Self-Propulsion of Two Contacting Bubbles Due to the Radiation Interaction Force.

In this paper, we consider a new bubble-based microswimmer composed of two contacting bubbles. Under the action of an acoustic field, both bubbles are oscillating, and locomotion of the two-bubble system is observed. A theory is developed that allows one to calculate the acoustic radiation interaction forces between two gas bubbles in an incompressible viscous liquid for any small separation distance between the bubbles. This theory is used to demonstrate that two acoustically excited bubbles can create a self-propelled microswimmer due to a nonzero net force experienced by the bubbles when they come in contact. Experimental evidence of the creation of such a swimmer and of its motion is provided.

Signatures of microstreaming patterns induced by non-spherically oscillating bubbles.

In this study, we report recent theoretical and experimental developments dealing with the axisymmetric flow surrounding non-spherically oscillating microbubbles. A wide variety of microstreaming patterns is revealed using a theoretical modeling providing exact analytical solutions of the second-order mean flows. The streaming pattern is highly dependent on the modal content of the bubble interface oscillation, including possibly spherical, translational, and nonspherical modes, as well as any combination of these modes. Experimental results on fluid flow induced by a single, non-spherically oscillating bubble in an unbounded fluid are presented and successfully compared to the theoretical predictions.

Induction of Microstreaming by Nonspherical Bubble Oscillations in an Acoustic Levitation System.

When located near biological barriers, oscillating microbubbles may increase cell membrane permeability, allowing for drug and gene internalization. Experimental observations suggest that the temporary permeabilization of these barriers may be due to shear stress that is exerted on cell tissues by cavitation microstreaming. Cavitation microstreaming is the generation of vortex flows which arise around oscillating ultrasound microbubbles. To produce such liquid flows, bubble oscillations must deviate from purely spherical oscillations and include either a translational instability or shape modes. Experimental studies of bubble-induced flows and shear stress on nearby surfaces are often restricted in their scope due to the difficulty of capturing shape deformations of microbubbles in a stable and controllable manner. We describe the design of an acoustic levitation chamber for the study of symmetry-controlled nonspherical oscillations. Such control is performed by using a coalescence technique between two approaching bubbles in a sufficiently intense ultrasound field. The control of nonspherical oscillations opens the way to a controlled cavitation microstreaming of a free surface-oscillating microbubble. High-frame rate cameras allow investigating quasi-simultaneously the nonspherical bubble dynamics at the acoustic timescale and the liquid flow at a lower timescale. It is shown that a large variety of fluid patterns may be obtained and that they are correlated to the modal content of the bubble interface. We demonstrate that even the high-order shape modes can create large-distance fluid patterns if the interface dynamics contain several modes, highlighting the potential of nonspherical oscillations for targeted and localized drug delivery.

Acoustic microstreaming produced by nonspherical oscillations of a gas bubble. IV. Case of modes n and m.

This paper is the conclusion of work done in our previous papers [A. A. Doinikov et al., Phys. Rev. E 100, 033104 (2019)10.1103/PhysRevE.100.033104; Phys. Rev. E 100, 033105 (2019)10.1103/PhysRevE.100.033105]. The overall aim of the study is to develop a theory for modeling the velocity field of acoustic microstreaming produced by nonspherical oscillations of a gas bubble. In our previous papers, general equations were derived to describe the velocity field of acoustic microstreaming produced by modes m and n of bubble oscillations. Particular cases of mode interaction were derived, such as the 0-n, 1-1, 1-m, and n-n interactions. Here the general case of interaction between modes n and m, n>m, is solved analytically. Solutions are expressed in terms of complex mode amplitudes, meaning that the mode amplitudes are assumed to be known and serve as input data for the calculation of the velocity field of microstreaming. No restrictions are imposed on the ratio of the bubble radius to the viscous penetration depth. The n-m interaction results in specific streaming patterns: At large distance from the bubble interface the pattern exhibits 2|n-m| lobes, while 2min(m,n) lobes exist in the bubble vicinity. The spatial organization of the recirculation zones is unique for the interaction of two distinct nonspherical modes and therefore appears as a signature of the n-m interaction.

TRPV4 promotes acoustic wave-mediated BBB opening via Ca2+/PKC-δ pathway.

INTRODUCTION: Numerous studies have shown the ability of low-energy acoustic waves such as focused ultrasound or shockwave to transiently open blood-brain barrier (BBB) and facilitate drug delivery to the brain. Preclinical and clinical evidences have well demonstrated the efficacy and safety in treating various brain disorders. However, the molecular mechanisms of acoustic waves on the BBB are still not fully understood. OBJECTIVES: The present study aimed at exploring the possible molecular mechanisms of acoustic wave stimulation on brains. METHODS BRIEFLY DESCRIBE THE EXPERIMENTAL DESIGN: The left hemisphere of the rat's brain was treated with pulsed ultrasound from a commercial focused shockwave or a planar ultrasound device, and the right hemisphere served as a control. One hour after the mechanical wave stimulation or overnight, the rats were sacrificed and the brains were harvested for protein or histological analysis. Agonists and antagonists related to the signal transduction pathways of tight junction proteins were used to investigate the possible intracellular mechanisms. RESULTS: Intracellular signal transduction analysis shows calcium influx through transient receptor potential vanilloid 4 (TRPV4) channels, and the activation of PKC-δ pathway to mediate dissociation of ZO-1 and occludin after acoustic wave stimulation. The activation of TRPV4 or PKC-δ signaling further increased the expression level of TRPV4, suggesting a feedback loop to regulate BBB permeability. Moreover, the tight junction proteins dissociation can be reversed by administration of PKC-δ inhibitor and TRPV4 antagonist. CONCLUSION: The present study shows the crucial role of TRPV4 in acoustic wave-mediated BBB permeability, specifically its effect on compromising tight junction proteins, ZO-1 and occludin. Our findings provide a new molecular perspective to explain acoustic wave-mediated BBB opening. Moreover, activation of TRPV4 by agonists may reduce the threshold intensity level of acoustic waves for BBB opening, which may prevent undesirable mechanical damages while maintaining efficient BBB opening.

Nonspherical modes nondegeneracy of a tethered bubble.

When excited at sufficiently high acoustic pressures, a wall-attached bubble may exhibit asymmetric nonspherical modes. These vibration modes can be decomposed over the set of spherical harmonics Y_{nm}(θ,ϕ) for a degree n and order m. We experimentally capture the time-resolved dynamics of asymmetric bubble oscillations in a top-view configuration. A spatiotemporal modal analysis is performed and allowed recovering the set of zonal (m=0), tesseral (0

Secondary radiation force between two closely spaced acoustic bubbles.

Two acoustic bubbles may attract or repel due to the secondary radiation force acting on them. We use here a dual-frequency levitation chamber in order to trap two oscillating microbubbles at close, fixed distance, and to perform measurements of the interaction force. We successfully compare our measurements to a commonly used theoretical model that assumes linear spherical oscillations, and disregards attenuation and multiple scattering between bubbles. The deviation from the model arises when nonspherical surface oscillations are triggered, leading to an additional hydrodynamic force induced by second-order liquid flow.

A Single High-Intensity Shock Wave Pulse With Microbubbles Opens the Blood-Brain Barrier in Rats.

Focused extracorporeal shockwave (FSW), one kind of focused high-intensity pulsed ultrasound, has been shown to induce blood-brain barrier (BBB) opening in targeted brain areas in rat animal models with minimal detrimental effects below threshold intensity levels or iterations. In the current study, we found that the thresholds could be further reduced by the addition of microbubbles (ultrasound contrast agents or UCA; SonoVue). FSW with 2 × 106 MBs/kg of UCA (20% of clinical dosage) at an intensity level of 0.1 (peak positive pressure 5.4 MPa; peak negative pressure -4.2 MPa; energy flux density 0.03 mJ/mm2) resulting in a 100% BBB opening rate without detectable hemorrhage or apoptosis in the brain. Significantly reduced free radical production was found compared with 0.5 MHz focused ultrasound at a peak negative pressure of 0.44 MPa (1% duty cycle and 4 × 107 MBs/kg of UCA). FSW devices offer advantages of commercial availability and high safety, and thus may facilitate future research and applications of focal BBB opening for oncological and pharmacological purposes.

Subharmonic spherical bubble oscillations induced by parametric surface modes.

A potential source of subharmonic bubble emissions is revealed experimentally by high-speed imaging. When an acoustic bubble is driven at sufficiently large pressure amplitudes, energy transfer from surface to volume oscillations can lead to the triggering of subharmonic spherical oscillations. This experimental evidence is in agreement with recent theoretical modeling of nonspherical bubble dynamics accounting for nonlinear mode coupling. Implications for the monitoring of stable cavitation activity are discussed.

Acoustic microstreaming produced by nonspherical oscillations of a gas bubble. III. Case of self-interacting modes n-n.

This paper is the continuation of work done in our previous papers [A. A. Doinikov et al., Phys. Rev. E 100, 033104 (2019)2470-004510.1103/PhysRevE.100.033104; Phys. Rev. E 100, 033105 (2019)].2470-004510.1103/PhysRevE.100.033105 The overall aim of the study is to develop a theory for modeling the velocity field of acoustic microstreaming produced by nonspherical oscillations of an acoustically driven gas bubble. In our previous papers, general equations have been derived to describe the velocity field of acoustic microstreaming produced by modes m and n of bubble oscillations. After solving these general equations for some particular cases of modal interactions (cases 0-n, 1-1, and 1-m), in this paper the general equations are solved analytically for the case that acoustic microstreaming results from the self-interaction of an arbitrary surface mode n≥1. Solutions are expressed in terms of complex mode amplitudes, meaning that the mode amplitudes are assumed to be known and serve as input data for the calculation of the velocity field of acoustic microstreaming. No restrictions are imposed on the ratio of the bubble radius to the viscous penetration depth. The self-interaction results in specific streaming patterns: a large-scale cross pattern and small recirculation zones in the vicinity of the bubble interface. Particularly the spatial organization of the recirculation zones is unique for a given surface mode and therefore appears as a signature of the n-n interaction. Experimental streaming patterns related to this interaction are obtained and good agreement is observed with the theoretical model.

Confocal lens focused piezoelectric lithotripter.

This work focuses on the evaluation of a type of piezoelectric lithotripter with similar dimensions of a commercial lithotripter and composed of either 3 or 4 large lens focused piezoelectric transducers set either in a confocal coplanar C-shape or a confocal spherical shape. Each transducer is made with a 92 mm diameter 220 kHz flat piezoelectric ceramic disc and a 3D printed acoustic lens. Both confocal setups pressure field were measured with a fiber optic hydrophone, and in vitro fragmentations of 13 mm diameter and 14 mm length cylindrical model stones were done in a 2 mm mesh basket. The acoustic characterization of the three transducers confocal setup revealed a disc shaped focal volume, with a 2.2 mm width on one axis and a 9.6 mm width on the other, and a peak positive pressure of 40.9 MPa and a peak negative pressure of -16.9 MPa, while the focus of the four transducers confocal setup was similar to a traditional narrow focus high pressure lithotripter with a focus width of 2.1 mm, and a peak positive pressure of 71.9 MPa and peak negative pressure of -24.3 MPa. Both confocal setups showed in vitro fragmentation efficiency close to a commercial electroconductive lithotripter.

Acoustic microstreaming produced by nonspherical oscillations of a gas bubble. I. Case of modes 0 and m.

A theory is developed that allows one to model the velocity field of acoustic microstreaming produced by nonspherical oscillations of an acoustically driven gas bubble. It is assumed that some of the bubble oscillation modes are excited parametrically and hence can oscillate at frequencies different from the driving frequency. Analytical solutions are derived in terms of complex amplitudes of oscillation modes, which means that the mode amplitudes are assumed to be known and serve as input data when the velocity field of acoustic microstreaming is calculated. No restrictions are imposed on the ratio of the bubble radius to the viscous penetration depth. The present paper is the first part of our study in which a general theory is developed and then applied to the case that acoustic microstreaming is generated by the interaction of the breathing mode (mode 0) with a mode of arbitrary order m≥1. Examples of numerical simulations and a comparison with experimental results are provided.

Acoustic microstreaming produced by nonspherical oscillations of a gas bubble. II. Case of modes 1 and m.

This paper continues a study that was started in our previous paper [A. A. Doinikov et al., Phys. Rev. E 100, 033104 (2019)10.1103/PhysRevE.100.033104]. The overall aim of the study is to develop a theory for modeling the velocity field of acoustic microstreaming produced by nonspherical oscillations of an acoustically driven gas bubble. In the previous paper, general equations were derived that describe the velocity field of acoustic microstreaming produced by modes n and m of bubble oscillations. In the present paper, the above equations are solved analytically in the case that acoustic microstreaming is the result of the interaction of the translational mode (mode 1) with a mode of arbitrary order m≥1. Solutions are expressed in terms of complex mode amplitudes, which means that the mode amplitudes are assumed to be known and serve as input data for the calculation of the velocity field of acoustic microstreaming. No restrictions are imposed on the ratio of the bubble radius to the viscous penetration depth. Analytical results are illustrated by numerical examples.

Contrast Agent Microbubble Jetting during Initial Interaction with 200-kHz Focused Ultrasound.

The initial response of microbubbles flowing through a 500-µm polycarbonate capillary to a burst of 200-kHz focused ultrasound, at peak-negative pressure amplitudes from 0.7-1.5 MPa, was investigated with dual-perspective high-speed imaging. Directed jetting through the acoustic focus is demonstrated according to the pressure gradients acting across the cavitating microbubbles. At lower amplitudes, repeated microbubble-jetting is accompanied by sudden, intermittent translation. At higher amplitudes a rebound jet also forms, before disintegration into a cavitation cloud.

Safety evaluation of frequent application of microbubble-enhanced focused ultrasound blood-brain-barrier opening.

Focused ultrasound (FUS) with the presence of microbubbles induces blood brain barrier (BBB) opening in targeted areas and facilitates drug delivery. However, recent studies have indicated that FUS-BBB opening with excessive exposure levels may be associated with inflammatory response and cellular/tissue damage. Multiple weekly FUS exposures have been shown to be safe for human subjects. However the effect of more frequent FUS exposures is still unknown. This study examines whether frequent focused ultrasound blood brain barrier opening is associated with aggravated behavioral, histopathologic change or brain tissue damage. Two protocols of focused ultrasound blood brain barrier opening were devised using different microbubble doses (0.15 µl/kg and 0.4 µl/kg). Focused ultrasound exposure at a threshold level of BBB-opening, below-threshold level, or above level for intracerebral hemorrhage were delivered every 2 days. Animal behavioral and physiological changes were examined and recorded. Brain tissue was examined for hemorrhage and apoptosis. Results indicate that frequent exposure of excessive focused ultrasound (1.4 mechanical index) produced minor and short-term behavioral changes despite significant tissue damage, while frequent BBB opening with threshold or below-threshold FUS exposure (0.33-0.8 mechanical index) did not cause behavioral or histological change. Immunofluorescent examination of rat brain tissue indicated that excessive doses of microbubble administration induce an apparent cellular apoptotic response, which may be exacerbated by intracerebral hemorrhage. Experimental results suggest that frequent focused ultrasound blood brain barrier opening with sufficient ultrasound exposure level and a microbubble dose can be safe and pose minimal risk to brain tissue.

Ultrafast monitoring and control of subharmonic emissions of an unseeded bubble cloud during pulsed sonication.

In the aim of limiting the destructive effects of collapsing bubbles, the regime of stable cavitation activity is currently targeted for sensitive therapeutic applications such as blood-brain barrier opening by ultrasound. This activity is quantified through the emergence of the subharmonic component of the fundamental frequency. Due to the intrinsically stochastic behavior of the cavitation phenomenon, a better control of the different (stable or inertial) cavitation regimes is a key requirement in the understanding of the mechanisms involving each bubble-induced mechanical effect. Current strategies applied to stable cavitation control rely on the use of either seeded microbubbles or a long-lasting pulse to reinitiate subharmonic emission. The present work aims at developing an ultrafast (inferior to 250 µs) monitoring and control of subharmonic emissions during long-pulsed (50 ms) sonication. The use of a FPGA-based feedback loop provides reproducible level of subharmonic emissions combined with temporal stability during the sonication duration. In addition, stable cavitation events are differentiated from the broadband noise characterizing inertial cavitation activity, with perspectives in the discrimination of the involved mechanisms underlying bubble-mediated therapeutic applications.

Focused shockwave induced blood-brain barrier opening and transfection.

Despite extensive efforts in recent years, the blood-brain barrier (BBB) remains a significant obstacle for drug delivery. This study proposes using a clinical extracorporeal shockwave instrument to open the BBB, combined with a laser assisted bi-axial locating platform to achieve non-invasive, controllable-focus and reversible BBB opening in the brains of rats. Under shockwave treatment with an intensity level of 5 (P-9.79 MPa, energy flux density (EFD) 0.21 mJ/mm2) and a pulse repetition frequency of 5 Hz, the BBB could be opened after 50 shocks without the use of an ultrasound contrast agent. With the proposed method, the BBB opening can be precisely controlled in terms of depth, size and location. Moreover, a shockwave based gene transfection was demonstrated using a luciferase gene.

A derivation of the stable cavitation threshold accounting for bubble-bubble interactions.

The subharmonic emission of sound coming from the nonlinear response of a bubble population is the most used indicator for stable cavitation. When driven at twice their resonance frequency, bubbles can exhibit subharmonic spherical oscillations if the acoustic pressure amplitude exceeds a threshold value. Although various theoretical derivations exist for the subharmonic emission by free or coated bubbles, they all rest on the single bubble model. In this paper, we propose an analytical expression of the subharmonic threshold for interacting bubbles in a homogeneous, monodisperse cloud. This theory predicts a shift of the subharmonic resonance frequency and a decrease of the corresponding pressure threshold due to the interactions. For a given sonication frequency, these results show that an optimal value of the interaction strength (i.e. the number density of bubbles) can be found for which the subharmonic threshold is minimum, which is consistent with recently published experiments conducted on ultrasound contrast agents.

Accompanying the frequency shift of the nonlinear resonance of a gas bubble using a dual-frequency excitation.

An asymptotic method is applied to analyze the nonlinear oscillations of a gas bubble driven by a dual-frequency excitation. More specifically, the latter is considered as a combination of two neighboring, incommensurate frequencies and is treated as a nonstationary excitation. This implies that both amplitude and phase of the bubble response are slowly oscillating at the time scale of the frequency difference, thus leading to a regime of aperiodic oscillations. The approximate solution is successfully compared with numerical simulations and reveals the possibility of achieving larger bubble response amplitude compared to the monofrequency excitation for sufficiently high driving pressure and specific values of the frequency difference. The asymptotic theory captures the generation of additional spectral components coming from the nonlinear mixing of both driving frequencies. This mechanism is responsible for a global enhancement of the dual-frequency bubble response as it enables an energy transfer towards more efficient components which are successively tuned with the nonlinearly shifted resonance frequency of the bubble, thus limiting the saturation due to softening.

Dynamics of nonspherical microbubble oscillations above instability threshold.

Time-resolved dynamics of nonspherical oscillations of micrometer-sized bubbles are captured and analyzed using high-speed imaging. The axisymmetry of the bubble shape is ensured with certainty for the first time from the recordings of two synchronous high-speed cameras located at 90^{∘}. The temporal dynamics of finite-amplitude nonspherical oscillations are then analyzed for various acoustic pressures above the instability threshold. The experimental results are compared with recent theories accounting for nonlinearities and mode coupling, highlighting particular effects inherent to these mechanisms (saturation of the instability, triggering of nonparametric shape modes). Finally, the amplitude of the nonspherical oscillations is given as function of the driving pressure both for quadrupolar and octupolar bubbles.