Effect of surfactant addition on removal of microbubbles using ultrasound

It is difficult to control the bubble in a liquid by the external operation, because the behavior of the bubble is controlled in buoyancy and flow of liquid. On the other hand, microbubbles, whose diameter is several decades μm, stably disperse in static liquid because of their small buoyancy and electrical repulsion. When an ultrasound, whose frequency was 2.4 MHz, was irradiated, the milky white microbubbles suspended solution became rapidly clear. In this study, the effects of surfactant addition on the removal of microbubbles from a liquid in an ultrasonic field were investigated. The efficiency of removal of microbubbles decreased with surfactant addition. Surfactant type influenced the size of agglomerated microbubbles, and the efficiency of removal of microbubbles changed. The surface of microbubble was modified by surfactant adsorption, and the steric inhibition influenced the removal of microbubbles.     

Optimal design and experimental investigation of surfactant encapsulated microbubbles

The diagnostic capabilities of ultrasound imaging can be improved with contrast-specific nonlinear imaging modalities such as harmonic and subharmonic imaging. The nonlinear response of an encapsulated microbubble in an acoustic field is strongly influenced by the shell viscoelastic properties that are determined by the shell composition and thickness. In this paper, the subharmonic performance of a surfactant encapsulated microbubble was optimized by choosing the appropriate composition of shell material with the aid of theoretical model. To study the effects of viscoelastic properties of microbubble shell materials on the nonlinear scattered response of microbubbles, a theoretical model-modified Herring equation for the oscillation of encapsulated microbubbles in the ultrasound field was employed. Based on this model, a computer aided design system was developed to optimize and analyze the acoustic properties, particularly subharmonic responses, of microbubbles under different shell parameters. Furthermore, surfactant encapsulated microbubbles with different viscoelastic properties were prepared by changing the shell composition. Their shell viscoelastic behavior was measured indirectly as dilational modulus of monolayer film formed with surfactant molecular. Moreover, in vitro quantitative acoustic properties measurements of these microbubbles were carried out to evaluate their subharmonic performance. Both of the theoretical simulation and acoustic measurement showed that the surfactant encapsulated microbubbles with good subharmonic properties could be designed and prepared by adjusting the shell material composition with the guide of the computer aided design system.     

多层膜磁性微泡的非线性声振动特性

超顺磁性氧化铁纳米粒子与造影剂微泡结合形成磁性微泡,用于产生多模态造影剂,以增强医学超声和磁共振成像.将装载有纳米磁性颗粒的微泡包膜层看作由磁流体膜与磷脂膜组合而成的双层膜结构,同时考虑磁性纳米颗粒体积分数a对膜密度及黏度的影响,从气泡动力学基本理论出发,构建多层膜结构磁性微泡非线性动力学方程.数值分析了驱动声压和频率等声场参数、颗粒体积分数、膜层厚度以及表面张力等膜壳参数对微泡声动力学行为的影响.结果表明,当磁性颗粒体积分数较小且a≤0.1时,磁性微泡声响应特性与普通包膜微泡相似,微泡的声频响应与其初始尺寸和驱动压有关;当驱动声场频率f为磁性微泡共振频率f0的2倍(f=2f0)时,微泡振动失稳临界声压最低;磁性颗粒的存在抑制了泡的膨胀和收缩但抑制效果非常有限;磁性微泡外膜层材料的表面张力参数K及膜层厚度d也会影响微泡的振动,当表面张力参数及膜厚取值分别为0.2—0.4 N/m及50—150 nm时,可观察到气泡存在不稳定振动响应区.     

超声造影剂微气泡的包膜黏弹特性的定量表征研究

包膜黏弹特性显著影响微气泡超声造影剂的诊断及治疗应用效果. 本文结合原子力显微镜技术及声衰减特性测量提出了一种对微气泡造影剂包膜黏弹特性定量表征的新方法. 首先采用原子力显微镜技术进行机械特性分析得到包膜微气泡的有效硬度及体弹性模量; 然后测量声衰减特性, 基于微气泡动力学理论, 计算包膜微气泡的体黏度系数. 为验证方法的有效性, 实验制备了直径为1-5 μm的白蛋白包膜微气泡造影剂, 原子力显微镜测量的有效硬度和体弹性模量分别为0.149±0.012 N/m和8.31±0.667 MPa, 并与粒径无关. 声衰减特性测量和动力学理论拟合的包膜微气泡的体黏度系数为0.374±0.003 Pa·s. 该方法可推广至其他种类包膜微气泡的黏弹特性表征, 对超声造影剂的制备及其诊断和治疗应用有积极意义.     

Scaling of the viscoelastic shell properties of phospholipid encapsulated microbubbles with ultrasound frequency

Phospholipid encapsulated microbubbles are widely employed as clinical diagnostic ultrasound contrast agents in the 1–5 MHz range, and are increasingly employed at higher ultrasound transmit frequencies. The stiffness and viscosity of the encapsulating “shells” have been shown to play a central role in determining both the linear and nonlinear response of microbubbles to ultrasound. At lower frequencies, recent studies have suggested that shell properties can be frequency dependent. At present, there is only limited knowledge of how the viscoelastic properties of phospholipid shells scale at higher frequencies. In this study, four batches of in-house phospholipid encapsulated microbubbles were fabricated with decreasing volume-weighted mean diameters of 3.20, 2.07, 1.82 and 1.61 μm. Attenuation experiments were conducted in order to assess the frequency-dependent response of each batch, resulting in resonant peaks in response at 4.2, 8.9, 12.6 and 19.5 MHz, respectively. With knowledge of the size measurements, the attenuation spectra were then fitted with a standard linearized bubble model in order to estimate the microbubble shell stiffness S_p and shell viscosity S_f, resulting in a slight increase in S_p (1.53–1.76 N/m) and a substantial decrease in S_f (0.29 × 10⁻⁶–0.08 × 10⁻⁶ kg/s) with increasing frequency. These results performed on a single phospholipid agent show that frequency dependent shell properties persist at high frequencies (up to 19.5 MHz).     

Ultrasonic bubbles in medicine: influence of the shell

Ultrasound contrast agents consist of microscopically small bubbles encapsulated by an elastic shell. These microbubbles oscillate upon ultrasound insonification, and demonstrate highly nonlinear behavior, ameliorating their detectability. (Potential) medical applications involving the ultrasonic disruption of contrast agent microbubble shells include release-burst imaging, localized drug delivery, and noninvasive blood pressure measurement. To develop and enhance these techniques, predicting the cracking behavior of ultrasound-insonified encapsulated microbubbles has been of importance. In this paper, we explore microbubble behavior in an ultrasound field, with special attention to the influence of the bubble shell. A bubble in a sound field can be considered a forced damped harmonic oscillator. For encapsulated microbubbles, the presence of a shell has to be taken into account. In models, an extra damping parameter and a shell stiffness parameter have been included, assuming that Hooke's Law holds for the bubble shell. At high acoustic amplitudes, disruptive phenomena have been observed, such as microbubble fragmentation and ultrasonic cracking. We analyzed the occurrence of ultrasound contrast agent fragmentation, by simulating the oscillating behavior of encapsulated microbubbles with various sizes in a harmonic acoustic field. Fragmentation occurs exclusively during the collapse phase and occurs if the kinetic energy of the collapsing microbubble is greater than the instantaneous bubble surface energy, provided that surface instabilities have grown big enough to allow for break-up. From our simulations it follows that the Blake critical radius is not a good approximation for a fragmentation threshold. We demonstrated how the phase angle differences between a damped radially oscillating bubble and an incident sound field depend on shell parameters.     

调频超声脉冲驱动微气泡运动偏移的研究

提出调频超声辐射力技术驱动微泡群,以加强微泡的吸附效率.基于改进的RP方程及粒子轨迹方程研究了微泡群整体的运动位移与调频信号的中心频率、调频范围、信号声压,以及微泡半径分布关系.研究结果表明调频信号在驱动半径具有宽泛分布的气泡群,以及半径分布远离谐振半径的气泡群时,作用效果好于传统正弦波信号.例如中心频率1 MHz、调频范围0.75 MHz的调频脉冲作用高斯分布（平均半径3.5 μm、均方差为1）的微泡群200 μs,可比同等声压的正弦波多约12%的微气泡产生位移30 μm. 关键词： 超声辐射力 调频波 高斯分布     

Difference-frequency ultrasound generation from microbubbles under dual-frequency excitation

The difference-frequency (DF) ultrasound generated by using parametric effect promises to improve detection depth owing to its low attenuation, which is beneficial for deep tissue imaging. With ultrasound contrast agents infusion, the harmonic components scattered from the microbubbles, including DF, can be generated due to the nonlinear vibration. A theoretical study on the DF generation from microbubbles under the dual-frequency excitation is proposed in formula based on the solution of the RPNNP equation. The optimisation of the DF generation is discussed associated with the applied acoustic pressure, frequency, and the microbubble size. Experiments are performed to validate the theoretical predictions by using a dual-frequency signal to excite microbubbles. Both the numerical and experimental results demonstrate that the optimised DF ultrasound can be achieved as the difference frequency is close to the resonance frequency of the microbubble and improve the contrast-to-tissue ratio in imaging.     

Agglomeration and rapid ascent of microbubbles by ultrasonic irradiation

Microbubbles have some different characteristics from conventional bubbles. To apply the useful properties for gas-liquid contact operation in industry, however, a separate technology of microbubbles has to be realized. In this study, promotion of microbubble separation using ultrasound was proposed. By irradiating with ultrasound, milky white microbubbles suspended solution changed instantaneously to be clear. The interesting behavior of microbubbles observed in the ultrasonic field was investigated by microscopic and macroscopic visualizations. The rapid ascent of microbubbles was caused by their agglomeration, where the Bjerknes force of attraction and electrical repulsive force on microbubble surface acted. Ultrasonic irradiation into microbubble suspended solution was very useful for dynamic operation of microbubbles.     

Acoustic wave in a suspension of magnetic nanoparticle with sodium oleate coating

The ultrasonic propagation in the water-based magnetic fluid with doubled layered surfactant shell was studied. The measurements were carried out both in the presence as well as in the absence of the external magnetic field. The thickness of the surfactant shell was evaluated by comparing the mean size of magnetic grain extracted from magnetization curve with the mean hydrodynamic diameter obtained from differential centrifugal sedimentation method. The thickness of surfactant shell was used to estimate volume fraction of the particle aggregates consisted of magnetite grain and surfactant layer. From the ultrasonic velocity measurements in the absence of the applied magnetic field, the adiabatic compressibility of the particle aggregates was determined. In the external magnetic field, the magnetic fluid studied in this article becomes acoustically anisotropic, i.e., velocity and attenuation of the ultrasonic wave depend on the angle between the wave vector and the direction of the magnetic field. The results of the ultrasonic measurements in the external magnetic field were compared with the hydrodynamic theory of Ovchinnikov and Sokolov (velocity) and with the internal chain dynamics model of Shliomis, Mond and Morozov (attenuation).     

Resonance behaviors of encapsulated microbubbles oscillating nonlinearly with ultrasonic excitation

The resonance behaviors of a few lipid-coated microbubbles acoustically activated in viscoelastic media were comprehensively examined via radius response analysis. The size polydispersity and random spatial distribution of the interacting microbubbles, the rheological properties of the lipid shell and the viscoelasticity of the surrounding medium were considered simultaneously. The obtained radius response curves present a successive occurrence of linear resonances, nonlinear harmonic and sub-harmonic resonances with the acoustic pressure increasing. The microbubble resonance is radius-, pressure- and frequency-dependent. Specifically, the maximum bubble expansion ratio at the main resonance peak increases but the resonant radius decreases as the ultrasound pressure increases, while both of them decrease with the ultrasound frequency increasing. Moreover, compared to an isolated microbubble case, it is found that large microbubbles in close proximity prominently suppress the resonant oscillations while slightly increase the resonant radii for both harmonic and subharmonic resonances, even leading to the disappearance of the subharmonic resonance with the influences increasing to a certain degree. In addition, the results also suggest that both the encapsulating shell and surrounding medium can substantially dampen the harmonic and subharmonic resonances while increase the resonant radii, which seem to be affected by the medium viscoelasticity to a greater degree rather than the shell properties. This work offers valuable insights into the resonance behaviors of microbubbles oscillating in viscoelastic biological media, greatly contributing to further optimizing their biomedical applications.     

Frequency relationships for ultrasonic activation of free microbubbles, encapsulated microbubbles, and gas-filled micropores.

The ultrasonic activation of free microbubbles, encapsulated microbubbles, and gas-filled micropores was explored using available linear theory. Encapsulated microbubbles, used in contrast agents for diagnostic ultrasound, have relatively high resonance frequencies and damping. At 2 MHz the resonance radii are 1.75 microns for free microbubbles, 4.0 microns for encapsulated microbubbles, and 1.84 microns for gas-filled micropores. Higher-pressure amplitudes are needed to elicit equivalent subharmonic, fundamental, or second-harmonic responses from the encapsulated microbubbles, and this behavior increases for higher frequencies. If an encapsulated microbubble becomes destabilized during exposure,the resulting liberated microbubble would be about twice the linear resonance size, which would be likely to produce subharmonic signals. Scattered signals used for medical imaging purposes may be indicative of bioeffects potential: The second harmonic signal is proportional to local shear stress for a microbubble on a boundary, and a strong subharmonic signal may imply destabilization and nucleation of free-microbubble cavitation activity. The potential for bioeffects from contrast agent gas bodies decreases rapidly with increasing frequency. This information should be valuable for understanding of the etiology of bioeffects related to contrast agents and for developing exposure indices and risk management strategies for their use in diagnostic ultrasound.     

Phospholipid-stabilized microbubbles: Influence of shell chemistry on cavitation threshold and binding to giant uni-lamellar vesicles

We demonstrate the feasibility of covalently linking a single microbubble to a single, giant uni-lamellar vesicle (GUV). Such a combination of GUV plus microbubble might prove useful as a new drug delivery vehicle involving microbubble cavitation-induced sonoporation of the vesicle bilayer as a release mechanism. We therefore applied the well known methodology of passive cavitation detection to measure the influence of lipid shell chemistry on inertial cavitation thresholds for externally added microbubbles. We find that cavitation threshold changes significantly with changes in either molecular weight or mole fraction of poly(ethylene glycol), historically used to impede gas dissolution and microbubble coalescence. We attribute changes in cavitation threshold to changes in microbubble resonance frequency resulting from changes in microbubble shell bending elasticity. To further demonstrate the influence of shell chemistry on microbubble behavior, we describe how several common bubble phenomena - and some new - respond to changes in lipid chain length.     

An acoustic backscattering technique for the detection of transient cavitation produced by microsecond pulses of ultrasound

An acoustic backscattering technique for detecting transient cavitation produced by 10-microseconds-long pulses of 757-kHz ultrasound is described. The system employs 10-microseconds-long, 30-MHz center frequency tone bursts that scatter from cavitation microbubbles. Experiments were performed with suspensions of hydrophobic polystyrene spheres in ultraclean water. Transient cavitation threshold pressures measured with the active cavitation detector (ACD) were always less than or equal to those measured using a passive acoustic detection scheme. The measured cavitation thresholds decreased with increasing dissolved gas content and increasing suspended particle concentration. Results also show that ultrasonic irradiation of the polystyrene sphere suspensions by the ACD lowered the threshold pressure measured with the passive detector. A possible mechanism through which suspensions of hydrophobic particles might nucleate bubbles is presented.     

Resonance frequency of microbubbles: effect of viscosity

The transmitted frequency at which a gas bubble of millimeter or submillimeter size oscillates resonantly in a low-viscosity liquid is approximately equal to the undamped natural frequency (referred to as the Minnaert frequency if surface tension effects are disregarded). Based on a theoretical analysis of bubble oscillation, this paper shows that such an approximation cannot be validated for microbubbles used in contrast-enhanced ultrasound imaging. The contrast-agent microbubbles represent either encapsulated bubbles of size less than 10 microm or free (nonencapsulated) bubbles of submicron size. The resonance frequency of the microbubbles deviates significantly from the undamped natural frequency over the whole range of microbubble sizes due to the increased viscous damping coefficient. The difference between these two frequencies is shown to have a tremendous impact on the resonant backscatter by the microbubbles. In particular, the first and second harmonics of the backscattered signal from the microbubbles are characterized by their own resonance frequencies, equal to neither the microbubble resonance frequency nor the undamped natural frequency.     

超声造影剂微泡非线性动力学响应的机理及相关应用

随着生命科学及现代医学的发展, 一体化无创精准诊疗已经日益成为人们关注的焦点问题, 而关于超声造影剂微泡的非线性效应的相关机理、动力学建模及其在超声医学领域中的应用研究也得到了极大的推动. 本文对下列课题进行了总结和讨论, 包括: 1)基于Mie散射技术和流式细胞仪对造影剂微泡参数进行定征的一体化解决方案; 2)通过对微泡包膜的黏弹特性进行非线性修正, 构建新的包膜微泡动力学模型; 3)探索造影剂惯性空化阈值与其包膜参数之间的相关性; 以及4)研究超声联合造影剂微泡促进基因/药物转染效率并有效降低其生物毒性的相关机理.     

Sonochemical reaction with microbubbles generated by hollow ultrasonic horn

A microbubble generator with a cylindrical hollow ultrasonic horn (HUSH), gas flow path, and an orifice inside it can produce high ultrasonic pressure around the generated microbubbles. We used this microbubble generator with a HUSH as a sonochemical reactor for the degradation of indigo carmine and evaluated the sonochemical reaction by simply inserting the horn end into a liquid. The experimental results revealed that the ultrasonic irradiation around ultrasonically generated microbubbles effectively degraded indigo carmine in water. In addition, degradation experiments performed by varying the ultrasonic power and gas flow rates indicated that a continuous gas supply and ultrasonic pressure were required for generating the microbubbles, without the generation of millimeter-scale bubbles, to enhance the sonochemical reaction in water.     

高密度超细颗粒高浓度悬浊液超声衰减的数值模拟分析

以拓展耦合相ECP理论模型为基础,通过对高浓度超细二氧化钛-水悬浊液和玻璃微珠-水悬浊液中超声衰减的数值计算分析,讨论了高密度差异颗粒两相介质在高浓度情况下,超声频率、颗粒粒径大小、颗粒浓度对超声波衰减的影响,为高密度超细颗粒在高浓度悬浊液中颗粒粒度和浓度的超声波测量提供理论支持。     

Ultrasonic investigation of magnetic nanoparticles suspension with PEG biocompatible coating

Water suspension of nanoparticles was studied by ultrasound spectroscopy. Nanoparticles have a core-shell structure with magnetic core Fe₃O₄ and surfactant shells. The surface of magnetic particles was coated with oleate sodium as the primary layer and polyethylene glycol as the secondary layer. The acoustic properties of suspensions, such as velocity and attenuation of ultrasonic waves, have been measured. From experimental data mechanical properties have been determined. Adiabatic compressibility of nanoparticles suspension decreased with increase of temperature. The changes of ultrasonic wave attenuation under the influence of the external magnetic field, show that magnetic liquids with high concentration of magnetic material (despite two surfactant shells) show tendency to aggregate.     

Direct observations of ultrasound microbubble contrast agent interaction with the microvessel wall

Many thousands of contrast ultrasound studies have been conducted in clinics around the world. In addition, the microbubbles employed in these examinations are being widely investigated to deliver drugs and genes. Here, for the first time, the oscillation of these microbubbles in small vessels is directly observed and shown to be substantially different than that predicted by previous models and imaged within large fluid volumes. Using pulsed ultrasound with a center frequency of 1 MHz and peak rarefactional pressure of 0.8 or 2.0 MPa, microbubble expansion was significantly reduced when microbubbles were constrained within small vessels in the rat cecum (p<0.05). A model for microbubble oscillation within compliant vessels is presented that accurately predicts oscillation and vessel displacement within small vessels. As a result of the decreased oscillation in small vessels, a large resting microbubble diameter resulting from agent fusion or a high mechanical index was required to bring the agent shell into contact with the endothelium. Also, contact with the endothelium was observed during asymmetrical collapse, not during expansion. These results will be used to improve the design of drug delivery techniques using microbubbles.