人工结构声场定量调控声流剪切力诱发声孔效应的研究

Sonoporation is the biophysical mechanism of ultrasound-induced drug delivery, which is defined as the transient membrane permeabilisation and uptake of extracellular molecules into cells with the assistance of the shock wave, microjet and microstreaming generated by the ultrasound agent microbubble’s cavitation. The microbubble-induced shear stress is a threshold indicator for membrane pore generation, beyond which the cellular membrane permeability increases. However the microbubble is non-stable and non-uniform, current methods have not provided a large number and many kinds of cells with precisely quantitative and controllable sonoporation. Therefore, the threshold has not been determined yet. This research will use the phononic crystal plate to modulate the incident acoustic wave to generate the periodic and localized acoustic field over a wide area, which can induce highly tunable acoustic radiation force to trap and align the cells in the acoustic field, and simultaneously generate the tunable acoustic streaming stress to realize the controllable sonoporation of the trapped and aligned cells. By designing and optimizing the artificial-structure-modulated acoustic field, modelling the forces exerted on the cell and the cell’s deformation in the artificial acoustic field, integrating three modules of acoustic manipulation, flow visualization, and post processing on a microfluidic device to construct the massively parallel platform for sonoporation, we will explore how the artificial-structure-modulated acoustic field will tune the sonoporation quantitatively, how the parameters of acoustic field and flow field will influence the sonoporation, and what the value of the shear stress threshold is. This study will develop a new kind of technique to investigate sonoporation, and provide the drug delivery with an alternative tool, and is important in science and application.

超声对细胞的声孔效应是超声给药的生物物理基础，主要通过超声场中微泡空化产生冲击波、微射流、声微流等方式调控细胞膜通透性实现。微泡空化诱发的剪切力可作为声孔效应阈值因子，但尚不确定阈值剪切力大小。这是由于微泡不稳定、尺寸不均一等原因，导致难以对多种类、大规模细胞提供可重复、有统计学意义、且能精确定量的可控声孔效应。因此，本项目拟利用声子晶体板（人工周期结构声场）调制发射波束，实现周期分布、宽范围局域场，产生可调控声辐射力捕获、排列细胞，同时产生可定量调控声流剪切力实现阵列细胞可控声孔效应。具体地，建立细胞在人工结构声场中受力形变物理-力学模型及计算方法和大规模、并行、多种类细胞声孔效应实验平台，揭示人工结构声场对声孔效应的调控机制，研究声参数、流场参数对声孔效应的影响，确定阈值剪切力。本研究可为声孔效应定量研究提供工具，为药物递送提供新手段，具有重要的科学意义和应用价值。

大规模、精确定量可控声孔效应研究对超声给药具有重要意义和价值。本项目利用声人工结构调制发射波束，实现周期分布、宽范围局域场，产生可调控声辐射力捕获、排列细胞，同时产生可定量调控声流剪切力实现阵列细胞可控声孔效应，揭示了人工结构声场对声致穿孔效应的调控机制，主要研究内容包括：1）设计声人工结构用于发射波束的调制，产生聚焦波束和用于细胞实验的局域场，实现对细胞周围声场环境和力学环境的精细调控。2）在此基础上，理论和实验上，系统研究了可调控声场的声辐射力效应和声流效应，揭示了细胞等颗粒在可调控超声场中的声泳机制，实现了声辐射力和声流剪切力的精细定量调控。3）设计制备了基于声人工结构的声-微流体器件，开展了可调控超声场对细胞的声致穿孔效应研究，实现了大量细胞的可定量调控声孔效应和给药研究。本研究可为声孔效应定量研究提供工具，为药物递送提供新手段，具有重要的科学意义和应用价值。