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针对传统超声透皮给药技术中声场聚焦模式单一、药物粒子穿透深度及分布范围受限等关键瓶颈问题，本研究提出了一种基于超声换能器阵列的多阶动态移焦发射策略，旨在实现声能量在皮肤深度方向的动态重分布，从而提升纳米粒子的透皮效率与分布均匀性。通过调控换能器阵元激励相位，构建多阶移动的声聚焦作用路径，并通过在体动物实验与有限元仿真联合验证其透皮给药效果。结果显示，与固定焦点模式相比，动态聚焦显著提升了药物粒子的经皮渗透深度与空间分布均匀性，其平均渗透深度可提高65.7%，荧光积分强度提升69.3%，并在皮肤组织中形成更均匀的沉积带结构。有限元仿真结果进一步揭示了该模式下粒子扩散演化行为与焦点动态轨迹之间的强耦合机制，证实动态移焦模式下的“多焦点接力式”驱动效应可在在显著优化粒子的经皮渗透效率的同时，有效降低局部能量沉积引发的潜在风险，为构建高效、安全、可控的超声透皮递药技术提供了重要的理论基础与技术支撑。Ultrasound-assisted transdermal drug delivery (UTDD) is a promising noninvasive strategy to overcome the skin barrier, yet conventional fixed-focus ultrasound approaches suffer from 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 were 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 minutes of ultrasound, fluorescence microscopy revealed that fixed focus enhanced penetration compared with natural permeation, while dynamic focusing further improved delivery, increasing average depth by 65.7%, maximum depth by 41.2%, and fluorescence intensity by 69.3% (Fig.1). Dynamic focusing also produced a more uniform and continuous deposition band, unlike the localized accumulation seen with fixed focus.
To elucidate the underlying mechanisms, a two-dimensional finite element model was established in COMSOL Multiphysics. Simulation results (Fig.2) revealed that, this “multi-focus relay” effect provided a continuous driving force pathway, enabling particles to follow the shifting focal positions. Trajectory analysis confirmed that the number of particles reaching deeper layers (up to 5 mm) increased by nearly 14 times under dynamic focusing compared with fixed focus, while the lateral distribution width expanded by 46.1%.
In conclusion, both experimental and simulation results demonstrate that phasedarray 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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