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     

A Simple Model for Nonlinear Confocal Ultrasonic Beams

A confocally and coaxially arranged pair of focused transmitter and receiver represents one of the best geometries for medical ultrasonic imaging and non-invasive detection. We develop a simple theoretical model for describing the nonlinear propagation of a confocal ultrasonic beam in biological tissues. On the basis of the parabolic approximation and quasi-linear approximation, the nonlinear Khokhlov-Zabolotskaya-Kuznetsov （KZK） equation is solved by using the angular spectrum approach. Gaussian superposition technique is applied to simplify the solution, and an analytical solution for the second harmonics in the confocal ultrasonic beam is presented. Measurements are performed to examine the validity of the theoretical model. This model provides a preliminary model for acoustic nonlinear microscopy.     

基于时间反转的骨裂纹超声成像模拟研究

提出了一种结合超声非线性和时间反转技术进行长骨中裂纹成像的技术.骨裂纹的超声散射信号中包含非经典非线性成分.从时反阵列接收的探测信号中,经滤波得到三次谐波;然后利用时间反转技术来对裂纹区域进行聚焦成像.在计算机仿真实验中,基于Preisach-Mayergoyz(PM)模型模拟了单个及两个骨裂纹产生的非线性信号,实现了时间反转的非线性成像,并讨论了裂纹的深度位置对成像结果的影响.该方法为骨裂纹的超声无损检测提供了一种新技术.     

Investigation on the relationship between overpressure and sub-harmonic response from encapsulated microbubbles

Sub-harmonic component generated from microbubbles is proven to be potentially used in noninvasive blood pressure measurement. Both theoretical and experimental studies are performed in the present work to investigate the dependence of the sub-harmonic generation on the overpressure with different excitation pressure amplitudes and pulse lengths. With4-MHz ultrasound excitation at an applied acoustic pressure amplitude of 0.24 MPa, the measured sub-harmonic amplitude exhibits a decreasing change as overpressure increases; while non-monotonic change is observed for the applied acoustic pressures of 0.36 MPa and 0.48 MPa, and the peak position in the curve of the sub-harmonic response versus the overpressure shifts toward higher overpressure as the excitation pressure amplitude increases. Furthermore, the exciting pulse with long duration could lead to a better sensitivity of the sub-harmonic response to overpressure. The measured results are explained by the numerical simulations based on the Marmottant model. The numerical simulations qualitatively accord with the measured results. This work might provide a preliminary proof for the optimization of the noninvasive blood pressure measurement through using sub-harmonic generation from microbubbles.     

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.     

Ultrasound-mediated transdermal drug delivery of fluorescent nanoparticles and hyaluronic acid into porcine skin in vitro

Transdermal drug delivery(TDD) can effectively bypass the first-pass effect. In this paper, ultrasound-facilitated TDD on fresh porcine skin was studied under various acoustic parameters, including frequency, amplitude, and exposure time. The delivery of yellow–green fluorescent nanoparticles and high molecular weight hyaluronic acid(HA) in the skin samples was observed by laser confocal microscopy and ultraviolet spectrometry, respectively. The results showed that,with the application of ultrasound exposures, the permeability of the skin to these markers(e.g., their penetration depth and concentration) could be raised above its passive diffusion permeability. Moreover, ultrasound-facilitated TDD was also tested with/without the presence of ultrasound contrast agents(UCAs). When the ultrasound was applied without UCAs,low ultrasound frequency will give a better drug delivery effect than high frequency, but the penetration depth was less likely to exceed 200 μm. However, with the help of the ultrasound-induced microbubble cavitation effect, both the penetration depth and concentration in the skin were significantly enhanced even more. The best ultrasound-facilitated TDD could be achieved with a drug penetration depth of over 600 μm, and the penetration concentrations of fluorescent nanoparticles and HA increased up to about 4–5 folds. In order to get better understanding of ultrasound-facilitated TDD, scanning electron microscopy was used to examine the surface morphology of skin samples, which showed that the skin structure changed greatly under the treatment of ultrasound and UCA. The present work suggests that, for TDD applications(e.g., nanoparticle drug carriers, transdermal patches and cosmetics), protocols and methods presented in this paper are potentially useful.     

超声多普勒检测动脉内出血的多维度复合模型研究

建立检测内出血点的量化技术有助于进一步提高超声止血的效率。提出了描述动脉血管内出血的多维度复合模型。由一个描述破裂血管的二维模型和一个描述下游血管系统响应的一维模型组成。计算机仿真及初步的活体实验结果证明了理论模型的有效性,并表明内出血时的血流速度波形会产生大幅度单波峰或收缩速度峰的相位延迟,该结果可作为自动快速检测血管破裂的量化参数。      

Performance improvement of magneto-acousto-electrical tomography for biological tissues with sinusoid-Barker coded excitation

By combining magnetics, acoustics and electrics, the magneto-acoustic-electrical tomography(MAET) proves to possess the capability of differentiating electrical impedance variation and thus improving the spatial resolution. However,the signal-to-noise ratio(SNR) of the collected MAET signal is still unsatisfactory for biological tissues with low-level electrical conductivity. In this study, the formula of MAET measurement with sinusoid-Barker coded excitation is derived and simplified for a planar piston transducer. Numerical simulations are conducted for a four-layered gel phantom with the 13-bit sinusoid-Barker coded excitation, and the performances of wave packet recovery with side-lobe suppression are improved by using the mismatched compression filter, which is also demonstrated by experimentally measuring a three-layered gel phantom. It is demonstrated that comparing with the single-cycle sinusoidal excitation, the amplitude of the driving signal can be reduced greatly with an SNR enhancement of 10 dB using the 13-bit sinusoid-Barker coded excitation. The amplitude and polarity of the wave packet filtered from the collected MAET signal can be used to achieve the conductivity derivative at the tissue boundary. In this study, we apply the sinusoid-Barker coded modulation method and the mismatched suppression scheme to MAET measurement to ensure the safety for biological tissues with improved SNR and spatial resolution, and suggest the potential applications in biomedical imaging.     

Correlation between microbubble-induced acoustic cavitation and hemolysis in vitro

Microbubbles promise to enhance the efficiency of ultrasound-mediated drug delivery and gene therapy by taking advantage of artificial cavitation nuclei.The purpose of this study is to examine the ultrasound-induced hemolysis in the application of drug delivery in the presence of microbubbles.To achieve this goal,human red blood cells mixed with microbubbles were exposed to 1-MHz pulsed ultrasound.The hemolysis level was measured by a flow cytometry,and the cavitation dose was detected by a passive cavitation detecting system.The results demonstrate that larger cavitation dose would be generated with the increase of acoustic pressure,which might give rise to the enhancement of hemolysis.Besides the experimental observations,the acoustic pressure dependence of the radial oscillation of microbubble was theoretically estimated.The comparison between the experimental and calculation results indicates that the hemolysis should be highly correlated to the acoustic cavitation.     

Effect of secondary radiation force on aggregation between encapsulated microbubbles

Secondary radiation force can be an attractive force causing aggregates of encapsulated microbubbles in ultrasonic molecular imaging. The influence of the secondary radiation force on aggregation between two coated bubbles is investigated in this study. Numerical calculations are performed based on four simultaneous differential equations of radial and translational motions. Results show that the secondary force can change from attraction to repulsion during approach, and stable microbubble pairs can be formed in the vicinity of resonant regions; the possibility of microbubble aggregations can be reduced by using low exciting amplitude, ultrasonic frequencies deviating from the resonant frequencies or microbubbles with small compressibility.