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...     

超声波作用下泡群的共振声响应

从球状泡群气泡动力学方程出发, 考虑泡群间次级声辐射的影响, 得到了声场中两泡群共同存在时气泡振动的动力学方程, 并以此为基础探讨声波驱动下双泡群振动系统的共振响应特征. 由于泡群间气泡间的相互作用, 系统存在低频共振和高频共振现象, 两不同共振频率的数值与泡群内气泡的本征频率相关. 泡群内气泡的本征频率又受到初始半径、泡群大小和泡群内气泡数量的影响. 气泡自由振动和驱动声波的耦合激起泡群内气泡的受迫振动, 气泡初始半径、气泡数密度和驱动声波频率等都会影响泡群内气泡的振动幅值和初相位. 关键词： 气泡群 共振 声响应 超声空化     

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。     

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.     

次Bjerknes力作用下气泡的体积振动和散射声场

利用Lagrange方程得到了次Bjerknes力作用下气泡的体积振动方程,并探讨了次Bjerknes力作用下不同参数对气泡体积振动振幅和振动初相位的影响,研究了振动初相位差为π和0的气泡对在液体中形成的散射声场特征.结果表明:次Bjerknes作用力下,相邻气泡半径、气泡间距、多方指数均能影响气泡的体积振动振幅,气泡对的均衡半径、气泡间距和驱动频率则对气泡振动初相位产生明显影响;相距很近、相位相差为π的两个气泡的散射声压与气泡体积振动振幅、气泡间距、驱动频率和振动初相位有关,随声场距离成反比减小,与声场位置有关,其平均散射声功率是单个孤立气泡的1/6(kd_(12))~2半径相同、相距很近、相位相同的两个6气泡的散射声压与气泡振动初相位、体积振动振幅、气泡间距、驱动频率有关,随声场距离成反比减小,其平均散射声功率是单个孤立气泡的4倍.     

包膜超声造影微泡次谐波特性的优化设计与实验研究

基于包膜超声造影微泡在超声场中的理论振动模型,对其次谐波特性进行优化设计,从理论上计算和分析了微泡粒径、膜弹性及声压等对微泡次谐波响应的影响,以期获得其用于非破坏性次谐波成像的最佳条件。另外通过改变膜材料的配比, 制备了具有不同膜弹性的超声造影微泡,对其声学特性进行了体外声学实验测定。仿真计算和实验结果表明,在合适的膜材料配比条件下,制得的平均粒径为3μm左右的包膜微泡,可获得满意的次谐波响应,并且其用于非破坏性次谐波成像时的最佳工作声压约200-400 kPa。     

声场中气泡群的动力学特性

以水为工作介质,考虑了液体的轻微可压缩性,研究了声场中气泡群的动力学特性,对单一型和混合型气泡群内微泡的初始半径、气泡的数目及声频率和声压对气泡动力学特性进行了数值研究．分析了各参数对气泡运动特性和气泡崩溃时所产生压力脉冲的影响．研究了单一型气泡群内气泡动力学的混沌特性,分析了气泡处于混沌特性下两次崩溃压力脉冲特征,结果表明：适合的参数有利于提高声空化处理效果．     

双泡耦合声空化动力学过程模拟

为了对双泡耦合的声空化过程进行模拟,本文从流体动力学控制方程和流体体积分数模型出发,在Fluent软件中构建双泡耦合超声空化三维有限元仿真模型,对超声波驱动下流体中双泡耦合声空化动力学过程进行数值模拟,并通过对空化气泡周围声场的变化进行分析研究双泡耦合声空化的非线性动力学特性.结果显示:在超声波驱动下,球形气泡先缓慢扩张,扩张到最大半径后迅速收缩直至溃灭;耦合双气泡间存在相互作用力,使得空化气泡的扩张受到抑制、气泡收缩时间增长;空化气泡在收缩阶段的能量转换能力增强,相比单气泡声空化,耦合双气泡溃灭时气泡内部的压强更大.本文分析结果将为超声空化泡群的动力学过程模拟提供参考.     

声场中水力空化泡的动力学特性

以水为工作介质,考虑了液体黏性、表面张力、可压缩性及湍流作用等情况,对文丘里管反应器中空化泡在声场作用下的动力学行为特性进行了数值研究.分析了超声波频率、声压及喉径比对空化泡运动特性以及空化泡崩溃时所形成泡温以及压力脉冲的影响.结果表明,超声将水力空化泡运动调制成稳态空化,有利于增强空化效果. 关键词： 超声波 水力空化 湍流 气泡动力学     

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.     

Harmonic responses and cavitation activity of encapsulated microbubbles coupled with magnetic nanoparticles

Encapsulated microbubbles coupled with magnetic nanoparticles, one kind of hybrid agents that can integrate both ultrasound and magnetic resonance imaging/therapy functions, have attracted increasing interests in both research and clinic communities. However, there is a lack of comprehensive understanding of their dynamic behaviors generated in diagnostic and therapeutic applications. In the present work, a hybrid agent was synthesized by integrating superparamagnetic iron oxide nanoparticles (SPIOs) into albumin-shelled microbubbles (named as SPIO-albumin microbubbles). Then, both the stable and inertial cavitation thresholds of this hybrid agent were measured at varied SPIO concentrations and ultrasound parameters (e.g., frequency, pressure amplitude, and pulse length). The results show that, at a fixed acoustic driving frequency, both the stable and inertial cavitation thresholds of SPIO-albumin microbubble should decrease with the increasing SPIO concentration and acoustic driving pulse length. The inertial cavitation threshold of SPIO-albumin microbubbles also decreases with the raised driving frequency, while the minimum sub- and ultra-harmonic thresholds appear at twice and two thirds resonance frequency, respectively. It is also noticed that both the stable and inertial cavitation thresholds of SonoVue microbubbles are similar to those measured for hybrid microbubbles with a SPIO concentration of 114.7 μg/ml. The current work could provide better understanding on the impact of the integrated SPIOs on the dynamic responses (especially the cavitation activities) of hybrid microbubbles, and suggest the shell composition of hybrid agents should be appropriately designed to improve their clinical diagnostic and therapeutic performances of hybrid microbubble agents.     

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.     

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.     

Subharmonic behavior of phospholipid-coated ultrasound contrast agent microbubbles

Coated microbubbles, unlike tissue are able to scatter sound subharmonically. Therefore, the subharmonic behavior of coated microbubbles can be used to enhance the contrast in ultrasound contrast imaging. Theoretically, a threshold amplitude of the driving pressure can be calculated above which subharmonic oscillations of microbubbles are initiated. Interestingly, earlier experimental studies on coated microbubbles demonstrated that the threshold for these bubbles is much lower than predicted by the traditional linear viscoelastic shell models. This paper presents an experimental study on the subharmonic behavior of differently sized individual phospholipid coated microbubbles. The radial subharmonic response of the microbubbles was recorded with the Brandaris ultra high-speed camera as a function of both the amplitude and the frequency of the driving pulse. Threshold pressures for subharmonic generation as low as 5 kPa were found near a driving frequency equal to twice the resonance frequency of the bubble. An explanation for this low threshold pressure is provided by the shell buckling model proposed by Marmottant et al. [J. Acoust. Soc. Am. 118, 3499-3505 (2005)]. It is shown that the change in the elasticity of the bubble shell as a function of bubble radius as proposed in this model, enhances the subharmonic behavior of the microbubbles.     

Resonance frequencies of lipid-shelled microbubbles in the regime of nonlinear oscillations

Knowledge of resonant frequencies of contrast microbubbles is important for the optimization of ultrasound contrast imaging and therapeutic techniques. To date, however, there are estimates of resonance frequencies of contrast microbubbles only for the regime of linear oscillation. The present paper proposes an approach for evaluating resonance frequencies of contrast agent microbubbles in the regime of nonlinear oscillation. The approach is based on the calculation of the time-averaged oscillation power of the radial bubble oscillation. The proposed procedure was verified for free bubbles in the frequency range 1-4 MHz and then applied to lipid-shelled microbubbles insonified with a single 20-cycle acoustic pulse at two values of the acoustic pressure amplitude, 100 kPa and 200 kPa, and at four frequencies: 1.5, 2.0, 2.5, and 3.0 MHz. It is shown that, as the acoustic pressure amplitude is increased, the resonance frequency of a lipid-shelled microbubble tends to decrease in comparison with its linear resonance frequency. Analysis of existing shell models reveals that models that treat the lipid shell as a linear viscoelastic solid appear may be challenged to provide the observed tendency in the behavior of the resonance frequency at increasing acoustic pressure. The conclusion is drawn that the further development of shell models could be improved by the consideration of nonlinear rheological laws.     

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.     

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.     

声波在含气泡液体中的线性传播

为了探讨含气泡液体对声波传播的影响, 研究了声波在含气泡液体中的线性传播. 在建立含气泡液体的声学模型时引入气泡含量的影响,建立气泡模型时引用 Keller的气泡振动模型并同时考虑气泡间的声相互作用,得到了经过修正的气泡振动方程. 通过对含气泡液体的声传播方程和气泡振动方程联立并线性化求解,在满足 (ω R₀)/c << 1 的前提下,得到了描述含气泡液体对声波传播的衰减系数和传播速度. 通过数值分析发现,在驱动声场频率一定的情况下,气泡含量的增加及气泡的变小均会导致衰减系数增加和声速减小;气泡的体积分数和大小一定时, 驱动声场频率在远小于气泡谐振频率的情况下,声速会随驱动频率的增加而减小; 气泡间的声相互作用对声波传播速度及含气泡液体衰减系数的影响不明显.最终认为气泡的大小、 数量和驱动声场频率是影响声波在含气泡液体中线性传播的主要因素. 关键词： 含气泡液体 线性声波 声衰减系数 声速     

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