFPs based on UCA microbubbles' subharmonic scattering. A customized ultrasound scanner was used to generate subharmonic signals from microbubbles' nonlinear oscillations, and the optimal acoustic pressure was determined in vitro when the subharmonic amplitude reached the most sensitive to hydrostatic pressure changes. This optimal acoustic pressure was then applied to predict IFPs in tumor-bearing mouse models, which were further compared with the reference IFPs measured using a standard tissue fluid pressure monitor. An inverse linear relationship and good correlation (r = -0.853, p < 0.001) existed between the subharmonic amplitude and tumor IFPs at the optimal acoustic pressure of 555 kPa, and pressure sensitivity was 1.019 dB/mmHg. No statistical differences were found between the pressures measured by the standard device and those estimated via the subharmonic amplitude, as confirmed by cross-validation (mean absolute errors from 2.00 to 3.09 mmHg, p > 0.05). Our findings demonstrated that in vitro optimized acoustic parameters for UCA microbubbles' subharmonic scattering can be applied for the noninvasive estimation of tumor IFPs.

Viability of contrast-enhanced voiding urosonography as an alternative to fluoroscopy during video urodynamics.

Pediatric urodynamic studies are performed to evaluate bladder function, commonly in conjunction with a voiding cystourethrogram (VCUG). Contrast-enhanced voiding urosonography (CeVUS) has been approved in the evaluation of vesicoureteral reflux and has been shown to have equal or superior diagnostic value to VCUG. In this technical innovation, we have shown that ultrasound contrast agent microbubbles are compatible with the equipment used for urodynamic evaluation. We have also shown that it is feasible to use contrast ultrasound in pediatric urodynamic examinations.The purpose of our study was to assess the technical feasibility of CeVUS during urodynamics with an in vitro test followed by a vivo evaluation.This single-center prospective study enrolled 25 patients aged 0-18years who underwent CeVUS instead of VCUG at their regularly scheduled appointment.During the in vitro saline experiment, the radiologic and urologic equipment were found to be compatible. Microbubbles were observed at flow rates of 10 and 20 ml/min.

Effect of pulse duty ratio on temperature rise induced by focused ultrasound combined with magnetic microbubbles

Development of acoustic/magnetic contrast agent microbubbles with various diagnostic and therapeutic functions has attracted more and more attention in medical ultrasound, biomedical engineering and clinical applications. Superparamagnetic iron oxide nanoparticles (SPIO) have unique magnetic characteristics and wonderful biocompatibility, so they can be used as MRI contrast agents to improve image contrast, spatial resolution and diagnostic accuracy. Our previous work shows that the multimodal diagnostic and therapeutic microbubble agents can be successfully constructed by embedding SPIO particles into the coating shell of conventional ultrasound contrast agent (UCA) microbubbles, which in turn changes the size distribution and shell properties of UCA microbubbles, thereby affecting their acoustic scattering, cavitation and thermal effects. However, previous studies only considered the influence factors such as acoustic pressure and microbubble concentration. The relevant investigation regarding the influence of ultrasound temporal characteristics on the dynamic response of magnetic microbubbles is still lacking. This work systematically measures the temperature enhancement effect of the SPIO-albumin microbubble solution flowing in the vascular gel phantom exposed to pulsed ultrasound with various temporal settings (e.g. duty cycle, PRF and single pulse length). Meanwhile, a two-dimensional finite element model is developed to simulate and verify the experimental observations. The results show that the increase of duty cycle of pulse signal should be the crucial factor affecting the temperature enhancement effect of flowing SPIO-albumin microbubble solution under the exposure to high-intensity focused ultrasound. The current results help us to better understand the influence of different acoustic setting parameters on the thermal effect of dual-modal magnetic UCA microbubbles, and provide useful guidance for ensuring the safety and effectiveness of the application of SPIO-albumin microbubbles in clinics.

First experiments with carbon black pigment dispersion acting as a Janus ultrasound contrast agent

Abstract Background: Theranostic ultrasound contrast agents comprise a therapeutic component whose controlled release is triggered by an ultrasound pulse. However, once the therapeutic component has been released from an ultrasound contrast agent microbubble, its intended uptake cannot be monitored, as its acoustically active host has been destroyed. Acoustic Janus particles, whose hydrophobic and hydrophilic properties depend on the external acoustic regime, are of potential use as contrast agents and drug-delivery tracers. The purpose of this study was to evaluate the hypothesis that submicron particles with Janus properties may act as ultrasound contrast agents whose hydrophobicity changes over time. Methods: Fifty samples of carbon black were subjected to 5-minute sonication with pulses with a center frequency of 10 MHz and a 1% duty cycle, after which the optical absorption coefficients were measured in n-octanol and water. These coefficients were compared with those of unsonicated samples. Results: Our preliminary results show that the difference between the linear absorption coefficients of sonicated and unsonicated samples was Δα = 80 ± 13 m−1 immediately after sonication, indicating that the carbon black particles were less hydrophobic after sonication than prior to it. Forty-eight hours after sonication, the difference in linear optical absorption coefficients had lessened to Δα = 16 ± 9 m−1, indicating that the carbon black particles had become more hydrophobic over time, but not equal to the hydrophobicity situation prior to sonication. Conclusion: The experiments confirmed that submicron carbon black particles have acoustic Janus properties.

Correlation Between Portal Vein Pressure and Subharmonic Scattering Signals From SonoVue Microbubbles in Canines.

The current gold standard for the clinical diagnosis of portal hypertension (PH) is an invasive and indirect estimation of portal vein pressure (PVP). Therefore, the need for a non-invasive PVP measurement method is urgent. Subharmonic scattering of ultrasound contrast agent (UCA) microbubbles is under investigation in clinical research as a pressure indicator. However, the driving acoustic pressure must be optimized to improve the ambient pressure sensitivity of the subharmonic amplitude for different UCAs. In this study, for the first time, we obtained the relationship between the PVP and the amplitude of the subharmonic signal scattered from SonoVue microbubbles by using two canines to build the PH model. The results revealed a desirable linear correlation between the subharmonic amplitude and PVP (<20 mmHg) at the incident acoustic pressure of 453 kPa (r=-0.910, p < 0.005; sensitivity: -2.003 dB/mmHg); this was one order of magnitude higher in sensitivity than that of the in vitro case with a detectable pressure variation of approximately 1 mmHg. This indicates the feasibility of using UCA microbubbles to accurately measure low ambient pressures in vivo and further exhibits the potential of the method for non-invasive pressure estimation in clinical applications.

Shell viscosity estimation of lipid-coated microbubbles.

Understanding the shell rheology of ultrasound contrast agent microbubbles is vital for anticipating their bioeffects in clinical practice. Past studies using sophisticated acoustic and optical techniques have made enormous progress in this direction, enabling the development of shell models that adequately reproduce the nonlinear behaviour of the coated microbubble under acoustic excitation. However, there have also been puzzling discrepancies and missing physical explanations for the dependency of shell viscosity on the equilibrium bubble radius, which demands further experimental investigations. In this study, we aim to unravel the cause of such behaviour by performing a refined characterisation of the shell viscosity. We use ultra-high-speed microscopy imaging, optical trapping and wide-field fluorescence to accurately record the individual microbubble response upon ultrasound driving across a range of bubble sizes. An advanced model of bubble dynamics is validated and employed to infer the shell viscosity of single bubbles from their radial time evolution. The resulting values reveal a prominent variability of the shell viscosity of about an order of magnitude and no dependency on the bubble size, which is contrary to previous studies. We find that the method called bubble spectroscopy, which has been used extensively in the past to determine the shell viscosity, is highly sensitive to methodology inaccuracies, and we demonstrate through analytical arguments that the previously reported unphysical trends are an artifact of these biases. We also show the importance of correct bubble sizing, as errors in this aspect can also lead to unphysical trends in shell viscosity, when estimated through a nonlinear fitting from the time response of the bubble.

The influence of inter-bubble spacing on the resonance response of ultrasound contrast agent microbubbles

Ultrasound-driven microbubbles, typically between 1 and 8 µm in diameter, are resonant scatterers that are employed as diagnostic contrast agents and emerging as potentiators of targeted therapies. Microbubbles are administered in populations whereby their radial dynamics – key to their effectiveness - are greatly affected by intrinsic (e.g. bubble size) and extrinsic (e.g. boundaries) factors. In this work, we aim to understand how two neighbouring microbubbles influence each other. We developed a finite element model of a system of two individual phospholipid-encapsulated microbubbles vibrating in proximity to each other to study the effect of inter-bubble distance on microbubble radial resonance response. For the case of two equal-sized and identical bubbles, each bubble exhibits a decrease between 7 and 10% in the frequency of maximum response (fMR) and an increase in amplitude of maximum response (AMR) by 9–11% as compared to its isolated response in free-space, depending on the bubble size examined. For a system of two unequal-sized microbubbles, the large bubble shows no significant change, however the smaller microbubble shows an increase in fMR by 7–11% and a significant decrease in AMR by 38–52%. Furthermore, in very close proximity the small bubble shows a secondary off-resonance peak at the corresponding fMR of its larger companion microbubble. Our work suggests that frequency-dependent microbubble response is greatly affected by the presence of another bubble, which has implications in both imaging and therapy applications. Furthermore, our work suggests a mechanism by which nanobubbles show significant off-resonance vibrations in the clinical frequency range, a behaviour that has been observed experimentally but heretofore unexplained.

High-order singular value decomposition of contrast pulsing sequences for improved clutter suppression

Contrast-enhanced ultrasound is a diagnostic tool used to visualize blood flow in the cardiovascular system. The use of ultrasound contrast agent (microbubbles) in combination with contrast pulsing scheme (CPS) improves the sensitivity and specificity of ultrasound flow imaging by enhancing the signal in the blood compartment. The commonly used CPS are pulse inversion (PI), amplitude modulation (AM), and amplitude-modulated pulse inversion (AMPI). Using differences in phase or amplitude of multiple pulses, the linear tissue clutter signal can be suppressed. However, this process can be degraded by motion or non-linear propagation of the ultrasound wave. These effects cause the cancellation of linear clutter signal to be ineffective We propose using higher-order singular value decomposition (HOSVD) with spatial, temporal, and pulsing dimensions as the input to improve clutter suppression under the conditions of motion and non-linear propagation. We performed systematic in-vitro- experiment emulating these conditions, as well as in-vivo cardiac measurements. The results showed that HOSVD increases the clutter suppression of all the 3 CPS compared to the conventional linear processing. The improvement of clutter reduction could be beneficial to various cardiac evaluation like myocardial perfusion or intra ventricular flow assessment.

First-cycle oscillation excursions of Pickering-stabilised microbubbles subjected to a high-amplitude ultrasound pulse

Abstract Pickering stabilisation is a manufacturing process involving the adsorption of colloidal particles at gas-liquid interfaces. It is used to create the shells of stable, long-lived ultrasound contrast agent microbubbles. The purpose of the present study is to determine whether high-amplitude sonication influences the integrity of Pickering-stabilised shells. To this purpose, Pickering-stabilised microbubbles were subjected to high-speed photography at 10 million frames per second during 1-MHz, 1-MPa sonication. In addition, radial excursions as a function of time were simulated using the Rayleigh-Plesset equation for free gas microbubbles and microbubbles encapsulated by Pickering-stabilised shells of 7.6-Nm−1 stiffness. The maximum expansions observed from camera recordings were either agreeing with those computed for Pickering-stabilised microbubbles or corresponding to greater values. The results indicate that optically identical microbubbles may undergo shell disruption of different severity. We conclude that the disruption occurs during sonication and not prior to it. These findings may aid in the development of Pickering-stabilised agents that facilitate ultrasoundtriggered release.

Microbubbles Contrast Agents: General Overview as Diagnostics and Therapeutic Agent.

Recent discoveries have unfolded many powerful emerging applications in the field of drug delivery science. For the past few years, ultrasound mediated microbubble contrast agents have been an emerging modality for diagnostic and drug delivery applications. Microbubbles are small spherical bubbles composed of a gas core encapsulated by a shell with different materials. The composition of the microbubble determines its stiffness, encapsulation efficiency, stability, and clearance from the system. A gas-filled microbubble, when activated by an acoustic pulse, can produce large volumetric oscillations and, once administered intravenously, can act as a cavitating nuclei, allowing for a wide range of ultrasound-assisted drug delivery applications. Microbubbles offer a fantastic approach to ultrasound triggered drug delivery with various drug loading techniques and targeting strategies for the uptake of bioactive substances such as polynucleotides, proteins, genes, and small-molecule drugs. Microbubbles can be used for several diagnostic and therapeutic purposes for accurate detection and treatment of various life-threatening diseases.

Probing the mechanisms of sonodynamic therapy

Drugs that can be activated by a physical stimulus at a target site offer great potential for limiting toxic side effects, e.g., in cancer therapy. In photodynamic therapy, light is used as the stimulus, but clinical applications are limited due to the poor penetration of light in tissue. Multiple studies have demonstrated that ultrasound can also be used to activate some light-responsive drugs. This potentially extends the range of therapeutic applications considerably, but the mechanisms underpinning drug activation, dubbed sonodynamic therapy (SDT), remain unclear. It was recently demonstrated that multi-bubble sonoluminescence could be detected from a suspension of microbubble ultrasound contrast agents when exposed to ultrasound under conditions similar to those used in SDT. Moreover, the addition of an SDT drug produced a reduction in optical emissions at the wavelength corresponding to its activation. Numerous questions, however, remain and the aim of this talk is to review recent studies of SDT and new evidence for the roles of sonoluminescence, sonoporation, and other phenomena hypothesized to play a role in its mechanism of action.