The synergistic effect of ultrasound transdermal drug delivery based on multi-stage dynamic focal-shifting

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.