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.     

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.     

Nonlinear response to ultrasound of encapsulated microbubbles

The acoustic backscatter of encapsulated gas-filled microbubbles immersed in a weak compressible liquid and irradiated by ultrasound fields of moderate to high pressure amplitudes is investigated theoretically. The problem is formulated by considering, for the viscoelastic shell of finite thickness, an isotropic hyperelastic neo-Hookean model for the elastic contribution in addition to a Newtonian viscous component. First and second harmonic scattering cross-sections have been evaluated and the quantitative influence of the driving pressure amplitude on the harmonic resonance frequencies for different initial equilibrium bubble sizes and for different encapsulating physical properties has been determined. Conditions for optimal second harmonic imaging have been also investigated and some regions in the parameters space where the second harmonic intensity is dominant over the fundamental have been identified. Results have been obtained for albumin, lipid and polymer encapsulating shells, respectively.     

Interaction of microbubbles with high intensity pulsed ultrasound

High intensity pulsed ultrasound, interacting with microbubble contrast agents, is potentially useful for drug delivery, cancer treatment, and tissue ablation, among other applications. To establish the fundamental understanding on the interaction of a microbubble (in an infinite volume of water) with an ultrasound pressure field, a numerical study is performed using the boundary element method. The response of the bubble, in terms of its shape at different times, the maximum bubble radius obtained, the oscillation time, the jet velocity, and its translational movement, is studied. The effect of ultrasound intensity and initial bubble size is examined as well. One important outcome is the determination of the conditions under which a clear jet will be formed in a microbubble in its interaction with a specific sound wave. The high speed jet is crucial for the aforementioned intended applications.     

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.     

"Compression-only" behavior: a second-order nonlinear response of ultrasound contrast agent microbubbles

Oscillating phospholipid-coated ultrasound contrast agent microbubbles display a so-called "compression-only" behavior, where it is observed that the bubbles compress efficiently while their expansion is suppressed. Here, a theoretical understanding of the source of this nonlinear behavior is provided through a weakly nonlinear analysis of the shell buckling model proposed by Marmottant et al. [J. Acoust. Soc. Am. 118, 3499-3505 (2005)]. It is shown that the radial dynamics of the bubble can be considered as a superposition of a linear response at the fundamental driving frequency and a second-order nonlinear low-frequency response that describes the negative offset of the mean bubble radius. The analytical solution deduced from the weakly nonlinear analysis shows that the compression-only behavior results from a rapid change of the shell elasticity with bubble radius. In addition, the radial dynamics of single phospholipid-coated microbubbles was recorded as a function of both the amplitude and the frequency of the driving pressure pulse. The comparison between the experimental data and the theory shows that the magnitude of compression-only behavior is mainly determined by the initial phospholipids concentration on the bubble surface, which slightly varies from bubble to bubble.     

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.     

A photometer to measure light scattering in optical glass

A photometer is described for the measurement of light-scattering in high-quality, optical bulk glass. The photometer operates continuously over the wavelength range 0.5 to 1m and can measure scattering coefficients down to a level of 5×10^–7 cm^–1. A photon counting technique is used for light measurement and calibration is by reflection of the incident beam from an ideal diffusing screen. Measurements with high-purity benzene are in good agreement with computed and previous experimental values. Results of scattering from two samples of optical glass are given.     

Characterization of ultrasound contrast microbubbles using in vitro experiments and viscous and viscoelastic interface models for encapsulation

Zero-thickness interface models are developed to describe the encapsulation of microbubble contrast agents. Two different rheological models of the interface, Newtonian (viscous) and viscoelastic, with rheological parameters such as surface tension, surface dilatational viscosity, and surface dilatational elasticity are presented to characterize the encapsulation. The models are applied to characterize a widely used microbubble based ultrasound contrast agent. Attenuation of ultrasound passing through a solution of contrast agent is measured. The model parameters for the contrast agent are determined by matching the linearized model dynamics with measured attenuation data. The models are investigated for its ability to match with other experiments. Specifically, model predictions are compared with scattered fundamental and subharmonic responses. Experiments and model prediction results are discussed along with those obtained using an existing model [Church, J. Acoust. Soc. Am. 97, 1510 (1995) and Hoff et al., J. Acoust. Soc. Am. 107, 2272 (2000)] of contrast agents.     

Ambient pressure dependence of the ultra-harmonic response from contrast microbubbles

Sub-harmonic response from ultrasound contrast agent microbubbles has been demonstrated to be an effective modality for noninvasive pressure measurement. In the present study, the dependence of ultra-harmonic response on the ambient overpressure was investigated by both experimental measurements and simulations. In the measurements, the microbubbles were exposed to Gaussian pulses with varied driving frequencies and pulse lengths, at an acoustic pressure of 0.3 MPa. The amplitudes of sub- and ultra-harmonic components were measured when the ambient overpressures varied from 0-25 kPa. At the driving frequency of 1.33 MHz, the ultra-harmonic energy decreased but the sub-harmonic energy increased with the increasing overpressure; while at the driving frequency of 4 MHz, both the sub- and ultra-harmonic components showed the same tendency that the corresponding energy decreased as the overpressure was increased. A 4-MHz Gaussian pulse with 64 cycles could provide an ultra-harmonic response with both good ambient pressure sensitivity and high linearity. Furthermore, the effects of shell parameters of a microbubble on the generation of ultra- and sub-harmonic responses were discussed based on simulations using Marmottant's model. This study suggests that the ultra-harmonic response from contrast microbubbles might be applicable for noninvasive pressure measurement.     

脉冲超声激励下SonoVue微泡的瞬态空化特性

将SonoVue微泡从临床疾病诊断拓展至治疗引起了诸多研究人员的兴趣。为了平衡治疗效率和生物安全性,深入理解声学参数和SonoVue微泡瞬态空化的关系至关重要。本研究自行制备仿体容器放置SonoVue微泡,使用1 MHz发射换能器激励其产生空化效应,另一个7.5 MHz的聚焦换能器接收声信号,经放大及高速数据采集后送上位机处理。通过深入分析信号的时频域特征,我们提出以宽带信号的能量及其随时间变化曲线的半高宽来表征瞬态空化的剂量(ICD)和相对持续时间(ICP),并确定:瞬态空化的发生和ICD依赖于峰值负声压,但ICP随峰值负声压的增加而减小;脉冲重复频率和脉冲持续时间都和ICD及ICP正相关;且脉冲持续时间的影响较大。这些结果有望为SonoVue微泡的治疗应用提供理论支持。     

Fourier-transform light scattering of individual colloidal clusters

We present measurements of the scalar-field light scattering of individual dimer, trimer, and tetrahedron shapes among colloidal clusters. By measuring the electric field with quantitative phase imaging at the sample plane and then numerically propagating to the far-field scattering plane, the two-dimensional light-scattering patterns from individual colloidal clusters are effectively and precisely retrieved. The measured scattering patterns are consistent with simulated patterns calculated from the generalized multiparticle Mie solution.     

Study on the multiple scattering effects of ultrasound contrast agents

In this paper, the multiple scattering of interacting encapsulated microbubbles in suspensions is calculated using two novel approaches--Kargl's effective medium approach and Ye and Ding's approach of 2nd-order correction. Two types of contrast agents with bubbles of different sizes and concentrations are chosen for our numerical simulations. One is Albunex, which is depicted by Church and has a size range of several microns, and the other is sodium laureate solution (before fractionation) described by Soetanto and Chan and has an average size of 35.5 microm. The numerical results from these two approaches are compared with that from the linear approximation. It is found that the multiple scattering effects on attenuation and dispersion of sound in suspensions are evident in the cases of high bubble volume fractions, basically greater than the order of 1 x 10(-4), and much more obvious for larger bubbles with average size of tens of microns.     

A preliminary in vitro assessment of polymer-shelled microbubbles in contrast-enhanced ultrasound imaging

This paper focuses on the use of poly (vinyl alcohol)-shelled microbubbles as a contrast agent in ultrasound medical imaging. The objective was an in vitro assessment of the different working conditions and signal processing methods for the visual detection (especially in small vessels) of such microbubbles, while avoiding their destruction. Polymer-shelled microbubbles have recently been proposed as ultrasound contrast agents with some important advantages. The major drawback is a shell that is less elastic than that of the traditional lipidic microbubbles. Weaker echoes are expected, and their detection at low concentrations may be critical. In vitro experiments were performed with a commercial ultrasound scanner equipped with a dedicated acquisition board. A concentration of 100 bubbles/mm³, excitation pressure amplitudes from 120 kPa to 320 kPa, and a central frequency of 3 MHz or 4.5 MHz were used. Three multi-pulse techniques (i.e., pulse inversion, contrast pulse sequence based on three transmitted signals, and contrast pulse sequence in combination with the chirp pulse) were compared. The results confirmed that these microbubbles produce a weaker ultrasound response than lipidic bubbles with a reduced second-order nonlinear component. Nevertheless, these microbubbles can be detected by the contrast pulse sequence technique, especially when the chirp pulse is adopted. The best value of the contrast-to-tissue ratio was obtained at an excitation pressure amplitude of 230 kPa: although this pressure amplitude is higher than what is typically used for lipidic microbubbles, it does not cause the rupture of the polymeric contrast agent.     

Modeling of the acoustic response from contrast agent microbubbles near a rigid wall

In ultrasonic targeted imaging, specially designed encapsulated microbubbles are used, which are capable of selectively adhering to the target site in the body. A challenging problem is to distinguish the echoes from such adherent agents from echoes produced by freely circulating agents. In the present paper, an equation of radial oscillation for an encapsulated bubble near a plane rigid wall is derived. The equation is then used to simulate the echo from a layer of contrast agents localized on a wall. The echo spectrum of adherent microbubbles is compared to that of free, randomly distributed microbubbles inside a vessel, in order to examine differences between the acoustic responses of free and adherent agents. It is shown that the fundamental spectral component of adherent bubbles is perceptibly stronger than that of free bubbles. This increase is accounted for by a more coherent summation of echoes from adherent agents and the acoustic interaction between the agents and the wall. For cases tested, the increase of the fundamental component caused by the above two effects is on the order of 8-9 dB. Bubble aggregates, which are observed experimentally to form near a wall due to secondary Bjerknes forces, increase the intensity of the fundamental component only if they are formed by bubbles whose radii are well below the resonant radius. If the formation of aggregates contributes to the growth of the fundamental component, the increase can exceed 17 dB. Statistical analysis for the comparison between adhering and free bubbles, performed over random space bubble distributions, gives p-values much smaller than 0.05.     

激光拉曼散射测量ICF靶丸燃料含量

 提出了一种基于显微激光拉曼散射的惯性约束聚变塑料靶丸非放射性燃料气体含量的测量方法,该方法克服了过去不能直接对氘气进行非破坏测量的困难,可以显著提高测量效率与精度,通过标定可以方便应用于打靶零时刻的燃料总量监测。由于入射光与散射光都需要透过微球材料,因此,球壳材料性能特点就会对测量结果产生显著影响,针对微球材料的荧光波长、激光波长和功率以及探测系统光栅性能等因素进行了详细考察与讨论,给出了确切测试结果。     

激光拉曼散射测量ICF靶丸燃料含量

提出了一种基于显微激光拉曼散射的惯性约束聚变塑料靶丸非放射性燃料气体含量的测量方法,该方法克服了过去不能直接对氘气进行非破坏测量的困难,可以显著提高测量效率与精度,通过标定可以方便应用于打靶零时刻的燃料总量监测。由于入射光与散射光都需要透过微球材料,因此,球壳材料性能特点就会对测量结果产生显著影响,针对微球材料的荧光波长、激光波长和功率以及探测系统光栅性能等因素进行了详细考察与讨论,给出了确切测试结果。     

Resonant scattering of a lepton by a lepton in the pulsed light field

The process of resonant scattering of a lepton by a lepton in the field of pulsed light wave in general relativistic case is studied theoretically. The approximation when a pulsewidth is considerably greater than the characteristic time of wave oscillation is considered. The analytical expression for the resonant differential cross-section of concerned process is derived within the framework of the first order of the perturbation theory with respect to external laser field; it contains the resonant peak, the altitude and the width of which are defined by the external pulsed wave characteristics. It is demonstrated, that the resonant differential cross-section of scattering of an electron by an electron (an electron by a positron, an electron by a muon) in the pulsed light field may be several orders of magnitude greater than the corresponding one in the external field absence. The derived results may be verified experimentally for example by scientific facility at SLAC National Accelerator Laboratory.     

Using pulsed wave ultrasound to evaluate the suitability of hydroxyl radical scavengers in sonochemical systems

Hydroxyl radical (OH) scavengers are commonly used in sonochemistry to probe the site and nature of reaction in aqueous cavitational systems. Using pulsed wave (PW) ultrasound with comparative sonochemistry we evaluated the performance of OH scavengers (i.e., formic acid, carbonic acid, terephthalic acid/terephthalate, iodide, methanesulfonate, benzenesulfonate, and acetic acid/acetate) in a sonochemical system to determine which OH scavengers react only in bulk solution and which OH scavengers interact with cavitation bubbles. The ability of each scavenger to interact with cavitation bubbles was assessed by comparing the pulse enhancement (PE) of 10 μM of a probe compound, carbamazepine (CBZ), in the presence and absence of a scavenger. Based on PE results, acetic acid/acetate appears to scavenge OH in bulk solution, and not interact with cavitation bubbles. Methanesulfonate acts as reaction promoter, increasing rather than inhibiting the degradation of CBZ. For formic acid, carbonic acid, terephthalic acid/terephthalate, benzenesulfonate, and iodide, the PE was significantly decreased compared to in the absence of the scavenger. These scavengers not only quench OH in bulk solution but also affect the cavity interface. The robustness of acetic acid/acetate as a bulk OH scavenger was validated for pH values between 3.5 and 8.9 and acetic acid/acetate concentrations from 0.5 to 0.1 M.