Pulsed Ultrasound-Mediated Drug Delivery Enhancement Through Human Sclera.

Purpose: The purpose of this study was to characterize whether pulsed ultrasound (PUS) affects transscleral drug delivery.

Methods: Fluorescein sodium (NaF, 376 Da) and fluorescein isothiocyanate-conjugated dextran 40 (FD-40, 40 kDa) were used as model drugs. Human sclera grafts were placed in modified Franz diffusion cells and were treated by PUS (1 megahertz [MHz], 0.71 W/cm2, duty cycle 30%, application time 5 minutes) once or repeatedly under various conditions to assess permeation enhancement and reservoir effect. The safety of PUS application was assessed on human sclera grafts ex vivo and rabbit eyes in vivo by histology and temperature measurements.

Results: Single PUS application yielded a significant increase in FD-40 permeation (P <  0.05). Repeated PUS applications led to a further enhancement in FD-40 permeation and also significantly promoted NaF permeation (more than 8.51-fold, P <  0.05). The human scleral permeability was temporarily modified by PUS, as evidenced by the increased scleral permeability during PUS application and the unchanged permeability coefficients at steady state. The reservoir effect of human sclera was also enhanced by PUS application. Cavitation was detected under PUS. A minor increase in graft temperature rise (<1°C) and no ocular damage was caused by PUS.

Conclusions: PUS is an efficient and safe method to enhance model drugs to transport across human sclera by increasing the scleral permeability transiently and improving the reservoir effect. The enhancement was correlated with the molecule size and further promoted by the repeated PUS application.

Translational relevance: Our study provides proof of concept for using PUS to enhance drug delivery to the posterior eye segment.