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.     

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.     

纳米包膜造影微泡在脉冲超声场中的瞬态非线性特性研究

对包膜造影微泡的研究中,使用的基本上都是单泡模型。但是一般实验均是针对微泡群设计的;同时对微泡背向散射信号的分析采用的都是传统的谱分析。本文中严格控制实验条件,获得了单个微泡在脉冲超声场中的背向散射回波信号;然后经短时傅里叶变换,研究了微泡的瞬态非线性特性,揭示了微泡振动中非线性谐波随着时间的变化情况,是此前相关工作中未见报告的.     

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.     

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.      

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。     

非球形包膜微泡近场局部高压研究

基于流体力学,导出了超声驱动下的非球形包膜微泡的外部流体压强的解析表达式.数值模拟表明,虽然包膜微泡的非球形状对远场流体压强没有明显影响,但会造成近场局部位置有极大的流体压强,其明显高于同等条件下的球形包膜微泡周围相应位置上的流体压强.这一现象对包膜微泡的实际应用,如强超声治疗、靶向给药和细胞微穿孔等有着重要的意义.随着驱动频率向包膜微泡本征频率的靠近或微泡偏离球形程度的增大,所产生的近场局部高压也越大.     

观测包膜微泡在超声场中的动力学行为

运用长距离显微成像系统与锁相积分拍摄技术相结合的方法, 拍到了单个造影剂微泡在两种不同频率和不同声压下的周期性振动图像. 根据这些图像得到了微泡直径的实验数据, 并分别用Hoff模型和Rayleigh-Plesset模型对数据进行拟合, 并对数据进行了频谱分析. 结果表明:Hoff模型对实验数据的拟合结果优于Rayleigh-Plesset模型的拟合结果; 二次谐波的相对强度随着声压幅度的升高而增大. 关键词： 包膜微泡 锁相积分拍摄方法 频谱     

试样激励下轻敲模式原子力声显微镜的非线性动力学特性

利用Euler-Bernoulli梁理论和DMT针尖-样品作用力模型建立了试样激励下轻敲模式原子力声显微镜(AFAM)系统的动力学方程,并应用非线性动力学分析方法对AFAM微悬臂梁的振动特性进行研究。通过合理改变超声激励幅值、超声激励频率和针尖-样品初始间距等模型参数模拟得到微悬臂梁的超谐波、次谐波、准周期和混沌振动现象,采用时间序列、频谱、相空间、Poincare截面和Lyapunov指数等方法对不同非线性振动特性进行表征。通过分析不同模型参数条件下微悬臂梁针尖-样品作用力特性,探索了微悬臂梁不同非线性振动现象的产生机制。此外,研究了AFAM微悬臂梁运动的分岔特性,发现当超声激励幅值和针尖-样品初始间隙连续变化时,周期、准周期和混沌运动交替出现。研究结果对AFAM系统非线性动力学行为分析和混沌振动控制提供了理论参考。      

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.     

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.     

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.     

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.     

Using light scattering to measure the response of individual ultrasound contrast microbubbles subjected to pulsed ultrasound in vitro

Light scattering was used to measure the radial pulsations of individual ultrasound contrast microbubbles subjected to pulsed ultrasound. Highly diluted Optison or Sonazoid microbubbles were injected into either a water bath or an aqueous solution containing small quantities of xanthan gum. Individual microbubbles were insonified by ultrasound pulses from either a commercial diagnostic ultrasound machine or a single element transducer. The instantaneous response curves of the microbubbles were measured. Linear and nonlinear microbubble oscillations were observed. Good agreement was obtained by fitting a bubble dynamics model to the data. The pulse-to-pulse evolution of individual microbubbles was investigated, the results of which suggest that the shell can be semipermeable, and possibly weaken with subsequent pulses. There is a high potential that light scattering can be used to optimize diagnostic ultrasound techniques, understand microbubble evolution, and obtain specific information about shell parameters.     

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.     

Influence of nesting shell size on brightness longevity and resistance to ultrasound-induced dissolution during enhanced B-mode contrast imaging

This study aims to bridge the gap between transport mechanisms of an improved ultrasound contrast agent (UCA) and its resulting behavior in a clinical imaging study. Phospholipid-shelled microbubbles nested within the aqueous core of a polymer microcapsule are examined for their use and feasibility as an improved UCA. The nested formulation provides contrast comparable to traditional formulations, specifically an SF₆ microbubble coated by a DSPC PEG-3000 monolayer, with the advantage that contrast persists at least nine times longer in a mock clinical, in vitro setting. The effectiveness of the sample was measured using a contrast ratio in units of decibels (dB) which compares the brightness of the nested microbubbles to a reference value of a phantom tissue mimic. During a 40 min imaging study, six nesting formulations with average outer capsule diameters of 1.95, 2.53, 5.55, 9.95, 14.95, and 20.51 μm reached final contrast ratio values of 0.25, 2.35, 3.68, 4.51, 5.93, and 8.00 dB, respectively. The starting contrast ratio in each case was approximately 8 dB and accounts for the brightness attributed to the nesting shell. As compared with empty microcapsules (no microbubbles nested within), enhancement of the initial contrast ratio increased systematically with decreasing microcapsule size. The time required to reach a steady state in the temporal contrast ratio profile also varied with microcapsule diameter and was found to be 420 s for each of the four smallest shell diameters and 210 s and 150 s, respectively, for the largest two shell diameters. All nested formulations were longer-lived and gave higher final contrast ratios than a control sample comprising un-nested, but otherwise equivalent, microbubbles. Specifically, the contrast ratio of the un-nested microbubbles decreased to a negative value after 4 min of continuous ultrasound exposure with complete disappearance of the microbubbles after 15 min whereas all nested formulations maintained positive contrast ratio values for the duration of the 40 min trial. The results are consistent with two distinct stages of gas transport: in the first stage, passive diffusion occurs under ambient conditions across the microbubble monolayer within the first few minutes after formulation until the aqueous interior of the microcapsule is saturated with gas; in the second stage ultrasound drives additional gas dissolution even further due to pressure modulation. It is important to understand the chemistry and transport mechanisms of this contrast agent under the influence of ultrasound to attain better perspicacity for enhanced applications in imaging. Results from this study will facilitate future preclinical studies and clinical applications of nested microbubbles for therapeutic and diagnostic imaging.     

A comparison of the fragmentation thresholds and inertial cavitation doses of different ultrasound contrast agents

Contrast bubble destruction is important in several new diagnostic and therapeutic applications. The pressure threshold of destruction is determined by the shell material, while the propensity for of the bubbles to undergo inertial cavitation (IC) depends both on the gas and shell properties of the ultrasound contrast agent (UCA). The ultrasonic fragmentation thresholds of three specific UCAs (Optison, Sonazoid, and biSpheres), each with different shell and gas properties, were determined under various acoustic conditions. The acoustic emissions generated by the agents, or their derivatives, characteristic of IC after fragmentation, was also compared, using cumulated broadband-noise emissions (IC "dose"). Albumin-shelled Optison and surfactant-shelled Sonazoid had low fragmentation thresholds (mean = 0.13 and 0.15 MPa at 1.1 MHz, 0.48 and 0.58 MPa at 3.5 MHz, respectively), while polymer-shelled biSpheres had a significant higher threshold (mean = 0.19 and 0.23 MPa at 1.1 MHz, 0.73 and 0.96 MPa for thin- and thick-shell biSpheres at 3.5 MHz, respectively, p<0.01). At comparable initial concentrations, surfactant-shelled Sonazoid produced a much larger IC dose after shell destruction than did either biSpheres or Optison (p<0.01). Thick-shelled biSpheres had the highest fragmentation threshold and produced the lowest IC dose. More than two and five acoustic cycles, respectively, were necessary for the thin- and thick-shell biSpheres to reach a steady-state fragmentation threshold.