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An Investigation of the Role of Cavitation in Low-Frequency Ultrasound-Mediated Transdermal Drug Transport

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Abstract

Purpose. Low-frequency ultrasound (20 kHz) has been shown to increase the skin permeability to drugs, a phenomenon referred to as low-frequency sonophoresis (LFS). Many previous studies of sonophoresis have proposed that ultrasound-induced cavitation plays the central role in enhancing transdermal drug transport. In this study, we sought to definitively test the role of cavitation during LFS, as well as to identify the critical type(s) and site(s) of cavitation that are responsible for skin permeabilization during LFS.

Methods. Pig full-thickness skin was treated by 20 kHz ultrasound, and the effect of LFS on the skin permeability was monitored by measuring the increase in the skin electrical conductance. A high-pressure LFS cell was constructed to completely suppress cavitation during LFS. An acoustic method, as well as chemical and physical dosimetry techniques, was utilized to monitor the cavitation activities during LFS.

Results. The study using the high-pressure LFS cell showed definitively that ultrasound-induced cavitation is the key mechanism via which LFS permeabilizes the skin. By selectively suppressing cavitation outside the skin using a high-viscosity coupling medium, we further demonstrated that cavitation occurring outside the skin is responsible for the skin permeabilization effect, while internal cavitation (cavitation inside the skin) was not detected using the acoustic measurement method under the ultrasound conditions examined. Acoustic measurement of the two types of cavitation activities (transient vs. stable) indicates that transient cavitation plays the major role in LFS-induced skin permeabilization. Through quantification of the transient cavitation activity at two specific locations of the LFS system, including comparing the dependence of these cavitation activities on ultrasound intensity with that of the skin permeabilization effect, we demonstrated that transient cavitation occurring on, or in the vicinity of, the skin membrane is the central mechanism that is responsible for the observed enhancement of skin permeability by LFS.

Conclusions. LFS-induced skin permeabilization results primarily from the direct mechanical impact of gas bubbles collapsing on the skin surface (resulting in microjets and shock waves).

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Authors
  1. Hua Tang
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  2. Chiao Chun Joanne Wang
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  3. Daniel Blankschtein
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  4. Robert Langer
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Tang, H., Wang, C.C.J., Blankschtein, D. et al. An Investigation of the Role of Cavitation in Low-Frequency Ultrasound-Mediated Transdermal Drug Transport. Pharm Res 19, 1160–1169 (2002). https://doi.org/10.1023/A:1019898109793

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