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(color online) Microstreaming velocity fields generated by a pulsating bubble with (a) no membrane; (b) with the values of bubble-cell distance d being (b) 2R 0 and (c) 4R 0 .
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Sonoporation mediated by microbubbles is being extensively studied as a promising technology to facilitate gene/drug delivery to cells. However, the theoretical study regarding the mechanisms involved in sonoporation is still in its infancy. Microstreaming generated by pulsating microbubble near the cell membrane is regarded as one of the most impo...
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Context 1
... Therefore, the influences of bubble-cell distance (d) and shell visco-elastic properties on microstreaming shear stress are investigated thoroughly in the present work. Figure 2 illustrates the microstreaming velocity fields generated by a pulsating bubble with/without the cell mem- brane. If the bubble sits in a free field in the absence of the cell membrane (Fig. 2(a)), a symmetric velocity field is dis- tributed in the liquid surrounding the bubble with the velocity radially decaying from the bubble surface. ...
Context 2
... influences of bubble-cell distance (d) and shell visco-elastic properties on microstreaming shear stress are investigated thoroughly in the present work. Figure 2 illustrates the microstreaming velocity fields generated by a pulsating bubble with/without the cell mem- brane. If the bubble sits in a free field in the absence of the cell membrane (Fig. 2(a)), a symmetric velocity field is dis- tributed in the liquid surrounding the bubble with the velocity radially decaying from the bubble surface. When the bubble sits in the vicinity of the membrane with a bubble-to-cell dis- tance d = 2R 0 , the microstreaming velocity field around the bubble becomes asymmetric (Fig. 2(b)). The liquid ...
Context 3
... of the cell membrane (Fig. 2(a)), a symmetric velocity field is dis- tributed in the liquid surrounding the bubble with the velocity radially decaying from the bubble surface. When the bubble sits in the vicinity of the membrane with a bubble-to-cell dis- tance d = 2R 0 , the microstreaming velocity field around the bubble becomes asymmetric (Fig. 2(b)). The liquid velocity on the top of the bubble is larger than between the bubble and the membrane, as the vibration of the bottom half of the bub- ble is restricted by the cell membrane. However, when the bubble-cell distance is larger (e.g. d = 4R 0 ), the asymmetric velocity distribution turns inconspicuous, which suggests that the ...
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Citations
... Furthermore, shear stress produced by cavitation after sonoporation of conidia has been reported to cause changes in cell permeability. Consequently, if cells are in the vicinity of cavitating bubbles, transient pores derived from the viscoelastic shear forces of these microstreams may appear on their surface [55][56][57]. During shock wave treatment, bubbles normally do not oscillate; however, both bubble expansion and compression have much higher energy, and strong shear stress can be expected. ...
Since the discovery of extracorporeal lithotripsy, there has been an increased interest in studying shock wave-induced cavitation, both to improve this technique and to explore novel biotechnological applications. As shock waves propagate through fluids, pre-existing microbubbles undergo expansion and collapse, emitting high-speed microjets. These microjets play a crucial role in the pulverization of urinary stones during lithotripsy and have been utilized in the delivery of drugs and genetic materials into cells. Their intensity can be amplified using tandem shock waves, generated so that the second wave reaches the bubbles, expanded by the first wave, during their collapse. Nevertheless, there is little information regarding the control of microjet emissions. This study aimed to demonstrate that specific effects can be obtained by tuning the delay between the first and second shock waves. Suspensions containing Aspergillus niger, a microscopic fungus that produces metabolites with high commercial value, were exposed to single-pulse and tandem shock waves. Morphological changes were analyzed by scanning and transmission electron microscopy. Proteins released into the medium after shock wave exposure were also studied. Our findings suggest that, with enhanced control over cavitation, the detachment of proteins using conventional methods could be significantly optimized in future studies.
... According to Nyborg's theory, [39,40] if the pulsating bubble is close to the vessel wall, the x component of shear stress on the cells can be quantified by ...
Magnetic microbubbles (MMBs) can be controlled and directed to target site by a suitable external magnetic field, have potential in therapeutic drug-delivery application. However, few studies focus on their dynamics in blood vessels under the action of magnetic and ultrasonic fields, even little insight into mechanism generated in diagnostic and therapeutic application. In this case, equations of MMBs were established for simulating translation, radial pulsation and the both coupled effect. Meanwhile, the acoustic streaming and shear stress on vessel wall were also presented, which are associated with drug release. Results suggest that the magnetic pressure increases bubble pulsation amplitude, and the translation coupled with pulsation are manipulated by magnetic force, causing the retention in target area. As the bubble approaches the vessel wall, the acoustic streaming and shear stress increase with magnetic field enhancement. Responses of bubble to a uniform and a gradient magnetic field were explored in this work. The mathematical models derived in this work could provide theoretical support for experimental phenomenon in literature and also agree with the reported models.
... Many of these studies 8,10,17-20 have found that the shear and circumferential stress on the wall increases as the pressure which drives the bubble's oscillation (i.e. the acoustic pressure) is increased. With respect to the acoustic frequency, several previous studies 10, 17,18,[21][22][23] have found that the stresses and vessel displacement are maximized at various specific frequencies related to the resonance of the bubbles, vessel elasticity and gap between walls. At the same time, studies of the effect of bubble and vascular parameters on stress have been reported. ...
... that the shear stress was largely independent of the vessel radius, while the expansion of the bubble led, inevitably, to an increase in circumferential stress. 26 Several other studies, investigating the effect of separation between the bubble and the vessel wall, 21,25,26 have reported a marked decrease in stresses (shear and circumferential) with increasing distance between bubble and wall. In addition, Hosseinkhah et al. 15 compared the stresses during the collapse and expansion phases of an oscillating bubble (1 μm in radius) when sonicated at 1 MHz and 800 kPa, and showed that when the distance between the bubble and the wall was less than 6-7 μm, both shear and circumferential stresses during the bubble collapse were higher than during bubble expansion. ...
Understanding the stress patterns produced by microbubbles (MB) in blood vessels is important in enhancing the efficacy and safety of ultrasound-assisted therapy, diagnosis and drug delivery. In this study, the wall stress produced by a non-spherical oscillation of MBs within the lumen of micro-vessels was numerically analyzed using a three-dimensional finite element method. We systematically simulated configurations containing an odd number of bubbles from three to nine, equally spaced along the long axis of the vessel, insonated at an acoustic pressure of 200 kPa. We observed that 3 MBs were sufficient to simulate the stress state of an infinite number of bubbles. As the bubble spacing increased the interaction between them weakened to the point that they could be considered to act independently. In the relationship between stress and acoustic frequency there were differences between the single and 3 MB cases. The stress induced by 3MBs was greater than the single bubble case. When the bubbles were near the wall, the shear stress peak was largely independent of vessel radius, but the circumferential stress peak increased with the radius. This study offers further insight into our understanding of, the magnitude and distribution of stresses produced by multiple ultrasonically excited MBs inside capillaries.
... Using a lumped-parameter model that took the bubble shell and the fluid viscosity into account, Qin and Ferrara investigated the natural frequency of nonlinear oscillations of UCAs in a partially compliant and stiffness vessels [21]. In addition, many asymmetric models were proposed to simulate the asymmetric oscillations and acoustic responses of the bubble in a small vessel, ______________________________ based on the boundary element method (BEM), the finite element method (FEM) or the combination of these two methods [16], [7], [13]. These numerical results predicted that vascular damage could occur during vascular injections due to the elevated wall shear stress and circumferential stress. ...
... Consequently, these UDMs induced elevated shear stress levels maybe greatly enhance the permeability of blood vessel wall. Several models have been proposed for the microbubble-cell interaction in sonoporation focusing on different aspects: cell expansion and microbubble jet velocity [28], the shear stress exerted on the cell membrane [30], microstreaming of the shear stress exerted on the cell membrane in combination with microstreaming [13] generated by an oscillating microbubble. In contrast to the other models, Man et al. [15] proposed that microbubble-generated shear stress does not induce pore formation, but is, instead, the results of microbubble fusion with the membrane and subsequent "pull out" of cell membrane lipid molecules by the oscillating microbubble. ...
... UDM at relatively low frequencies could increase vascular permeability [26]. Meanwhile, we demonstrated the stresses patterns of the entire vessel wall, not just a specified point of vessel wall [7], [13]. On the other hand, we focused on the vessel stresses for different initial bubble radii and frequencies, as shown in Fig. 13, which were important for the shear intensity [18], and vessel sonoporation/ permeability [27]. ...
Purpose:
The goal of this study was to evaluate the biomechanical effects such as sonoporation or permeability, produced by ultrasound- driven microbubbles (UDM) within microvessels with various parameters.
Methods:
In this study, a bubble-fluid-solid coupling system was established through combination of finite element method. The stress, strain and permeability of the vessel wall were theoretically simulated for different ultrasound frequencies, vessel radius and vessel thickness.
Results:
the bubble oscillation induces the vessel wall dilation and invagination under a pressure of 0.1 MPa. The stress distribution over the microvessel wall was heterogeneous and the maximum value of the midpoint on the inner vessel wall could reach 0.7 MPa as a frequency ranges from 1 to 3 MHz, and a vessel radius and an initial microbubble radius fall within the range of 3.5-13 μm and 1-4 μm, respectively. With the same conditions, the maximum shear stress was equal to 1.2 kPa and occurred at a distance of ±5 μm from the midpoint of 10 μm and the maximum value of permeability was 3.033 × 10^-13.
Conclusions:
Results of the study revealed a strong dependence of biomechanical effects on the excitation frequency, initial bubble radius, and vessel radius. Numerical simulations could provide insight into understanding the mechanism behind bubble-vessel interactions by UDM, which may explore the potential for further improvements to medical applications.
... [14][15][16][17] Inertial and non-inertial cavitation inside microvessels can generate significant shear and circumferential stresses through liquid jets and microstreaming, which will lead to various biological responses in blood vessels. [18][19][20][21][22][23][24][25] For example, the shear stress induced by oscillating bubbles on the blood vessel wall can lead to the activation of the ion channel, reversible perforation of the membrane, and cell detachment and lysis. 26 Bubble-induced circumferential stress, on the other side, is often related to the rupture of vessels. ...
Photo-mediated ultrasound therapy (PUT) is a novel technique using combined laser and ultrasound to generate enhanced cavitation activity inside blood vessels. The stresses produced by oscillating bubbles during PUT are believed to be responsible for the induced bio-effects in blood vessels. However, the magnitudes of these stresses are unclear. In this study, a two-dimensional axisymmetric finite element method-based numerical model was developed to investigate the oscillating bubble-produced shear and circumferential stresses during PUT. The results showed that increased stresses on the vessel wall were produced during PUT as compared with ultrasound-alone. For a 50-nm radius bubble in a 50-μm radius blood vessel, the produced circumferential and shear stresses were in the range of 100 kPa–400 kPa and 10 Pa–100 Pa, respectively, during PUT with the ultrasound frequency of 1 MHz, ultrasound amplitude of 1400 kPa–1550 kPa, and laser fluence of 20 mJ/cm², whereas the circumferential and shear stresses produced with ultrasound-alone were less than 2 kPa and 1 Pa, respectively, using the same ultrasound parameters. In addition, the produced stresses increased when the ultrasound pressure and laser fluence were increased but decreased when the ultrasound frequency and vessel size were increased. For bubbles with a radius larger than 100 nm, however, the stresses produced during PUT were similar to those produced during ultrasound-alone, indicating the effect of the laser was only significant for small bubbles.
... Earlier on, Wu et al. determined reparable sonoporation threshold in Jurkat lymphocytes to be 12 ± 4 Pa using a vibrating Mason horn to generate microstreaming [44]. Theoretical studies show that maximum shear stress induced by the microstreaming can be as high as several thousand of Pascals (around 20-3000 Pa for a bubble with initial radius R 0 = 1.5 µm, located 6-2.25 µm away from the cell and excited by 5 MHz, 200 kPa sound wave) [45], which is sufficiently strong to tear the cell membrane open, leading to cytoskeleton rearrangements, and resulting in nucleus contraction [46][47][48][49][50][51][52]. In addition, acoustic radiation force generated by stably cavitating microbubbles is demonstrated to push microbubbles towards cell surface, and eventually break cell membrane integrity through bubble compression against plasma membrane [41,48,53]. ...
... In the meantime, they are more likely to fragment into smaller "daughter" bubbles postrupture, through which sustains the cavitation behavior for longer duration by introducing more cavitation nuclei [84]. To explore the influence of bubble viscoelastic parameters on sonoporation outcomes, Wang et al. simulated the microstreaming shear stress generated by a cavitating bubble and suggested that bubbles with reduced viscosity and elasticity may achieve more efficient sonoporation [45]. ...
... Based on fluorescent observations (Fig. 5a-c), Wang et al. found that the decrease in the bubble-cell distance (R D/d ) not only enhanced membrane permeability, but also induced more severe cytoskeleton disassembly for HeLa cell [49]. Their experimental observations are supported by numerical simulations (Fig. 5d), which suggested that larger the deformation of cell membrane could be intensified with increased acoustic pressure or reduced bubble-cell distance [45,49,54,92]. Moreover, specific ligands or antibodies were often attached/loaded to microbubbles to enable microbubble attachment to specific cells, which may further enhance the drug delivery efficiency through shorting the bubble-cells distance to smallest possible [125,129]. ...
The past several decades have witnessed great progress in “smart drug delivery”, an advance technology that can delivery gene or drugs into specific locations of patients’ body with enhanced delivery efficiency. Ultrasound-activated mechanical force induced by the interactions between microbubbles and cells, which can stimulate so-called “sonoporation” process, has been regarded as one of the most promising candidates to realize spatiotemporal-controllable drug delivery to selected regions. Both experimental and numerical studies were performed to get in-depth understanding on how the microbubbles interact with cells during sonoporation processes, under different impact parameters. The current work gives an overview of the general mechanism underlying microbubble-mediated sonoporation, and the possible impact factors (e.g., the properties of cavitation agents and cells, acoustical driving parameters and bubble/cell micro-environment) that could affect sonoporation outcomes. Finally, current progress and considerations of sonoporation in clinical applications are reviewed also.
... [10,11] Moreover, there are some results indicating that microbubble collapse is mitigated as the driving frequency increases, or the microbubble is closer to the rigid boundary. [12] Theoretical attempts to model microbubble sonication in a confined configuration usually utilizes the boundary integral method, [11] finite element method [13] or method of images, [14,15] which describes the nonlinear oscillations of a microbubble near rigid boundaries and on the effects of boundaries such as a single wall, two parallel walls, or a tube, and so on. Most investigations focused on a cavitation microbubble occurring near a flat boundary. ...
The goal of this article is to establish the conditions of excitation where one has to deal with ultrasound contrast agent (UCA) microbubbles pulsating near biological tissues with spherical boundary in ultrasound field for targeted drug delivery and cavitation-enhanced thrombolysis, etc., and contributes to understanding of mechanisms at play in such an interaction. A modified model is presented for describing microbubble dynamics near a spherical boundary (including convex boundary and concave boundary) with an arbitrary-sized aperture angle. The novelty of the model is such that an oscillating microbubble is influenced by an additional pressure produced by the sound reflection from the boundary wall. It is found that the amplitude of microbubble oscillation is positively correlated to the curve radius of the wall and negatively correlated to the aperture angle of the wall and the sound reflection coefficient. Moreover, the natural frequency of the microbubble oscillation for such a compliable wall increases with the wall compliance, but decreases with the reduction of the wall size, indicating distinct increase of the natural frequency compared to a common rigid wall. The proposed model may allow obtaining accurate information on the radiation force and signals that may be used to advantage in related as drug delivery and contrast agent imaging.
... The equation is widely used since it can accurately represent the different microbubble oscillation regimes mentioned below. It can be modified to account for the viscoelastic coating [31][32][33][34] , the presence of a nearby substrate 35 and non-spherical microbubble oscillations 36 . The Rayleigh-Plesset equation is a non-linear differential equation and for any driving pressure, it can be 4 solved to give the radius of a microbubble as a function of time 6,37 . ...
... This nonlinear and/or non-spherical response is evident from the microbubble echo that now not only contains the fundamental driving frequency but also harmonics and subharmonics thereof (figure 2, blue curve). Non-linear and non-spherical behavior can lead to microstreaming patterns around the microbubbles since the fluid around the microbubbles will be affected in an inhomogeneous, asymmetric way 31,38 . Microstreaming can transport molecules to and away from the microbubbles, such as drugs for instance, and can generate shear stresses on structures around the microbubbles 57,67 . ...
... Langmuir 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 12 Finally, numerical modeling and experimental studies have been performed to investigate microbubble shell shedding when a microbubble is oscillating asymmetrically in the presence of a nearby membrane 36 . Microbubbles that oscillate near a membrane will create axisymmetric microstreaming patterns since their vibration will be affected by the presence of that membrane 31,36,91 . ...
In the last couple of decades, ultrasound-driven microbubbles have proven excellent candidates for local drug delivery applications. Besides being useful drug carriers, microbubbles have demonstrated the ability to enhance cell and tissue permeability and as a consequence, drug uptake herein. Notwithstanding the large amount of evidence for their therapeutic efficacy, open issues remain. Due to the vast amount of ultrasound- and microbubble-related parameters that can be altered, and the variability in different models, the translation from basic research to (pre-)clinical studies has been hindered. This review aims at connecting the knowledge gained from fundamental microbubble studies to the therapeutic efficacy seen in in vitro and in vivo studies, with an emphasis on a better understanding of the response of a microbubble upon exposure to ultrasound and its interaction with cells and tissues. More specifically, we address the acoustic settings and microbubble-related parameters i.e. bubble size and physico-chemistry of the bubble shell that play a key role in microbubble-cell interactions and in the associated therapeutic outcome. Additionally, new techniques that may provide additional control over the treatment, such as monodisperse microbubble formulations, tunable ultrasound scanners and cavitation detection techniques, are discussed. An in-depth understanding of the aspects presented in this work could eventually lead the way to more efficient and tailored microbubble-assisted ultrasound therapy in the future.
... It has also been well accepted that the presence of the microbubble shell material would play an influencing role in the microbubble dynamic response. [27][28][29][30][31][32][33][34][35][36][37] Therefore, the influence of UCA shell visco-elasticity properties (viz., surface tension coefficient and viscosity coefficient) on the bubble-bubble interaction is also studied in the following. ...
Theoretical studies on the multi-bubble interaction are crucial for the in-depth understanding of the mechanism behind the applications of ultrasound contrast agents (UCAs) in clinics. A two-dimensional (2D) axisymmetric finite element model (FEM) is developed here to investigate the bubblebubble interactions for UCAs in a fluidic environment. The effect of the driving frequency and the bubble size on the bubble interaction tendency (viz., bubbles attraction and repulsion), as well as the influences of bubble shell mechanical parameters (viz., surface tension coefficient and viscosity coefficient) are discussed. Based on FEM simulations, the temporal evolution of the bubbles radii, the bubblebubble distance, and the distribution of the velocity field in the surrounding fluid are investigated in detail. The results suggest that for the interacting bubblebubble couple, the overall translational tendency should be determined by the relationship between the driving frequency and their resonance frequencies. When the driving frequency falls between the resonance frequencies of two bubbles with different sizes, they will repel each other, otherwise they will attract each other. For constant acoustic driving parameters used in this paper, the changing rate of the bubble radius decreases as the viscosity coefficient increases, and increases first then decreases as the bubble shell surface tension coefficient increases, which means that the strength of bubblebubble interaction could be adjusted by changing the bubble shell visco-elasticity coefficients. The current work should provide a powerful explanation for the accumulation observations in an experiment, and provide a fundamental theoretical support for the applications of UCAs in clinics.
... We consider that the mechanism of the ultrasound-enhanced drug delivery is the microbubble cavitation, the surface of the porcine's skin may have obvious cavitations after ultrasound intervention. This indicates that the cavitation under ultrasound is an important mechanism to improve the permeability [32][33][34][35][36][37]. ...
Brucine is the active component in traditional Chinese medicine “Ma-Qian-Zi” (Strychnos nux-vomica Linn), with capabilities of analgesic, anti-inflammatory, anti-tumor and so on. It is crucial how to break through the impact of cuticle skin which reduces the penetration of drugs to improve drug transmission rate. The aim of this study is to improve the local drug concentration by using ultrasound. We used fresh porcine skin to study the effects of ultrasound on the transdermal absorption of brucine under the influence of various acoustic parameters, including frequency, amplitude and irradiation time. The transdermal conditions of yellow-green fluorescent nanoparticles and brucine in skin samples were observed by laser confocal microscopy and ultraviolet spectrophotometry. The results show that under ultrasonic conditions, the permeability of the skin to the fluorescent label and brucine (e.g., the depth and concentration of penetration) is increased compared to its passive diffusion permeability. The best ultrasound penetration can make the penetration depth of more than 110 microns, fluorescent nanoparticles and brucine concentration increased to 2-3 times. This work will provide supportive data on how the brucine is better used for transdermal drug delivery (TDD).
