Abstract
Enhanced skin permeability is known to be achieved during sonophoresis due to ultrasound-induced cavitation. However, the mechanistic role of cavitation during sonophoresis has been extensively investigated only for low-frequency (LFS, <100 kHz) applications. Here, mechanisms of permeability-enhancing stable and inertial cavitation were investigated by passively monitoring subharmonic and broadband emissions arising from cavitation isolated within or external to porcine skin in vitro during intermediate- (IFS, 100-700 kHz) and high-frequency sonophoresis (HFS, >1 MHz). The electrical resistance of skin, a surrogate measure of the permeability of skin to a variety of compounds, was measured to quantify the reduction and subsequent recovery of the skin barrier during and after exposure to pulsed (1 second pulse, 20% duty cycle) 0.41 and 2.0 MHz ultrasound over a range of acoustic powers (0-21.7 W) for 30 min. During IFS, significant skin resistance reductions and acoustic emissions from cavitation were measured exclusively when cavitation was isolated outside of the skin. Time-dependent skin resistance reductions measured during IFS correlated significantly with subharmonic and broadband emission levels. During HFS, significant skin resistance reductions were accompanied by significant acoustic emissions from cavitation measured during trials that isolated cavitation activity either outside of skin or within skin. Time-dependent skin resistance reductions measured during HFS correlated significantly greater with subharmonic than with broadband emission levels. The reduction of the skin barrier due to sonophoresis was reversible in all trials; however, effects incurred during IFS recovered more slowly and persisted over a longer period of time than HFS. These results quantitatively demonstrate the significance of cavitation during sonophoresis and suggest that the mechanisms and post-treatment longevity of permeability enhancement due to IFS and HFS treatments are different.