(303d) Investigation of the Mechanism of Ultrasound-Enhanced Transscleral Transport of Macromolecules

Motivated by the need of a non-invasive method to deliver drugs to the posterior segment of the eye, we previously proposed and demonstrated that ultrasound was effective in increasing the permeability of sclera and enhancing the transport of albumin protein through this ocular barrier. Effects observed at medium-frequency (1 MHz) ultrasound were modest albeit statistically significant. To maximize the effect of ultrasound enhancement, and to demonstrate the applicability of this approach for macromolecules of different sizes, we investigated the effects of changing ultrasound frequency on the transscleral penetration of dextrans ranging from 20 to 150 kDa. Our hypothesis about the contribution of cavitation was supported by the observation of maximum enhancement at the lowest frequency (40 kHz) in an ex vivo model, with a fresh rabbit sclera placed between the donor and receiver chamber in a diffusion cell. Using the diffusivity data and a restricted diffusion model, we found that the scleral pore size was enlarged by as much as 9 folds using low-frequency ultrasound for a temporary window of about 3 hours. In addition to passive diffusion, acoustic streaming due to stable cavitation (that is, ultrasound-induced small-scale oscillation of bubbles) was evident in increasing the transscleral penetration of dextran molecules less than 70 kDa.  Preliminary experiments conducted in live rabbits showed that low-frequency ultrasound was effective in enhancing the transscleral transport of macromolecules in vivo.  These results support that ultrasound is a promising method for ocular delivery.