Cavitation mechanisms in ultrasound-enhanced permeability of ex vivo porcine skin

Ultrasound-induced cavitation during sonophoresis is known to enhance transdermal drug delivery for local, regional, and systemic treatment. However, the precise mechanisms responsible for enhancement are not fully understood. Specifically, the physical location and type of permeability-enhancing cavitation during intermediate (IFS, 100-700 kHz) and high-frequency sonophoresis (HFS, >0.7 MHz) are unknown and likely different than for low-frequency sonophoresis (20-100 kHz). Here, the role of stable and inertial cavitation, both within and external to the tissue, was investigated during IFS and HFS. Cavitation was selectively isolated external or internal to porcine skin by degassing either the tissue or surrounding medium, respectively. Skin samples were sonicated for 30 minutes over a range of frequencies (0.41-2.0 MHz) and intensities (0-8.3 W/cm2) while passive cavitation detection was employed to capture subharmonic and broadband acoustic emissions. Skin permeability changes were quantified by measuring the electrical resistance of skin during insonation. Significant skin resistance changes were accompanied by significant acoustic emissions from cavitation external to the skin during sonophoresis at either frequency. Only during 2.0 MHz sonophoresis was a significant change in resistance and acoustic emissions observed from cavitation within the tissue. In all cases, increasing subharmonic emissions showed a strong correlation with decreasing skin resistance.