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.     

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。     

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     

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.     

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.     

非线性声场下包膜微泡动力学与频率响应分析

包膜微泡在非线性声场下的响应对高强度聚焦超声治疗具有重要意义.本文通过耦合Gilmore-AkulichevZener模型与脂质包膜的非线性模型,采用KZK方程仿真非线性声场,分析在不同超声频率、不同声压以及不同包膜材料的黏弹性下的微泡动力学行为和微泡振荡频率,并进一步对比了实际测量声场与KZK方程仿真声场下的微泡动力学行为和频率响应.研究结果表明:非线性声场会导致微泡壁的瞬时运动速率减小,声压和频率的改变对微泡动力学的影响与在线性声场中类似;包膜材料的不同可以使振荡频率中的谐波分量发生改变,其中包膜材料的弹性对微泡的频率响应影响较小,包膜的初始黏性和初始表面张力对微泡的振荡频率分布影响较大,当初始黏性越小时,二次分谐波的峰值越高,当初始表面张力越大时,主频的峰值越高.本研究进一步阐明非线性超声激励包膜微泡的微泡动力学,为包膜微泡在非线性声场下的频率响应分析奠定理论基础.     

超声微泡低频动力学特性及其生物效应

理论上利用有耗散函数的Lagrange方程,建立了有壳微泡的R(t)运动方程,开展了自由空间中有壳微泡动力学特性的研究,表明微泡内外半径增量随声压的增大、超声频率的降低、初始内径的增大及壳厚的减薄而迅速增大。实验上,利用Mie散射技术在80°散射角和前向Mie散射检测新技术实验测量了微泡R(t)曲线;利用体视显微镜,实时观察了超声微泡对动物活体微血管损伤,开展了超声微泡生物效应的动物和细胞试验研究。结果表明:(1)超声作用下,微泡引起肿瘤中微血管壁周期性膨胀收缩而发生管壁破裂,形成血栓和微血管栓塞,抑制了肿瘤生长;(2)超声联合微泡可以破坏微血管内皮生长因子(VEGF)和肝癌细胞,可以减少肿瘤血管和癌细胞再生,因此,低频超声联合微泡技术是一种值得探索抑制肿瘤生长的新技术。     

调频激励增强微气泡的次谐波理论和实验研究

超声造影剂的次谐波成像可以提高造影组织比，提供更好的图像质量. 提出一种利用调频脉冲激励以增强造影剂微气泡产生的次谐波新方法. 基于修正的Church方程，从理论上讨论了次谐波的产生与调频激励声压的关系及产生阈值，并且实验证实了优化调频信号的带宽及调频时间可以提高次谐波信号幅度及改善主瓣和旁瓣特性. 理论与实验表明，与传统脉冲信号激励相比，调频信号激励产生的次谐波幅度可提高约22dB. 关键词： 调频激励 超声造影剂 微气泡 次谐波     

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。     

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.     

Optimal design and experimental measurement of the subharmonic characterizations of encapsulated microbubble

Based on a theoretical motion equation of encapsulated microbubbles within an ultrasound field, the subharmonic characterizations of microbubbles are optimally designed and analyzed by a computer aided design system. The effects of size, shell elasticity and acoustic pressure on subharmonic response of microbubbles are calculated theoretically to obtain the optimal parameters for nondestructive subharmonic imaging. In addition, microbubbles with different shell elasticity are prepared, and their subharmonic responses are measured in vitro. The results of theoretical calculation and acoustic measurement show that good subharmonic enhancement can be obtained by using the encapsulated microbubbles with the mean size of 3 μm, which were prepared from the surfactant solution with the proper ratio of shell material. It is also shown that the best operating acoustic pressure is 200 to 400 kPa for nondestructive subharmonic imaging based on such kind of microbubbles.     

Optimal design and experimental investigation of surfactant encapsulated microbubbles

The diagnostic capabilities of ultrasound imaging can be improved with contrast-specific nonlinear imaging modalities such as harmonic and subharmonic imaging. The nonlinear response of an encapsulated microbubble in an acoustic field is strongly influenced by the shell viscoelastic properties that are determined by the shell composition and thickness. In this paper, the subharmonic performance of a surfactant encapsulated microbubble was optimized by choosing the appropriate composition of shell material with the aid of theoretical model. To study the effects of viscoelastic properties of microbubble shell materials on the nonlinear scattered response of microbubbles, a theoretical model-modified Herring equation for the oscillation of encapsulated microbubbles in the ultrasound field was employed. Based on this model, a computer aided design system was developed to optimize and analyze the acoustic properties, particularly subharmonic responses, of microbubbles under different shell parameters. Furthermore, surfactant encapsulated microbubbles with different viscoelastic properties were prepared by changing the shell composition. Their shell viscoelastic behavior was measured indirectly as dilational modulus of monolayer film formed with surfactant molecular. Moreover, in vitro quantitative acoustic properties measurements of these microbubbles were carried out to evaluate their subharmonic performance. Both of the theoretical simulation and acoustic measurement showed that the surfactant encapsulated microbubbles with good subharmonic properties could be designed and prepared by adjusting the shell material composition with the guide of the computer aided design system.     

宽带高功率贴片天线优化设计与实验

研制了中心频率为300 MHz的宽带高功率贴片天线,并进行了高功率实验研究。采用Taguchi全局优化算法对双层贴片天线的结构参数进行优化设计,使其驻波比小于3的带宽达到60.2%,最大增益8.1 dB。为提高其功率容量,对贴片、介质基底和馈电结构进行了改进和相应的绝缘设计。小信号测试结果与理论计算吻合,实测带宽达到64.2%。高功率实验中,馈入峰值89 kV和-81 kV的双极的脉冲,辐射因子达到75.2 kV,等效峰值辐射功率为188.5 MW,辐射场频谱的3 dB带宽为46%,实测能量方向图与模拟结果相符,半能量角宽约为90°。     

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.     

Finite element modeling of acoustic scattering from an encapsulated microbubble near rigid boundary

This article proposes a finite element model (FEM) for predicting the acoustic scattering from an encapsulated microbubble near rigid boundary. The validity of the model is first examined by comparing the acoustic nonlinear response of a free microbubble with that obtained by the Church model. Then this model is used to investigate the effect of the rigid boundary on acoustic scattering signals from microbubble. The results indicate that the resonance frequency decreases while the oscillation amplitude increases as the microbubble approaches the rigid boundary. In addition, the fundamental component of the acoustic scattering signal is enhanced compared with that of the free microbubble.     

Mathematical modeling of microbubble cavitation at 70 kHz and the importance of the subharmonic in drug delivery from micelles

In order to gain insight into the experimental observation of ultrasound-induced release of drugs from micelles, we modeled the dynamic oscillations of a 10-μm-diameter bubble insonated at 70 kHz. The Parlitz modification of the Keller–Miksis model was employed to generate bubble dynamics over a wide range of mechanical index values. The resulting Poincaré maps and bifurcation diagram show that bubble oscillations bifurcate at a MI value of 0.32, then return apparently to a single mode before displaying a sudden onset of chaotic behavior at 0.35. The experimental release of drug from micelles occurs at a MI value of 0.37 and correlates with the intensity of the subharmonic in (μW/cm²) of the acoustic spectrum. The dynamic model shows the return to single mode at a MI value of 0.43, and bifurcation leading to chaos at values above 0.5. The correlation between the chaotic behavior predicted by the model and drug release hints at insonation conditions that could facilitate drug delivery.     

Effect of an elastic wall on the dynamics of an encapsulated microbubble: A simulation study

The purpose of the present simulation study is to reveal how confining surfaces with different mechanical properties affect the acoustic response of a contrast agent microbubble. To this end, numerical simulations are carried out for three types of walls: a plastic (OptiCell) wall, an aluminium wall, and a biological tissue. For each wall, the behaviour of contrast microbubbles of three sizes is investigated. The spectral characteristics of the scattered pressure produced by the microbubbles are compared for two cases: the bubble oscillates far away from the wall and the same bubble oscillates in the immediate vicinity of the wall. The results of the simulations allow one to make the following main conclusions. The effect of the OptiCell wall on the acoustic bubble response is stronger than that of the aluminium and tissue walls. Changes in the bubble response near the wall are stronger when bubbles are excited above their resonance frequency. Considering changes in the fundamental and the 2nd harmonic with respect to the peak values of these components at different bubble radii, it is found that the changes are stronger for smaller bubbles and that the changes in the 2nd harmonic are stronger than those in the fundamental. These results allow one to gain an insight into conditions under which the effect of an elastic wall on the acoustic response of a contrast agent microbubble is easier to be detected.     

Finite-bandwidth Kramers-Kronig relations for acoustic group velocity and attenuation derivative applied to encapsulated microbubble suspensions

Kramers-Kronig (KK) analyses of experimental data are complicated by the conflict between the inherently bandlimited data and the requirement of KK integrals for a complete infinite spectrum of input information. For data exhibiting localized extrema, KK relations can provide accurate transforms over finite bandwidths due to the local-weighting properties of the KK kernel. Recently, acoustic KK relations have been derived for the determination of the group velocity (cg) and the derivative of the attenuation coefficient (alpha') (components of the derivative of the acoustic complex wave number). These relations are applicable to bandlimited data exhibiting resonant features without extrapolation or unmeasured parameters. In contrast to twice-subtracted finite-bandwidth KK predictions for phase velocity and attenuation coefficient (components of the undifferentiated wave number), these more recently derived relations for cg and alpha' provide stricter tests of causal consistency because the resulting shapes are invariant with respect to subtraction constants. The integrals in these relations can be formulated so that they only require the phase velocity and attenuation coefficient data without differentiation. Using experimental data from suspensions of encapsulated microbubbles, the finite-bandwidth KK predictions for cg and alpha' are found to provide an accurate mapping of the primary wave number quantities onto their derivatives.     

Microstreaming velocity field and shear stress created by an oscillating encapsulated microbubble near a cell membrane

Sonoporation mediated by microbubbles is being extensively studied as a promising technology to facilitate gene/drug delivery to cells. However, the theoretical study regarding the mechanisms involved in sonoporation is still in its infancy. Microstreaming generated by pulsating microbubble near the cell membrane is regarded as one of the most important mechanisms in the sonoporation process. Here, based on an encapsulated microbubble dynamic model with considering nonlinear rheological effects of both shell elasticity and viscosity, the microstreaming velocity field and shear stress generated by an oscillating microbubble near the cell membrane are theoretically simulated. Some factors that might affect the behaviors of microstreaming are thoroughly investigated, including the distance between the bubble center and cell membrane (d), shell elasticity (χ), and shell viscosity (κ). The results show that (i) the presence of cell membrane can result in asymmetric microstreaming velocity field, while the constrained effect of the membrane wall decays with increasing the bubble-cell distance; (ii) the bubble resonance frequency increases with the increase in d and χ, and the decrease in κ, although it is more dominated by the variation of shell elasticity; and (iii) the maximal microstreaming shear stress on the cell membrane increases rapidly with reducing the d, χ, and κ. The results suggest that microbubbles with softer and less viscous shell materials might be preferred to achieve more efficient sonoporation outcomes, and it is better to have bubbles located in the immediate vicinity of the cell membrane.