粘弹包膜气泡的声散射特性

在线性条件下研究了单个粘弹包膜气泡的声散射特性,并用WT散射法求解了造影剂的多气泡散射特性。首先建立了超声造影剂中单个粘弹包膜气泡的声散射物理模型,结合包膜内外声波方程和边界条件解得散射矩阵,并得到散射系数。通过数值计算用简化散射截面积曲线来表征单个气泡的声散射特性,用声色散曲线和衰减系数曲线来表征气泡的集总散射特性。研究结果表明:增加包膜的弹性参数μe的值,不仅使得气泡共振频率增高,还使气泡散射共振峰值相应加大;增加包膜的粘性参数μv的值,将使得散射的共振峰值降低;气泡的另两个参数λe和λv对散射特性几乎没有影响。     

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.     

包膜黏弹特性及声驱动参数对相互作用微泡动力学行为的影响

关于多气泡相互作用的理论研究对于深入理解超声造影剂在医疗领域中的应用机理具有重要意义。本工作建立了一个2维轴对称有限元模型来研究流体环境中超声造影剂双气泡相互作用,讨论了驱动超声频率和气泡尺寸对气泡之间吸引和排斥趋势的影响,得到了气泡半径与气泡之间距离随时间变化的曲线,以及气泡周围流体速度场的细节,并且研究了气泡包膜参数(即表面张力系数和粘度系数)对气泡相互作用的影响.结果表明,相互作用中的气泡对整体的相对运动趋势由驱动频率和共振频率之间的关系决定;在超声参数固定时,气泡包膜的粘弹特性可用来调控气泡间相互作用强度。结果对实验中观察到的气泡聚集现象进行了合理解释,并为超声造影剂在医疗实践中的应用提供了基础理论支撑.      

脉冲占空比对磁性微泡介导的聚焦超声温升效应的影响

集合多种诊断和治疗功能的声/磁造影剂微泡的研究与开发已经成为当前医学超声、生物医学工程及临床应用领域共同关注的热点问题.超顺磁氧化铁纳米颗粒具有独特的磁性特征和良好的生物相容性,可被用作核磁共振造影剂来提升影像对比度、空间分辨率及临床诊断准确性.我们的前期工作表明,通过将超顺磁氧化铁纳米颗粒挂载于常规超声造影剂微泡表面,可以成功构建多模态诊断及治疗介质,显著改变超声造影剂微泡的尺度分布及包膜粘弹系数等物理特性,进而影响微泡造影剂的声散射特性及其声空化效应和热效应.然而,此前的研究仅考虑了声场强度和微泡浓度等影响因素,对于脉冲超声时间特性对磁性微泡造影剂动力学响应的影响的相关研究仍有所欠缺.本文通过热电偶对凝胶仿体血管模型中流动的双模态磁性微泡在不同占空比超声脉冲信号作用下,产生温升效应开展了系统的实验测量,并基于有限元模型对实验结果进行了仿真验证.结果显示,脉冲信号占空比的提升是增强血管中磁性微泡在聚焦超声作用下温升效果的关键性时间影响因素.本文的研究成果将有助于更好地理解不同超声作用参数对双模态磁性微泡的热效应的影响机制,对保障双模态磁性微泡在临床热疗应用中的安全性和有效性具有重要的...     

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.     

组织内包膜微泡声空化动力学及其力学效应分析

声空化机械效应是聚焦超声治疗的重要物理机制.以脂类包膜微泡/纳米相变液滴为空化核可显著地增强空化效应,本文耦合空化动力学、组织和脂类包膜黏弹性模型,构建了组织内脂类包膜微泡声空化动力学模型,数值分析了微泡声空化动力学行为以及周围组织内机械应力的时空分布规律,并探究了包膜材料、组织黏弹性和驱动声压等关键参数的影响.包膜和组织黏弹性都将抑制微泡振动,但组织黏弹性的抑制作用更大.组织内机械应力在膨胀阶段为挤压应力,而在收缩阶段和反弹初始阶段为拉伸应力,且应力局部分布于微泡壁附近,随着距离增大而显著减小,其中拉伸应力衰减率明显更大.包膜黏弹性可减小应力,但声压较大时,应力减小可忽略不计.应力随着组织弹性增大而减小,随着组织黏度增大而先增大后减小,随着声压增大而增大.本研究可为进一步阐释聚焦超声治疗中组织机械损伤的内在机制奠定重要理论基础.     

纳米包膜造影微泡的小波检测技术研究

用小波变换的方法检测人体组织的微小血流灌注包膜造影微泡回波。结合超声造影剂微泡振动的物理模型,构造了不同外加声场条件下的气泡小波,对原始信号进行小波变换,将变换后得到的小波系数分离;进而从微小血流灌注组织杂波中检测出造影剂微泡回波信号。心肌条件下的计算机模拟以及对灌注组织的仿体实验结果表明:与普通母小波相比,基于气泡振动模型的小波,因为是通过理论模型构造所得,已先验表征了造影剂微泡在声场中的回波特性,因此与实验中产生的回波信号具有更为紧密的相关性,从而经小波变换后,造影剂微泡回波信号与组织杂波产生了更高强度的信噪比,及更明显的可分离和对比效果。同时,构造了一个完备的母小波函数库,进一步提高了本方法的适用性以及健壮性。     

有黏条件气泡声散射特性和衰减谱数值研究*

通过研究有黏条件下的气泡散射模型,数值分析水中单气泡声散射特性,进一步结合Beer-Lambert定律将其扩展到多气泡体系的声衰减预测。数值结果表明,随着谐波阶数递增,散射强度分布数值结果趋于稳定且前向散射增强。同时发现,无因次尺寸参量ka=0.1为过渡区与纯散射区的分界线,且在共振区间具有明显的吸收效应。对多气泡体系的声衰减预测也表明,ka 0.1时,该文气泡散射模型声衰减计算与经典ECAH模型结果吻合,在低浓度条件下声衰减谱随着剪切黏度的增加呈增宽趋势,且与体积浓度成正比例递增。模型预测的声衰减随粒径、声波频率、体积浓度分布数值特征能够为颗粒两相体系粒径及浓度表征提供理论依据。     

黏弹性吸声材料复弹性模量优化研究

针对黏弹性材料吸声效率问题,利用分层介质声传播理论和数值算法优化了不同物理条件下材料的复弹性模量。采用参数等效的方法分析了含气泡黏弹性材料的声学特性,并给出了此种材料优化后的弹性模量曲线。根据物理模型计算了一定边界条件下材料复弹性模量等吸声系数曲线,得到了几种背衬条件下黏弹性材料吸声系数大于0.8的弹性模量和损耗因子范围。研究表明调节黏弹性材料的复弹性模量可以有效提高材料的吸声性能,吸声系数大于0.8时其弹性模量和损耗因子范围在不同背衬条件下差异较大,发现一定厚度的钢背衬会降低调控复弹性模量的难度,对含气泡黏弹性材料的计算也可得到类似结果。      

人体血管壁超声传输衰减特性的研究

本文利用超声脉冲反射法，对人体血管壁声衰减特性进行了离体测量，给出了人体血管壁声能量衰减参数的测量值。这对超声在医学领域的应用以及超声连体非介入血栓消溶有着十分重要的意义。     

Nonlinear response of ultrasound contrast agent microbubbles:From fundamentals to applications

Modelling and biomedical applications of ultrasound contrast agent(UCA) microbubbles have attracted a great deal of attention. In this review, we summarize a series of researches done in our group, including(i) the development of an all-in-one solution of characterizing coated bubble parameters based on the light scattering technique and flow cytometry;(ii) a novel bubble dynamic model that takes into consideration both nonlinear shell elasticity and viscosity to eliminate the dependences of bubble shell parameters on bubble size;(iii) the evaluation of UCA inertial cavitation threshold and its relationship with shell parameters; and(iv) the investigations of transfection efficiency and the reduction of cytotoxicity in gene delivery facilitated by UCAs excited by ultrasound exposures.     

Characterization of ultrasound-induced fracture of polymer-shelled ultrasonic contrast agents by correlation analysis

Beyond a characteristic value of the negative peak pressure, ultrasound fracture the shell of ultrasonic contrast agents (UCAs). Existing criteria for ascertaining this threshold value exploit the dependence of the amplitude of the UCA acoustic response on the incident pressure. However, under the common experimental conditions used in this work, these criteria appear to be unreliable when they are applied to UCAs that are stabilized by a thick polymeric shell. An alternative criterion for determining the onset of shell fracture is introduced here, which uses variations of the shape of the acoustic time-domain response of an UCA suspension. Experimental evidence is presented that links the changes of the cross-correlation coefficient between consecutive time-domain signals to the fracture of the shells, and consequent release of air microbubbles. In principle, this criterion may be used to characterize similar properties of other types of particles that cannot undergo inertial cavitation.     

Study on the lifetime and attenuation properties of microbubbles coated with carboxylic acid salts

Four kinds of surfactants, sodium laurate, sodium myristate, sodium palmitate and sodium oleate were used to study the effects of surfactant coatings on the lifetime and attenuation of microbubbles. The changes in the size distribution of microbubbles prepared with these surfactants in saline were measured with a Coulter Multisizer (Coulter Electronics Ltd., Luton, UK). Frequency characteristics of ultrasonic attenuation of the microbubble suspensions were measured between 400 kHz and 6 MHz. From the changes in attenuation in the microbubble suspensions over time, it was found that the lifetime of microbubbles in a suspension also depends on the frequency of the irradiating ultrasound. The effect of surfactants on the frequency characteristics of attenuation was also studied, and characteristics of the surfactant coating, including shell elasticity and shell friction parameters were calculated from the measurement results. Microbubbles produced with sodium palmitate had the longest lifetime and the smallest average size. The shell had very little effect on the ultrasonic properties of microbubbles produced with sodium palmitate, suggesting that the sodium palmitate microbubbles behaved ultrasonically as free 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.     

Modeling non-spherical oscillations and stability of acoustically driven shelled microbubbles

The oscillation and destruction of microbubbles under ultrasound excitation form the basis of contrast enhanced ultrasound imaging and microbubble assisted drug and gene delivery. A typical microbubble has a size of a few micrometers and consists of a gas core encapsulated by a shell. These bubbles can be driven into surface mode oscillations, which not only contribute to the measured acoustic signal but can lead to bubble destruction. Existing models of surface model oscillations have not considered the effects of a bubble shell. In this study a model was developed to study the surface mode oscillations in shelled bubbles. The effects of shell viscosity and elasticity on the surface mode oscillations were modeled using a Boussinesq-Scriven approach. Simulation was conducted using the model with various bubble sizes and driving acoustic pressures. The occurrence of surface modes and the number of ultrasound cycles needed for the occurrence were calculated. The simulation results show a significant difference between shelled bubbles and shell free bubbles. The shelled bubbles have reduced surface mode amplitudes and a narrower bubble size range within which these modes develop compared to shell free bubbles. The clinical implications were also discussed.     

In vitro contrast-enhanced ultrasound measurements of capillary microcirculation: Comparison between polymer- and phospholipid-shelled microbubbles

The focus of contrast-enhanced ultrasound research has developed beyond visualizing the blood pool and its flow to new areas such as perfusion imaging, drug and gene therapy, and targeted imaging. In this work comparison between the application of polymer- and phospholipid-shelled ultrasound contrast agents (UCAs) for characterization of the capillary microcirculation is reported. All experiments are carried out using a microtube as a vessel phantom. The first set of experiments evaluates the optimal concentration level where backscattered signal from microbubbles depends on concentration linearly. For the polymer-shelled UCAs the optimal concentration level is reached at a value of about 2 × 10⁴ MB/ml, whereas for the phospholipid-shelled UCAs the optimal level is found at about 1 × 10⁵ MB/ml.Despite the fact that the polymer shell occupies 30% of the radius of microbubble, compared to 0.2% of the phospholipid-shelled bubble, approximately 5-fold lower concentration of the polymer UCA is needed for investigation compared to phospholipid-shelled analogues. In the second set of experiments, destruction/replenishment method with varied time intervals ranging from 2 ms to 3 s between destructive and monitoring pulses is employed. The dependence of the peak-to-peak amplitude of backscattered wave versus pulse interval is fitted with an exponential function of the time γ = A(1 − exp(−βt)) where A represents capillary volume and the time constant β represents velocity of the flow. Taking into account that backscattered signal is linearly proportional to the microbubble concentration, for both types of the UCAs it is observed that capillary volume is linearly proportional to the concentration of the microbubbles, but the estimation of the flow velocity is not affected by the change of the concentration. Using the single capillary model, for the phospholipid-shelled UCA a delay of about 0.2-0.3 s in evaluation of the perfusion characteristics is found while polymer-shelled UCA provide response immediately. The latter at the concentration lower than 3.6 × 10⁵ MB/ml have no statistically significant delay (p < 0.01), do not cause any attenuation of the backscattered signal or saturation of the receiving part of the system. In conclusion, these results suggest that the novel polymer-shelled microbubbles have a potential to be used for perfusion evaluation.     

Microstreaming velocity field and shear stress created by an oscillating encapsulated microbubble near a cell membrane

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 important mechanisms in the sonoporation process. Here, based on an encapsulated microbubble dynamic model with considering nonlinear rheological effects of both shell elasticity and viscosity, the microstreaming velocity field and shear stress generated by an oscillating microbubble near the cell membrane are theoretically simulated. Some factors that might affect the behaviors of microstreaming are thoroughly investigated, including the distance between the bubble center and cell membrane (d), shell elasticity (χ), and shell viscosity (κ). The results show that (i) the presence of cell membrane can result in asymmetric microstreaming velocity field, while the constrained effect of the membrane wall decays with increasing the bubble-cell distance; (ii) the bubble resonance frequency increases with the increase in d and χ, and the decrease in κ, although it is more dominated by the variation of shell elasticity; and (iii) the maximal microstreaming shear stress on the cell membrane increases rapidly with reducing the d, χ, and κ. The results suggest that microbubbles with softer and less viscous shell materials might be preferred to achieve more efficient sonoporation outcomes, and it is better to have bubbles located in the immediate vicinity of the cell membrane.