流动微泡群瞬态空化强度时域分布的比例反馈调节*

声波、血流环境及流动微泡群的稳定性都会影响焦区内瞬态空化强度(ICI)在超声作用时间内的分布,从而影响基于瞬态空化的治疗效率和生物安全性。本文在搭建仿体中流动微泡群瞬态空化发生和实时测量系统的基础上,设计了基于LabView FPGA的比例反馈控制器,在保持脉冲重复频率和脉冲长度不变的条件下,通过选择适当的比例系数,依据当前周期的声波激励下实时测量的ICI,实时调节下一周期声波信号的峰值负压,以调控ICI在时间上的分布。研究表明,在最优比例系数(1 × 107)下,和开环系统相比,ICI的稳定率提升~2.31 倍,ICI的时域下降速率减小~94.41%;在超声作用时间内总ICI也基本达到期望水平。这些结果表明该比例反馈控制器在调控脉冲超声激励下流动微泡群ICI时域分布的有效性,有望改进瞬态空化在相关疾病治疗中的效率和安全性。     

超声脉冲长度与重复频率对流动微泡群稳态空化特性的影响

为了深入理解超声脉冲长度(PL)与重复频率(PRF)对流动微泡群稳态空化特性的影响,本研究自行制备仿体血管,利用注射泵推动微泡群在其中恒速流动,使用1 MHz的聚焦换能器激励微泡群产生稳态空化,另一个7.5 MHz的平面换能器接收声信号,经前置放大及高速采集后送至上位机存储。在定义临界重复频率(Critical PRF,CPRF)的基础上,通过深入的时频域分析,我们发现PL和PRF共同决定流动微泡群的稳态空化特性:当PRF低于CPRF时,流动微泡群的稳态空化剂量(Stable Cavitation Dose,SCD)与PL呈正相关,且时域分布均匀;而当PRF大于CPRF时,其稳态空化特性由PL决定,在长PL (＞100μs)下,SCD随着PL增加逐渐减小,且时域分布不均匀;在短PL (＜50μs)下,SCD和PRF无显著相关关系,且时域分布均匀。本研究结果深入阐明了流动微泡群的稳态空化特性,期望可用其获取可预测可控的生物效应,并应用于相关临床治疗。      

超声波声孔效应中气泡动力学的研究

在超声快速制取组织细胞病理切片的过程中，发现激励信号对切片制取效果有明显的影响.为了掌握超声激励信号对组织细胞的影响规律，达到快速制取病理切片的最佳状态，从气泡空化模型入手，通过改变激励信号频率、声压、气泡初始半径和液体黏滞系数等参量，研究了声孔效应中气泡动力学激励机制.数值计算表明：空化泡振动随激励声压增强而升高，随液体黏滞系数增强而减弱；一定频率范围内空化泡振动能保持在膨胀、收缩和振荡的稳定空化状态，存在空化泡稳态振动的最佳激励频率；一定初始半径能保证空化泡产生稳定的振动，存在空化泡稳态振动幅度最大的初始半径.实际操作中，在频率、声压、初始半径和黏滞系数综合作用的若干空化阈内，声孔效应使超声快速法制取细胞组织切片获得最佳效果. 关键词： 声孔效应 超声空化 气泡振动 稳态空化域     

微泡对高强度聚焦超声声压场影响的仿真研究*

微泡对高强度聚焦超声(HIFU)治疗焦域具有增效作用,而HIFU治疗中不同声学条件下微泡对HIFU形成声压场的影响尚不清楚。本文基于气液混合声波传播方程、Keller气泡运动方程、时域有限差分(FDTD)法和龙格-库塔(RK)法数值仿真研究输入声压、激励频率、气泡初始空隙率和气泡初始半径对HIFU形成声压场的影响。研究结果表明,随着输入声压的增大,焦点处声压升高但焦点处最大声压与输入声压的比值减小,焦点位置几乎不变;随着激励频率和气泡初始半径的增大,焦点处声压升高且焦点位置向远离换能器方向移动;随着气泡初始空隙率的增大,焦点处声压降低且焦点位置向换能器方向移动。     

声驻波场中空化泡的动力学特性

以水为工作介质, 考虑了液体的可压缩性, 研究了驻波声场中空化泡的运动特性, 模拟了驻波场中各位置处空化泡的运动状态以及相关参数对各位置处空化泡在主Bjerknes力作用下运动方向的影响. 结果表明: 驻波声场中, 空化泡的运动状态分为三个区域, 即在声压波腹附近空化泡做稳态空化, 在偏离波腹处空化泡做瞬态空化, 在声压波节附近, 空化泡在主Bjerknes 力作用下, 一直向声压波节处移动, 显示不发生空化现象; 驻波场中声压幅值增加有利于空化的发生, 但声压幅值增加到一定上限时, 压力波腹区域将排斥空化泡, 并驱赶空化泡向压力波节移动, 不利于空化现象的发生; 当声频率小于初始空化泡的共振频率时, 声频率越高, 由于主Bjerknes 力的作用将有更多的空化泡向声压波节移动, 不利于空化的发生, 尤其是驻波场液面的高度不应是声波波长的1/4; 当声频率一定时, 空化泡初始半径越大越有利于空化现象的发生, 但当空化泡的初始半径超过声频率的共振半径时, 由于主Bjerknes力的作用将有更多的空化泡向声压波节移动, 不利于空化的发生.     

超声药物释放空化动力学行为研究

以直径1 μm的脂质体为空化研究对象,从修正的Rayleigh空化方程入手,研究机械系数(MI)对300 kHz和1 MHz超声作用时空化效应的影响。脂质体的药物释放以超声作用前后脂质体中钙黄绿素的荧光强度为量度。模拟结果表明:在微泡振荡过程中,由超声波驱动产生的负向最大泡壁运动速度促使微泡半径从最大快速减小接近于零,微泡积聚到最大能量。对于300 kHz和1 MHz的激励超声,存在一个拐点(MI)值,当MI小于接近0.4时,1 MHz微泡半径变化幅度强于300 kHz;当MI>0.4时,300 kHz微泡半径变化幅度强于1 MHz。这一结果预示在此范围内,300 kHz的药物释放效果好于1 MHz。本研究为超声空化效应研究及超声药物释放应用提供了理论依据。     

双泡超声空化计算分析

将由速度势叠加原理得到的双泡超声空化动力学微分方程归一化,通过matlab语言编程计算,分析了水中空化泡的线度、双泡间距、声压幅值、声波频率等因素对空化过程的影响. 在双泡超声空化动力学微分方程中引入双频超声,探讨了双泡双频超声问题. 研究表明泡的线度是决定空化特性的主要因素,声压幅值对空化特性的影响最大,其次是超声波的频率;双泡间的相互作用影响空化特性,这种影响随双泡间距的增大而减弱;双频超声对双泡空化特性的影响有限,这种影响在两超声分量的声压幅值相等时较强. 关键词： 超声空化 双泡 双频超声     

亚临界水中超声激励空化泡动力学分析

考察亚临界水中压力和温度对超声空化泡动力学的影响。应用非线性Rayleigh-Plesset方程模拟空化泡运动过程,并利用Matlab软件编程求数值解,用碘量法测定超声在亚临界水中的声空化产额。结果表明:当亚临界水的压力相似文献   

单泡超声空化仿真模型的建立及其动力学过程模拟*

为了模拟单泡超声空化的动力学特性,建立了单泡超声空化的有限元仿真模型,基于流体动力学控制方程和流体体积分数模型,利用有限元分析软件模拟了超声驱动下水中单泡的空化动力学过程。结果表明:单泡随时间的演化规律是先缓慢膨胀到最大后迅速塌缩;泡内压强与气体密度变化与单泡体积变化成反比;在膨胀阶段,泡外压强与气体密度沿着泡的径向向外递减;在压缩阶段,泡外在声压垂直方向的压强与气体密度要大于声压激励方向的压强和气体密度。该文分析结果将为超声空化动力学过程模拟及研究提供参考。     

声场作用下两空化泡相互作用的研究

建立了声场作用下两空化泡泡壁的运动方程,得出了双空化泡的共振频率,振动半径及空化噪声声压．由频率方程,振动半径和声压方程可以看出两气泡的运动情况与单气泡的运动情况有着明显的不同．共振频率,共振振幅及声压与两气泡之间的间距有关．在一定的简化条件下,运用MATLAB语言对共振频率,共振振幅及空化噪声声压进行了数值求解,发现共振频率和共振振幅随空泡间距的增大而增大,空化噪声声压随距离增大先增大后减小． 关键词： 超声 空化 频率 声压     

Improving temporal stability of stable cavitation activity of circulating microbubbles using a closed-loop controller based on pulse-length regulation

Stable cavitation (SC) has shown great potential for novel therapeutic applications. The spatiotemporal distribution of the SC activity of microbubbles circulating in a target region is not only correlated with the uniformity of treatment, but also with some undesirable effects. Therefore, it is important to achieve controllable and desirable SC activity in target regions for improved therapeutic efficiency and biosafety. This study proposes a closed-loop feedback controller based on pulse length (PL) regulation to improve the temporal stability of SC activity. Microbubbles circulating in a physiological flowing phantom were exposed to a 1 MHz focused transducer. The SC signals produced were initially received by another 7.5 MHz plane transducer, followed by high-speed signal acquisition and real-time processing. Based on the real-time-measured SC intensity excited by the current acoustic pulse, the proposed closed-loop feedback controller used three proportional coefficients to regulate the peak negative pressure (PNP) and PL of the next acoustic pulse during the acceleration and stable stages, respectively. The results show that the rise time and the temporal stability of the SC intensity of the microbubbles circulating in these two stages were improved significantly by the optimized proportional coefficients used in the proposed controller. Importantly, when compared with the traditional closed-loop feedback controller based on PNP regulation, the proposed closed-loop feedback controller based on PL regulation reduced the probability of a transition between stable and inertial cavitation, thus avoiding the risk of disadvantageous bioeffects in practical applications. These results demonstrate the effectiveness of the proposed PL-based closed-loop feedback controller and provide a feasible strategy for realization of controllable cavitation activity in applications.     

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.     

Evaluation of the properties of daughter bubbles generated by inertial cavitation of preformed microbubbles

Inertial cavitation (IC) of the preformed microbubbles is being investigated for ultrasound imaging and therapeutic applications. However, microbubbles rupture during IC, creating smaller daughter bubbles (DBs), which may cause undesired bioeffects in the target region. Thus, it is important to determine the properties of DBs to achieve controllable cavitation activity for applications. In this study, we theoretically calculated the dissolution dynamics of sulfur hexafluoride bubbles. Then, we applied a 1-MHz single tone burst with different peak negative pressures (PNPs) and pulse lengths (PLs), and multiple 5-MHz tone bursts with fixed acoustic conditions to elicit IC of the preformed SonoVue microbubbles and scattering of DBs, respectively. After the IC and scattering signals were received by a 7.5-MHz transducer, time- and frequency-domain analysis was performed to obtain the IC dose and scattering intensity curve. The theoretical dissolution curves and measured scattering intensity curves were combined to determine the effect of the incident pulse parameters on the lifetime, mean radius and distribution range of DBs. Increased PNP reduced the lifetime and mean size of the DBs population and narrowed the size distribution. The proportion of small DBs (less than resonance size) increased from 36.83% to 85.98% with an increase in the PNP from 0.6 to 1.6 MPa. Moreover, increased PL caused a shift of the DB population to the smaller bubbles with shorter lifetime and narrower distribution. The proportion of small bubbles increased from 25.74% to 95.08% as the PL was increased from 5 to 100 µs. Finally, increased IC dose caused a smaller mean size, shorter lifetime and narrower distribution in the DB population. These results provide new insight into the relationship between the incident acoustic parameters and the properties of DBs, and a feasible strategy for achieving controllable cavitation activity in applications.     

The mechanism of interaction between focused ultrasound and microbubbles in blood-brain barrier opening in mice

The activation of bubbles by an acoustic field has been shown to temporarily open the blood-brain barrier (BBB), but the trigger cause responsible for the physiological effects involved in the process of BBB opening remains unknown. Here, the trigger cause (i.e., physical mechanism) of the focused ultrasound-induced BBB opening with monodispersed microbubbles is identified. Sixty-seven mice were injected intravenously with bubbles of 1-2, 4-5, or 6-8 μm in diameter and the concentration of 10(7) numbers/ml. The right hippocampus of each mouse was then sonicated using focused ultrasound (1.5 MHz frequency, 100 cycles pulse length, 10 Hz pulse repetition frequency, 1 min duration). Peak-rarefactional pressures of 0.15, 0.30, 0.45, or 0.60 MPa were applied to identify the threshold of BBB opening and inertial cavitation (IC). Our results suggest that the BBB opens with nonlinear bubble oscillation when the bubble diameter is similar to the capillary diameter and with inertial cavitation when it is not. The bubble may thus have to be in contact with the capillary wall to induce BBB opening without IC. BBB opening was shown capable of being induced safely with nonlinear bubble oscillation at the pressure threshold and its volume was highly dependent on both the acoustic pressure and bubble diameter.     

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.     

Thresholds for cavitation produced in water by pulsed ultrasound

The threshold for transient cavitation produced in water by pulsed ultrasound was measured as a function of pulse duration and pulse repetition frequency at both 0.98 and 2.30 MHz. The cavitation events were detected with a passive acoustic technique which relies upon the scattering of the irradiation field by the bubble clouds associated with the events. The results indicate that the threshold is independent of pulse duration and acoustic frequency for pulses longer than approximately 10 acoustic cycles. The threshold increases for shorter pulses. The cavitation events are likely to be associated with bubble clouds rather than single bubbles.     

Dual-high-frequency ultrasound excitation on microbubble destruction volume

Objective and motivation

The goal of this work was to test experimentally that exposing air bubbles or ultrasound contrast agents in water to amplitude modulated wave allows control of inertial cavitation affected volume and hence could limit the undesirable bioeffects.

Methods

Focused transducer operating at the center frequency of 10 MHz and having about 65% fractional bandwidth was excited by 3 μs 8.5 and 11.5 MHz tone-bursts to produce 3 MHz envelope signal. The 3 MHz frequency was selected because it corresponds to the resonance frequency of the microbubbles used in the experiment. Another 5 MHz transducer was used as a receiver to produce B-mode image. Peak negative acoustic pressure was adjusted in the range from 0.5 to 3.5 MPa. The spectrum amplitudes obtained from the imaging of SonoVue^TM contrast agent when using the envelope and a separate 3 MHz transducer were compared to determine their cross-section at the - 6 dB level.

Results

The conventional 3 MHz tone-burst excitation resulted in the region of interest (ROI) cross-section of 2.47 mm while amplitude modulated, dual-frequency excitation with difference frequency of 3 MHz produced cross-section equal to 1.2 mm.

Conclusion

These results corroborate our hypothesis that, in addition to the considerably higher penetration depth of dual-frequency excitation due to the lower attenuation at 3 MHz than that at 8.5 and 11.5 MHz, the sample volume of dual-frequency excitation is also smaller than that of linear 3-MHz method for more spatially confined destruction of 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.