Mechanisms of ultrasound-microbubble cavitation for inducing the permeability of human skin.

Abstract

We have previously reported that ultrasound (US)-mediated microbubble (MB) cavitation (US-MB) changed the permeability of the skin and significantly enhanced transdermal drug delivery (TDD) without changing the structure of the skin. In this study we found that US-MB enhanced TDD via disruption of epidermal cell-cell junctions and increased matriptase activity. Matriptase is a membrane-bound serine protease regulated by its inhibitor hepatocyte growth factor activator inhibitor-1 (HAI-1), and it is expressed in most epithelial tissues under physiologic conditions. Matriptase is expressed in mice after chronic exposure to UV radiation. This study found that US-MB can be used to monitor active matriptase, which rapidly formed the canonical 120-kDa matriptase-HAI-1 complex. These processes were observed in HaCaT human keratinocytes when matriptase activation was induced by US-MB. The results of immunoblot analysis indicated that the matriptase-HAI-1 complex can be detected from 10min to 3h after US-MB. Immunohistochemistry (IHC) of human skin revealed that US-MB rapidly increased the activated matriptase, which was observed in the basal layer, with this elevation lasting 3h. After 3h, the activated matriptase extended from the basal layer to the granular layer, and then gradually decayed from 6 to 12h. Moreover, prostasin expression was observed in the epidermal granular layer to the spinous layer, and became more obvious in the granular layer after 3h. Prostasin was also detected in the cytoplasm or on the cell membrane after 6h. These results suggest that matriptase plays an important role in recovering from US-MB-induced epidermal cell-cell junction disruption within 6h. US-MB is therefore a potentially effective method for noninvasive TDD in humans.