Role of cavitation, surfactants, and their synergism in transdermal sonophoresis

[摘要] (cont.) The next investigation of this thesis focused on understanding the synergism between LFS and CPEs (e.g., surfactants). In spite of identifying that the origin of this synergism is the increased penetration and subsequent dispersion of CPEs in the skin in response to LFS treatment, no prior study had proposed a mechanism to explain how LFS induces the observed increased transport of CPEs. In this study, a physical mechanism by which the transport of all CPEs is expected to have significantly increased flux into the localized-transport regions (LTRs) of LFS-treated skin was proposed. Specifically, the collapse of acoustic cavitation microjets within LTRs was shown to induce a convective flux. In addition, because amphiphilic molecules are able to adsorb onto the gas/water interface of cavitation bubbles, amphiphiles were shown to have an additional adsorptive flux. In this sense, the cavitation bubbles were shown to effectively act as carriers for amphiphilic molecules, delivering surfactants directly into the skin when they collapse at the skin surface as cavitation microjets. The flux equations derived for the LTRs and non-LTRs of LFS-treated skin, compared to that for untreated skin, explained how the transport of all CPEs, and to an even greater extent amphiphilic CPEs, increases during LFS treatment. The flux model was supported with experiments involving a non-amphiphilic CPE (propylene glycol) and both nonionic and ionic amphiphilic CPEs (octyl glucoside and SLS), by measuring the flux of each CPE into untreated skin and the LTRs and non-LTRs of LFS-treated skin. Data showed excellent agreement with the expected trends from the flux model. The final study of this thesis investigated the effect of SLS on skin structural perturbation when utilized simultaneously with LFS. Pig full-thickness skin (FTS) and pig split-thickness skin (STS) treated with LFS/SLS and LFS were analyzed in the context of the aqueous porous pathway model to quantify skin perturbation through changes in skin pore radius and porosity-totortuosity ratio (e/t). In addition, skin treatment times required to attain specific levels of skin electrical resistivity were analyzed to draw conclusions about the effect of SLS on reproducibility and predictability of skin perturbation. It was found that LFS/SLS-treated FTS, LFS/SLS-treated STS, and LFS-treated FTS exhibited similar skin perturbation. However, LFStreated STS exhibited significantly higher skin perturbation, suggesting greater structural changes to the less robust STS induced by the purely physical enhancement mechanism of LFS. Evaluation of c/c values revealed that LFS/SLS-treated FTS and STS have similar transport pathways, while LFS-treated FTS and STS have lower cF/ values. In addition, LFS/SLS treatment times were much shorter than LFS treatment times for both FTS and STS. Moreover, the simultaneous use of SLS and LFS not only results in synergistic enhancement, as reflected in the shorter skin treatment times, but also in more predictable and reproducible skin perturbation. In conclusion, the research conducted in this thesis has contributed to the advancement of the molecular and cellular-level understanding of phenomena associated with LFS-mediated transdermal skin permeability enhancement. Additionally, the insights provided by this thesis could lead to the development of optimized LFS treatment protocols and improved LFS coupling solution formulations. This would permit attaining the desired skin permeability using milder LFS treatment conditions and smaller skin treatment areas. This could also lead to lower power requirements of LFS devices, thereby leading to miniaturization of devices and the creation of more commercially-viable LFS equipment.

[发布机构] Massachusetts Institute of Technology