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.     

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。     

增强超声空化效应的一个途径─—给空化声场一个随机微扰

在早期以声致发光和输入电功率之间关系的实验研究基础上，提出了给空化声场施加一个随机扰动，以提高高空化声场中声化学产额的动力学方法。对Ｎｏｌｔｉｎｇｋ－ｎｅｐｐｉｒａｓ方程进行了修正，增加了一个表征微扰的非线性项Ｆ‘（Ｒ０／ρＲ。并论述了如何在实验上实现从动力学角度增加声化学产额的途径。     

经颅聚焦超声联合微泡开放血脑屏障的数值仿真研究

近年大鼠等动物实验表明经颅聚焦超声联合微泡技术可无创开放血脑屏障实现药物递送,但在临床治疗时由于人体头颅非均质结构及其高声衰减特性,需优化超声经颅聚焦参数和微泡参数。本文基于人头颅CT数据、82阵元相控换能器和血管建立了三维数值仿真模型,研究超声及微泡参数对机械指数和靶区声发射的影响,评估血脑屏障开放程度及组织损伤的可能性。结果表明,声功率和微泡初始密度增大,机械指数和宽带噪声强度增大;频率增大,稳态空化强度增大;当微泡初始半径大于5μm时,稳态空化显著增强。该研究结果为经颅聚焦超声联合微泡技术诱导可控的BBB开放及安全有效递送治疗药物提供了理论数据和技术参考。     

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。     

微泡对高强度聚焦超声焦域影响的研究

微泡对高强度聚焦超声(HIFU)治疗具有增效作用,而HIFU治疗中不同声学条件下微泡对HIFU治疗焦域的影响尚不清楚。本文基于声传播方程、Yang-Church气泡运动方程、生物热传导方程、时域有限差分法(FDTD)、龙格-库塔(RK)法数值仿真研究输入功率、激励频率和气泡初始半径对HIFU在含气泡体模中形成焦域的影响,并利用含Sono Vue造影剂的仿组织体模研究进行实验验证。结果表明,增大输入功率、气泡初始半径和升高激励频率均可增大焦域,随着输入功率的增大,焦域形状可能发生变化,而随着激励频率升高和气泡初始半径的增大,焦域会向远离换能器的方向移动。     

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     

超声空化泡运动特性的研究进展

超声空化是一个极其复杂的物理现象,超声空化泡运动是影响超声空化效应的重要因素,研究超声空化泡的运动特性已受到学术界的极大重视。本文研究了近几年国内外学者基于超声作用下的空化泡运动特性的工作,从空化泡运动方程、数值模拟、实验研究等方面介绍了超声空化泡运动特性的研究进展。最后指出了研究中需解决的关键问题,同时对超声空化泡的研究趋势进行了展望。     

医学超声空化的研究进展

本文介绍了近期医学超声空化研究的若干进展,着重概括了它的研究方法与基本结果,在此基础上提出了一些问题与看法。     

基于微泡共振的快速微流体声学混合方法研究

微流体在生物医学、化学工程等领域应用广泛,并具有重大意义.在预处理中,液体混合也是关键且最为必要的前序.为了提高微流控腔道内液体混合的效率,本文提出基于单微泡振动的声学混合器,通过微泡共振,产生声微流,声微流形成的剪切力将在流体中产生微扰动,实现液体的混合.设计了底面直径为40μm的微孔结构,由于液体表面张力作用形成微泡,在共振频率为165 kHz的压电换能器激励下,气泡发生共振产生声微流.通过对压电换能器输入不同能量,获取混合液体的最优参数,可在37.5 ms内实现混合效果,混合均匀度达到92.7%.本文设计的单微泡振动混合器结构简单、混合效率高、混合时间短、输入能量低,可为生物化学等方面的研究提供强有力的技术支撑.     

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     

An in vitro feasibility study of controlled drug release from encapsulated nanometer liposomes using high intensity focused ultrasound

A liposome with a diameter ranging from 150 to 200 nm has been considered to be one of the optimal vehicles for targeted drug delivery in vivo since it is able to encapsulate drug and also circulate in the blood stream stably. Its small size, however, makes controlled release of its encapsulated content difficult. A feasibility study for applications of high intensity focused ultrasound (HIFU) of the mega-hertz frequency to induce controlled release of its content was carried out. This study, using the dynamic light scattering and transmission electron microscopic observation, demonstrated 21.2% of encapsulated fluorescent materials (FITC) could be released from liposomes with an average diameter of 210 nm when exposed to continuous (cw) ultrasound at 1.1 MHz (I_SPTA = 900 W/cm²) for 10 s and the percentage release efficiency can reach to 70% after 60 s irradiation. This result also reveals that rupture of relatively large liposomes (>100 nm) and generation of pore-like defects in the membrane of small liposomes (<100 nm) due to HIFU excitation might be the main causes of the release; the inertial cavitation took place during the irradiation. The controlled drug release from liposomes by HIFU may be proven to be a potential useful modality for clinical applications.     

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.     

Ultrasound mediated destruction of multifunctional microbubbles for image guided delivery of oxygen and drugs

We synthesized multifunctional activatible microbubbles (MAMs) for ultrasound mediated delivery of oxygen and drugs with both ultrasound and fluorescence imaging guidance. Oxygen enriched perfluorocarbon (PFC) compound was encapsulated in liposome microbubbles (MBs) by a modified emulsification process. DiI dye was loaded as a model drug. The ultrasound targeted microbubble destruction (UTMD) process was guided by both ultrasonography and fluorescence imaging modalities. The process was validated in both a dialysis membrane tube model and a porcine carotid artery model. Our experiment results show that the UTMD process effectively facilitates the controlled delivery of oxygen and drug at the disease site and that the MAM agent enables ultrasound and fluorescence imaging guidance of the UTMD process. The proposed MAM agent can be potentially used for UTMD-mediated combination therapy in hypoxic ovarian cancer.     

Prediction of vascular injury by cavitation microbubbles in a focused ultrasound field

Many studies have shown that microbubble cavitation is one mechanism for vascular injury under ultrasonic excitation. Previous work has attributed vascular damage to vessel expansions and invaginations due to the expansion and contraction of microbubbles. However, the mechanisms of vascular damage are not fully understood. In this paper, we investigate, theoretically and experimentally, the vessel injury due to stress induced by ultrasound-induced cavitation (UIC). A bubble-fluid-vessel coupling model is constructed to investigate the interactions of the coupling system. The dynamics process of vessel damage due to UIC is theoretically simulated with a finite element method, and a focused ultrasound (FU) setup is carried out and used to assess the vessel damage. The results show that shear stress contributes to vessel injury by cell detachment while normal stress mainly causes distention injury. Similar changes in cell detachment in a vessel over time can be observed with the experimental setup. The severity of vascular injury is correlated to acoustic parameters, bubble-wall distance, and microbubble sizes, and the duration of insonation..     

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.     

Lysozyme microspheres incorporated with anisotropic gold nanorods for ultrasound activated drug delivery

We report on the fabrication of lysozyme microspheres (LyMs) incorporated with gold nanorods (NRs) as a distinctive approach for the encapsulation and release of an anticancer drug, 5-Fluorouracil (5-FU). LyMs with an average size of 4.0 ± 1.0 µm were prepared by a sonochemical method and characterized using scanning electron microscopy (SEM), transmission electron microscopy (TEM) and Fourier-transform infrared spectroscopy (FTIR). The LyMs were examined using hydrophobic (nile red) as well as hydrophilic (trypan blue) dyes under confocal laser scanning microscopy (CLSM) to obtain information about the preferential distribution of fluorescent molecules. Notably, the fluorescent molecules were accumulated in the inner lining of LyMs as the core was occupied with air. The encapsulation efficiency of 5-FU for LyMs-NR was found to be ∼64%. The drug release from control LyMs as well as LyMs incorporated with NRs was investigated under the influence of ultrasound (US) at 200 kHz. The total release for control LyMs and LyMs incorporated with gold NRs was found to be ∼70 and 95% after 1 h, respectively. The density difference caused by NR incorporation on the shell played a key role in rupturing the LyMs-NR under US irradiation. Furthermore, 5-FU loaded LyMs-NR exhibited excellent anti-cancer activity against the THP-1 cell line (∼90% cell death) when irradiated with US of 200 kHz. The enhanced anti-cancer activity of LyMs-NR was caused by the transfer of released 5-FU molecules from bulk to the interior of the cell via temporary pores formed on the surface of cancer cells, i.e., sonoporation. Thus, LyMs-NR demonstrated here has a high potential for use as carriers in the field of drug delivery, bio-imaging and therapy.     

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。     

Recent ultrasound advancements for the manipulation of nanobiomaterials and nanoformulations for drug delivery

Recent advances in ultrasound (US) have shown its great potential in biomedical applications as diagnostic and therapeutic tools. The coupling of US-assisted drug delivery systems with nanobiomaterials possessing tailor-made functions has been shown to remove the limitations of conventional drug delivery systems. The low-frequency US has significantly enhanced the targeted drug delivery effect and efficacy, reducing limitations posed by conventional treatments such as a limited therapeutic window. The acoustic cavitation effect induced by the US-mediated microbubbles (MBs) has been reported to replace drugs in certain acute diseases such as ischemic stroke. This review briefly discusses the US principles, with particular attention to the recent advancements in drug delivery applications. Furthermore, US-assisted drug delivery coupled with nanobiomaterials to treat different diseases (cancer, neurodegenerative disease, diabetes, thrombosis, and COVID-19) are discussed in detail. Finally, this review covers the future perspectives and challenges on the applications of US-mediated nanobiomaterials.