Interactions of inertial cavitation bubbles with stratum corneum lipid bilayers during low-frequency sonophoresis

Abstract

Interactions of acoustic cavitation bubbles with biological tissues play an important role in biomedical applications of ultrasound. Acoustic cavitation plays a particularly important role in enhancing transdermal transport of macromolecules, thereby offering a noninvasive mode of drug delivery (sonophoresis). Ultrasound-enhanced transdermal transport is mediated by inertial cavitation, where collapses of cavitation bubbles microscopically disrupt the lipid bilayers of the stratum corneum. In this study, we describe a theoretical analysis of the interactions of cavitation bubbles with the stratum corneum lipid bilayers. Three modes of bubble-stratum corneum interactions including shock wave emission, microjet penetration into the stratum corneum, and impact of microjet on the stratum corneum are considered. By relating the mechanical effects of these events on the stratum corneum structure, the relationship between the number of cavitation events and collapse pressures with experimentally measured increase in skin permeability was established. Theoretical predictions were compared to experimentally measured parameters of cavitation events.

FIGURE 1

Three possible modes through which inertial cavitation may enhance SC permeability. (A) Spherical collapse near the SC surface emits shock waves, which can potentially disrupt the SC lipid bilayers. (B) Impact of an acoustic microjet on the SC surface. The microjet possessing a radius about one-tenth of the maximum bubble diameter impacts the SC surface without penetrating into it. The impact pressure of the microjet may enhance SC permeability by disrupting SC lipid bilayers. (C) Microjets may physically penetrate into the SC and enhance the SC permeability.

FIGURE 2

A schematic representation of a spherical shock wave propagating through the SC surface. The bubble collapses symmetrically with the center located at a distance x from the SC surface. The shock wave propagates spherically through the SC and permeabilizes the circular area whose diameter is given by the dotted chord in the figure.

FIGURE 3

Histological studies of porcine skin exposed to low-frequency ultrasound (20 kHz). (A) Porcine skin not exposed to ultrasound. (B) Porcine skin exposed to low-frequency ultrasound. The scale bar corresponds to 10 μm in both figures. No significant difference can be seen between the two figures. If the 10 μm microjets had penetrated into the SC, a significant disruption of the SC should have been observed.

FIGURE 4

(A) Typical pressure profile of a cavitation event recorded by the hydrophone after the signal is processed through a high pass filter. (B) An enlarged view of two individual bubble collapses. (C) The filtered signal in the absence of cavitation (control).

FIGURE 5

The enhancement of skin conductivity as a function of time at six ultrasound intensities: (•), 0.7 W/cm²; (○), 1.1 W/cm²; (▪), 1.6 W/cm²; (□), 2.4 W/cm²; (▴), 2.9 W/cm²; and (▵), 3.6 W/cm². The error bars represent the standard deviation values (n = 8).

FIGURE 6

(A) Distribution of collapse pressures at three ultrasound intensities: (•), 0.7 W/cm²; (▪), 1.6 W/cm²; and (▴), 2.9 W/cm². The plot shows the dependence of the number of collapses () with a collapse pressure between P_o and P_o + 100 bar. The distribution function fits experimental data well (r² = 0.87, 0.71, and 0.89 for 0.7 W/cm², 1.6 W/cm², and 2.9 W/cm², respectively). The error bars represent the standard deviation values (n = 4). (B) Dependence of the total number of collapse events (η) on ultrasound intensity. The error bars represent the standard deviation values (n = 4).

FIGURE 6

(A) Distribution of collapse pressures at three ultrasound intensities: (•), 0.7 W/cm²; (▪), 1.6 W/cm²; and (▴), 2.9 W/cm². The plot shows the dependence of the number of collapses () with a collapse pressure between P_o and P_o + 100 bar. The distribution function fits experimental data well (r² = 0.87, 0.71, and 0.89 for 0.7 W/cm², 1.6 W/cm², and 2.9 W/cm², respectively). The error bars represent the standard deviation values (n = 4). (B) Dependence of the total number of collapse events (η) on ultrasound intensity. The error bars represent the standard deviation values (n = 4).

FIGURE 7

Dependence of collapse pressures (P_o) on ultrasound intensity. Filled circles show the collapse pressure determined from the model, i.e., based on β_theory. Open circles show the collapse pressures measured using a hydrophone, i.e., based on β_exp.

FIGURE 8

The number of microjets per cm² per second (η_jet) necessary to explain the experimental sonophoresis data as a function of ultrasound frequency and intensity. The shaded region corresponds to the area bounded by predictions in limiting cases made by assuming jet velocities of 50 m/s and 150 m/s. Filled circles show the experimental measurements of aluminum foil pits. Error bars correspond to one standard deviation.