A mechanism-inspired integrated dual-frequency ultrasound transducer for cavitation-enhanced transdermal drug delivery.

Abstract

Ultrasound has gained widespread application in the field of transdermal drug delivery (TDD), including dermatological therapy and aesthetic medicine, owing to its non-invasive nature and cost-effectiveness. Despite its widespread use, clinical researchers have largely relied on empirical selection of low-frequency ultrasound (tens to hundreds of kHz) for single-frequency sonophoresis, and a mechanistic understanding of how ultrasound frequency regulates cavitation-from nucleation to bubble collapse-remains lacking, which limits the rational design of ultrasound-based TDD systems. In this study, we proposed a simulation framework that couples Zwart-Gerber-Belamri (ZGB) cavitation model (for nucleation) with Keller-Miksis (K-M) equation (for bubble dynamics), thereby addressing the limitation of existing models that treat nucleation and bubble growth/collapse separately. Using this model, we analyzed the relationship between ultrasound frequency and cavitation effects was analyzed. The results indicate that high-frequency ultrasound can facilitate faster generation of more cavitation nuclei, whereas low-frequency ultrasound is more conducive to the growth and collapse of pre-existing bubbles. Based on these findings, an integrated dual-frequency (400 kHz, 2 MHz) ultrasound transducer (iDFUT) was designed and fabricated to enhance the efficacy of dermatological treatments. Both in vitro and in vivo studies confirmed that this device significantly improves drug delivery efficiency. The proposed theoretical model, dual-frequency transducer design, and experimental validation form an integrated framework that directly links cavitation mechanisms to device optimization and therapeutic efficacy, offering a reliable technical reference for the rational development of ultrasound-mediated TDD systems.