超声造影剂微泡非线性动力学响应的机理及相关应用

Mechanism and applications of the nonlinear dynamic response to ultrasound contrast agent microbubbles

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;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.

Ultrasound contrast agent （UCA） refers to the agent that has specific acoustic properties to enhance the contrast in ultrasound imaging by composition of gas-filled microbubbles with micrometer-diameters. In a diagnostic ultrasound field, microbubbles in fluid create an acoustic impedance mismatch between fluid and surrounding tissue to increase the reflection of sound and achieve a better contrast. Ongoing developments improve diagnostic possibilities of UCA remarkably, whereas their potential therapeutic applications have also been investigated for a couple of decades. The nonlinear response of UCA microbubbles has clinical relevance from both diagnostic and therapeutic perspectives. The aim of this review is to introduce the latest research progress of our group regarding the mechanism and applications of the nonlinear dynamic response to UCA, which include （1） an all-in-one solution characterizing coated bubble parameters with the help of the light scattering technique and flow cytometry, which makes it possible to quickly integrate the size distribution with dynamic motions of thousands of microbubbles and easily verify the validities of different shelled bubble dynamic models; （2） the development of a new bubble dynamics model that takes into account both nonlinear shell elasticity and viscosity, which can not only be capable of simulating the ＂compression-only＂ behavior of microbubbles excited by large amplitude ultrasound but also eliminate the dependence of bubble shell parameters on bubble size; （3） the estimation of UCA inertial cavitation thresholds of two types of commercial UCA microbubbles （viz. , SonoVue microbubbles coated with lipid shells and KangRun microbubbles coated with albumin shells） and the evaluation of the relationship between microbubble inertial cavitation thresholds and their shell parameters; and （4） the researches of DNA transfection efficiency and the reduction of cytotoxicity in gene delivery facilitated by UCA excited by 1-MHz focused ultrasound pulses, and the results indicate that the measured DNA transfection efficiency and sonoporation pore size generally increase with the enhancement of inertial cavitation dose, while the cell viability decreases linearly with the increase of International Classification of Diseases （ICD）. These studies are of significance for better understanding the mechanism of ultrasound-induced microbubble nonlinear dynamics and investigating the effective quantification technique for microbubble cavitation activity, which are important for further optimizing therapeutic ultrasound effects and avoiding the side-effects.