超声造影微泡的制备及其动力学特性研究

Microscale complex interface evolution exists widely in fields such as physics, chemistry and biomedicine. In biomedicine, based on the ultrasound cavitation of a microbubble, techniques like medical ultrasound imaging, drug release from micro/nano-capsule, and high-intensity focused ultrasound for the treatment of tumours, have been developed. Existing problems include the generation of monodisperse microbubble suitable for ultrasound imaging, the understanding of shell’s effects on contrast agent behavior, time-resolved measurement of microbubbles evolution under tissue environment, need to be solved for the application of above techniques. Accordingly, this study has two main objectives: to develop a microfluidic design to mass produce devices that are capable of generating monodisperse microbubbles at a high production rate; and, to investigate encapsulated microbubble dynamics under ultrasound, especially for bubbles with diameter less than 10 micrometer, and under complex environment. This can be the cases when the microbubble is close to tissue, to cells or to other microbubbles, or even in the real tissue environment. It is expected that this understanding will provide guidance for applying microbubbles as ultrasound contrast agents.

微尺度复杂界面演化广泛地存在于物理，化学及生物医学等众多领域。以生物医学为例，基于微气泡对超声波的响应（声空化），人们开发出了超声联合造影、微纳胶囊的药物释放、高密度焦点式超声治疗等技术。其中亟待解决的难点问题包括超声造影微泡的制备、包膜对微泡动态行为的影响、组织环境下微泡动力过程的实时精准测量等。而这些都属于微尺度复杂界面运动的范畴。本项目以声空化的医学应用为背景，着眼于上述难点问题，拟开展两个方向的研究：（1）开发高产量制备单分散微泡的微流控芯片技术，且该微流体元件本身能被大批量生产；（2）开展包膜微泡在超声作用下的动力学特性研究，尤其是针对直径小于10微米的包膜微泡，在复杂环境下（比如当气泡贴近组织、细胞、或者别的微气泡，甚至是类似身体组织环境下），明晰其对超声波的响应机理，为造影微泡的使用提供指导。

传统超声造影微泡的制备方法效率低，生成的微泡单分散度低，且国内对超声成像的研究起步晚，没有成熟的商业化超声造影剂产品，主要依赖进口国外大量超声造影剂。本项目设计利用滴模态高通量制备可用于超声造影的高单分散度微气泡，主要开展了两部分研究工作：（1）强流动剪切下同轴流动聚焦制备微气泡的实验研究。将毛细玻璃管嵌套进不锈钢骨架，制作出耐压微流控芯片，可承受压力逾15个大气压，气泡产生喉道处平均剪切流速高达20 m/s，使得单根毛细管的微气泡产量超过0.7 MHz，高于文献中已报道的最高产率；获得了微气泡产率/尺寸随韦伯数We和毛细数Ca变化的尺度律，为后续高通量产业化生产打下基础。（2）内壁面附着细丝的毛细圆锥管内气液驱替实验。发现了可直接生成与圆锥孔口直径相当尺度微气泡的新现象，拓展了管内气液驱替研究；揭示了管内壁附着细丝在气液驱替中的作用、定压条件下锥形喷嘴内产生微气泡的动力学机制以及流动参数对微气泡尺寸及产率的影响机理。