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Ultrasound-assisted transdermal drug delivery (UTDD) is a promising non-invasive strategy to overcome the skin barrier. The traditional fixed-focus ultrasound approaches encounter the problems such as limited penetration depth, localized accumulation, and risk of thermal damage. To address these challenges, we propose a phased-array based dynamic focusing strategy, in which the acoustic focus is shifted sequentially along the depth direction. This approach aims to construct a continuous longitudinal acoustic radiation pathway that can sustain particle migration into deeper skin layers. In vivo experiments are conducted with FITC-labeled nanoparticles on rat dorsal skin under three conditions: natural permeation, fixed focus (~0.5 mm beneath the skin), and dynamic focusing (scanned from the surface to 1 mm). After 10-min ultrasound, fluorescence microscopy reveals that fixed focus enhances penetration compared with natural permeation, while dynamic focusing further improves delivery, increasing average depth by 65.7%, maximum depth by 41.2%, and fluorescence intensity by 69.3%. Dynamic focusing also produces a more uniform and continuous deposition band, which is unlike the localized accumulation seen with fixed focus. To elucidate the underlying mechanisms, a two-dimensional finite element model is established in COMSOL Multiphysics. The simulation results reveal that this “multi-focus relay” effect provides a continuous driving force pathway, enabling particles to follow the shifting focal positions. Trajectory analysis confirms that the number of particles reaching deeper layers (up to 5 mm) increases by nearly 14 times under dynamic focusing compared with that in the case of fixed focus, while the width of the lateral distribution extends by 46.1%. In conclusion, both experimental and simulation results demonstrate that phased-array dynamic focusing significantly enhances penetration depth, migration efficiency, and distribution uniformity of nanoparticles in UTDD. By constructing a continuous acoustic radiation pathway in the depth dimension, this approach improves delivery efficiency while mitigating local energy accumulation, providing a safer and more effective strategy for ultrasound-mediated transdermal therapy. -
Keywords:
- ultrasound transdermal drug delivery /
- dynamic focusing /
- ultrasonic transducer array /
- finite element simulation
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图 1 TDD药物吸收途径示意图
Figure 1. Schematic diagram of TDD drug absorption pathway
图 2 (a) 实验操作示意图; (b) 粒子渗透示意图, 其中绿色圆球为荧光粒子
Figure 2. (a) Schematic diagram of experimental operation; (b) schematic diagram of particle penetration, where green spheres are fluorescent particles.
图 3 (a) 聚焦发射的透皮给药原理示意图; (b) 有限元模型结构图
Figure 3. (a) Schematic diagram of transdermal drug delivery principle with focused emission; (b) finite element model structure diagram
图 4 荧光显微镜下的组织切片 (a)自然渗透组; (b)固定焦点聚焦组; (c)动态聚焦组
Figure 4. Tissue sections under fluorescence microscope: (a) Natural infiltration group; (b) fixed focus group; (c) dynamic focus group in turn.
图 5 组织切片荧光图像平均渗透深度、最大渗透深度、荧光积分强度三项指标柱状图
Figure 5. Histogram of three indicators: average penetration depth, maximum penetration depth and fluorescence integral intensity of fluorescence images of tissue sections.
图 6 动态聚焦情况下不同聚焦深度的声场仿真结果 (a)焦点位于皮下1 mm; (b)焦点位于皮下2 mm; (c)焦点位于皮下3 mm
Figure 6. Simulation results of acoustic field with different focusing depths under dynamic focusing: (a) The focus is 1 mm under the skin; (b) the focus is 2 mm under the skin; (c) the focus is 3 mm under the skin.
图 8 5%, 10%和20%三种占空比条件下, 运动至皮下5 mm处的粒子数量
Figure 8. The number of particles moving to 5 mm under the skin under three duty ratios of 5%, 10% and 20%.
图 9 三种典型位置粒子在两种声场中的三维运动路径(对应粉、绿、紫曲线), 其中黑色虚线描绘了声场焦点中心的变化 (a)固定焦点聚焦声场; (b)动态移焦声场
Figure 9. The three-dimensional motion paths of particles in three typical positions (corresponding to pink, green and purple curves) in two kinds of acoustic fields: (a) Acoustic field with fixed focus; (b) dynamically focused acoustic field. The black dotted line depicts the change of the focus center of the sound field.
表 1 不同聚焦深度下的焦域参数
Table 1. Focal parameters at different depth of focus.
预设焦点皮下深度 焦点横向宽度/mm 焦点纵向长度/mm x/mm y/mm 0.00 1.00 0.93 3.63 0.00 2.00 0.98 4.13 0.00 3.00 1.05 4.56 
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