微纳颗粒的光声协同精确操控及其在靶向给药方面的应用

Ultrasonic manipulation, one of the most important means of manipulating fine particles, has been widely applied in the biomedicine because of its special advantages such as low power consumption, strong penetrability, and low biological damage. However, the precise manipulation of the micro-nano particle is difficult to be achieved by using the ultrasonic because of the large wavelength of the ultrasonic. The process of the ultrasonic manipulation is not easy to be modulated and the degree of freedom of the manipulation is low. Thus, the single ultrasonic manipulation cannot satisfy the requirements of the precise manipulations of micro-nano particles. In this project, we will introduce the laser irradiation method into the ultrasonic manipulation. The photo-acoustic synergistic actions will realize the precise manipulations of the micro-nano particles and hence greatly improve the accuracy of the ultrasonic manipulation. In order to achieve these aims, we will investigate the influences of the parameters of the pulse laser on the photoacoustic effect of the various particles. The acoustic field distributions around these particles will be carefully discussed. We will study the couplings between the micro-nano particles excited by the pulse laser and the ultrasonic or the acoustic field modulated by the acoustic artificial structures. The influence of the acoustic field couplings on the acoustic radiation force on the particle will be investigated in detail. Then, the effects of the parameters of the pulse laser on the acoustic radiation force will be understood and the corresponding physical mechanisms will be clarified. A physical model of the photo-acoustic synergistic precise manipulation of the micro-nano particles will be established. Based on above researches, a new particle consisting of a metal nanoparticle core and a shell of the gel mixed with drugs will be designed and fabricated, which can response to the near-infrared light. We will verify experimentally the photo-acoustic synergistic precise manipulation of the micro-nano particles and explore their applications in the targeted drug delivery.

超声操控具有低功耗、强穿透性和低生物损伤等优点，是操控细微颗粒的重要手段之一，在生物医学等领域有广泛的应用。然而，由于超声波波长较大，对微纳尺度颗粒难以实现精确操控，如操控过程不易调控、操控自由度低等，难以满足靶向给药的精度。本项目拟在超声操控的基础上，协同激光辐照的方法，实现对微纳颗粒运动的精确操控，有效提升超声靶向给药的精度。为了实现上述目标，本项目拟研究脉冲激光各参数变化对不同颗粒光声效应的影响，详细分析多种对称、不对称微纳颗粒的光声场分布；研究入射超声或人工声学结构调制的入射声场与激光激励的微纳颗粒之间的耦合作用，明确声场耦合对声辐射力的调控机制；进而阐明脉冲激光的调制对声辐射力的影响及基本机理，构建光声协同精确操控微纳颗粒的物理模型。在上述工作基础上，设计并制备具有近红外响应的金纳米颗粒外包裹负载药物凝胶微粒，从实验上验证微纳颗粒的光声协同精确操控及其在靶向给药方面的可行性。

超声操控技术由于具有低功耗、高穿透性和低生物损伤等优点而成为操控微纳颗粒、细胞、细菌、病毒、微生物等微小物体的最重要手段之一，被广泛地应用于微纳组装、细胞生物学和生物医学检测与治疗等领域。然而，由于超声波波长较大，超声操控在微纳尺度下的精度不高；如果采用过高频率的超声，其穿透能力又较弱；此外，超声发射设备的可调性低，操控机制确立后难以更改，自由度较低。因此，单一的入射超声操控方法已难以满足迅猛发展的各学科对微小物体精确操控的需求。本项目通过协同激光辐照的方法，实现了对超声操控微粒运动行为的有效调制；同时还探究了多层复合微粒所受到声辐射力的调控机理。首先，研究了多种球形微粒的光声特性，详细探究了具有近红外光学响应的金纳米核壳结构颗粒及其外包裹凝胶外壳的三层微粒的光声特性，明确了激光参数、微粒结构参数和环境介质等对光声信号的影响。而后，我们分别构建了光-声协同作用于弹性微粒和细胞的声辐射力的理论计算模型，研究了入射超声与激光激励的微粒间声学耦合，详细探讨了激光参数和微粒结构与声学参数变化对其所受声辐射力的影响，阐明了入射激光辐照调控超声操控微粒运动行为的物理机理。同时，还研究了多种多层复合微粒在不同声场中受到的声辐射力，明确了微粒结构参数和声学参数等的变化对其所受声辐射力的影响。此外，我们还构建了多种新颖的声学人工结构对入射声场进行有效的调控，实现了多种有实际意义的声波束，例如涡旋声束、聚焦涡旋声束、艾里波束、花瓣声束等，并探索了其对微粒的俘获和操控。最后，制备了具有近红外光学响应的金纳米球壳外包裹凝胶外壳的三层微粒，初步探索了其光声特性和光声协同操控。在项目支持下，以通讯作者发表相关SCI论文34篇。申请国家发明专利3项，已授权1项。本项目的研究发展了光-声协同操控微纳颗粒的新方法，明确了多层复合微粒的声辐射力调控机制，设计出新型声镊子，将为声学微粒操控技术的进一步发展和应用提供依据。