测量单泡声致发光中气泡R(t)曲线的前向Mie散射技术

光干涉原理和Mie理论计算结果表明,单泡声致发光中气泡前向Mie散射的振荡信号,主要是由于气泡的透射光束和表面反射光束之间光干涉产生的.这些干涉波峰形成了测量气泡半径的空间标尺,标尺的单位长度δR由散射角θ,检测光波波长和流体光折射率确定,而每个波峰就是标尺的刻线,它们与该时刻的气泡半径大小一一对应.在30°-50°散射角范围内,利用前向Mie散射实验测定了单泡声致发光中气泡的最大半径,R(t)曲线及平衡半径,表明前向Mie散射是一种便捷的测定气泡运动特性的有效方法.     

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.     

声致发光单泡的Mie散射测量参数的理论计算

本文运用Mie散射理论系统地计算了适用于声致发光单泡的Mie散射测量参数，利用Dave倒推算法得出散射光强随半径及散射角的变化曲线I（R），I（θ），结果表明：适合于连续Mie散射测量，脉冲Mie散射测量及Mie散射定标的散射角及接收器张角是各不相同的。文中给出了合适的参数范围。     

单泡声致发光中气泡运动特性的Mie散射测量

运用光学Mie散射测量,实验研究了声致发光单泡的运动状态和发光光强受激励声场频率f及声压Pa变化的影响,结合动力学R-P方程拟合得到不同声压Pa下气泡半径随时间变化的动力学特征曲线——R(t)曲线,定量确定了气泡平衡半径Ro和压缩比Rmax/Ro,并通过气泡振子模型给出的势能方程估算了气泡塌缩阶段的能量损耗。结果表明:适当控制谐振频率(△f/fo-10-4,fo=21 kHz)和声压(1.2 atm-1.5 atm)可实现稳定的单泡声致发光;并且随着Pa的增大,气泡压缩比增大,回弹势能占总能量的比值逐渐减小(10-1-10-3),气泡在膨胀相聚集的大部分声能很可能以激波和热能形式释放。     

经颅聚焦超声联合微泡开放血脑屏障的数值仿真研究

近年大鼠等动物实验表明经颅聚焦超声联合微泡技术可无创开放血脑屏障实现药物递送,但在临床治疗时由于人体头颅非均质结构及其高声衰减特性,需优化超声经颅聚焦参数和微泡参数。本文基于人头颅CT数据、82阵元相控换能器和血管建立了三维数值仿真模型,研究超声及微泡参数对机械指数和靶区声发射的影响,评估血脑屏障开放程度及组织损伤的可能性。结果表明,声功率和微泡初始密度增大,机械指数和宽带噪声强度增大;频率增大,稳态空化强度增大;当微泡初始半径大于5μm时,稳态空化显著增强。该研究结果为经颅聚焦超声联合微泡技术诱导可控的BBB开放及安全有效递送治疗药物提供了理论数据和技术参考。     

测量单泡声致发光中气泡R(t)曲线的前向Mie散射技术

光干涉原理和Mie理论计算结果表明,单泡声致发光中气泡前向Mie散射的振荡信号,主要是由于气泡的透射光束和表面反射光束之间光干涉产生的. 这些干涉波峰形成了测量气泡半径的空间标尺,标尺的单位长度δR由散射角θ,检测光波波长和流体光折射率确定,而每个波峰就是标尺的刻线,它们与该时刻的气泡半径大小一一对应. 在30°—50°散射角范围内,利用前向Mie散射实验测定了单泡声致发光中气泡的最大半径,R(t)曲线及平衡半径,表明前向Mie散射是一种便捷的测定气泡运动特性的有效方法. 关键词： 单泡声致发光 前向Mie散射 光干涉     

金复合纳米微粒的消光特性

基于Mie光散射理论,研究了金壳介质芯的金复合纳米球壳微粒在光散射与吸收中的消光特性.对微粒增大时的多极子特性以及内半径变动时共振峰的移动作了计算和分析,证实了共振峰位置随内外半径比增大而增大的规律.还对纯金纳米微粒的多极子特性作了计算,并讨论了总消光效率中散射和吸收各自的贡献.     

微泡对高强度聚焦超声焦域影响的研究

微泡对高强度聚焦超声(HIFU)治疗具有增效作用,而HIFU治疗中不同声学条件下微泡对HIFU治疗焦域的影响尚不清楚。本文基于声传播方程、Yang-Church气泡运动方程、生物热传导方程、时域有限差分法(FDTD)、龙格-库塔(RK)法数值仿真研究输入功率、激励频率和气泡初始半径对HIFU在含气泡体模中形成焦域的影响,并利用含Sono Vue造影剂的仿组织体模研究进行实验验证。结果表明,增大输入功率、气泡初始半径和升高激励频率均可增大焦域,随着输入功率的增大,焦域形状可能发生变化,而随着激励频率升高和气泡初始半径的增大,焦域会向远离换能器的方向移动。     

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.     

壳层纳米颗粒的光散射行为研究

本文主要研究了Au-Si球型壳层纳米颗粒在电磁波作用下的散射行为,并将其与实心Au球、空心Au球、实心Si球和空心Si球的光散射行为进行了对比。利用Mie散射理论计算得出Au-Si球型壳层纳米颗粒在外加电磁波作用下的各阶电响应和磁响应,观察壳层结构的几何参数对电偶和磁偶共振峰位置的影响,并进一步研究Au材料中的电偶响应与Si材料中的电偶(磁偶)响应之间的耦合关系,找到其中的耦合规律。通过对单个球型壳层纳米颗粒散射行为的研究,为利用该颗粒周期性排列制备具有特殊电磁性质的人工特异材料提供理论指导。     

Forced vibrations of a bubble in a liquid-filled elastic vessel

There is increasing demand for accurate characterization of the in vivo behavior of microbubble agents used for ultrasound imaging and therapy. This study examines bubble-vessel interaction, in particular the propagation of disturbances along the vessel wall. Finite element simulations of a 3 μm radius microbubble suspended in a viscous liquid and enclosed in a 4 μm radius elastic vessel were performed, and the results compared with existing analytical results for wave propagation in elastic liquid-filled tubes. The vessel wall was shown to have a significant effect upon the amplitude of bubble oscillation and hence acoustic radiation from it, as well as distension of the vessel wall. It was found that the most important factor was the ratio of the excitation frequency to the natural "ring" frequency of the vessel which in turn depends upon its dimensions and mechanical properties. As this ratio increases, the motion of the vessel wall becomes increasingly localized to the site of the bubble. It was also shown that the validity of the results obtained using the applied model of vessel elasticity is limited to frequencies below the ring frequency, and this should be taken into account in the development of protocols for ultrasound safety and/or therapeutic procedures.     

Dynamical model of encapsulated gas microbubble under ultrasound based on elastic mechanics

Based on the theory of elastic mechanics, a dynamical model of an encapsulated gas microbubble under ultrasound is presented. The dynamical motion of the microbubble is divided into three states: buckled, elastic, and ruptured. The model describes the compression-only behavior appropriately and derives the transient variation of the resonance frequency of the damped oscillation and the relation between the critical rupture radius and initial outer radius. The normal stress in the tangential direction plays the principal role in the rupture and buckling of the encapsulating shell, resulting in likely rupture for a larger microbubble and resistance to rupture for a thicker-shell microbubble. Comparison of proposed dynamical model with Marmottant’s model has been given. The dynamical model can be employed in ultrasound medical diagnostics and therapy of drug incorporation or extravasation through further understanding the influence of the encapsulating shell.     

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.     

Forced linear oscillations of microbubbles in blood capillaries

A theoretical investigation of the forced linear oscillations of a gas microbubble in a blood capillary, whose radius is comparable in size to the bubble radius is presented. The natural frequency of oscillation, the thermal and viscous damping coefficients, the amplitude resonance, the energy resonance, as well as the average energy absorbed by the system, bubble plus vessel, have been computed for different kinds of gas microbubbles, containing air, octafluropropane, and perflurobutane as a function of the bubble radius and applied frequency. It has been found that the bubble behavior is isothermal at low frequencies and for small bubbles and between isothermal and adiabatic for larger bubbles and higher frequencies, with the viscous damping dominating over the thermal damping. Furthermore, the width of the energy resonance is strongly dependent on the bubble size and the natural frequency of oscillation is affected by the presence of the vessel wall and position of the bubble in the vessel. Therefore, the presence of the blood vessel affects the way in which the bubble absorbs energy from the ultrasonic field. The motivation of this study lies in the possibility of using gas microbubbles as an aid to therapeutic focused ultrasound treatments.     

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.     

Microbubble spectroscopy of ultrasound contrast agents

A new optical characterization of the behavior of single ultrasound contrast bubbles is presented. The method consists of insonifying individual bubbles several times successively sweeping the applied frequency, and to record movies of the bubble response up to 25 million frames/s with an ultrahigh speed camera operated in a segmented mode. The method, termed microbubble spectroscopy, enables to reconstruct a resonance curve in a single run. The data is analyzed through a linearized model for coated bubbles. The results confirm the significant influence of the shell on the bubble dynamics: shell elasticity increases the resonance frequency by about 50%, and shell viscosity is responsible for about 70% of the total damping. The obtained value for shell elasticity is in quantative agreement with previously reported values. The shell viscosity increases significantly with the radius, revealing a new nonlinear behavior of the phospholipid coating.     

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.     

Numerical modeling of microbubble backscatter to optimize ultrasound particle image velocimetry imaging: initial studies

We have developed a promising non-invasive ultrasound-based method for performing particle image velocimetry (PIV) in vivo. This method, termed echo PIV, provides multi-component blood velocity data with good (2 ms) temporal resolution. The method takes advantage of the non-linear ultrasound backscatter characteristics of small gas-filled microbubbles (ultrasound contrast) that are seeded into the blood stream. In this study, we use a numerical model to explore potential areas to focus future work in echo PIV.

Ultrasound backscatter from encapsulated microbubbles was modeled using a modified Rayleigh–Plesset equation (Church model, 1995), taking into account the protein/lipid shell layer as a thick, mass-conserving incompressible fluid surrounded by incompressible blood-like fluid. The equation of motion was solved numerically to characterize the fundamental and second harmonic components of the backscattered pressure. Results show a significant advantage in using the second harmonic component for echo PIV, especially for small bubble sizes less than 3 μm in diameter at 2.2 MHz frequency. The effect of the shell thickness ranging from 10 to 500 nm on the vibration amplitude of the bubble was examined and it is shown that the presence of the shell requires mechanical index (MI)>0.2 of incident pressure amplitude to improve bubble detectability. Analysis of the effect of pulse length shows a tradeoff between axial resolution (short pulse length) and bubble detectability (longer pulse length) will most likely be required. The effect of varying MI between 0.1 and 0.6 was also studied at a center frequency of 2.2 MHz and the results indicate that the resonance of the second harmonic is maximized for bubbles with diameter of approximately 2.75 μm. Bubble non-linearities at MI>0.2 induced a resonant frequency shift away from the integer multiple of the incident frequency in the second harmonic backscatter. For a given bubble size, there is a combination of optimal incident frequency and mechanical index range that maximizes the ratio of the second harmonic compared to the fundamental. This resonant frequency decreases with increasing bubble radius. Further, a narrow bandwidth pulse is shown to increase signal strength. Both of these effects may cause conflict with factors governing spatial resolution. Optimization of the incident frequency, microbubble size and mechanical index to enhance bubble detectability will depend on the particular clinical application. These theoretical predictions provide further understanding of the physics behind our echo PIV technique, and should be useful for guiding the design of echo PIV systems.