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Drug Delivery Into the Eye With the Use of Ultrasound

Department of Bioengineering (V.Z., S.V.), Center for Industrial and Medical Ultrasound, Applied Physics Laboratory (V.Z., S.V.), and Departments of Biological Structure and Ophthalmology (J.I.C.), University of Washington, Seattle, Washington USA.

Address correspondence and reprint requests to Vesna Zderic, PhD, Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, 1013 NE 40th St, Seattle, WA 98105 USA. E-mail: vesna{at}u.washington.edu.

Objective. To evaluate ultrasound enhancement of drug delivery through the cornea and the histologic appearance of the cornea up to 24 hours after treatment. Methods. Corneas were exposed to ultrasound at a frequency of 880 kHz and intensities of 0.19 to 0.56 W/cm² (continuous mode) with an exposure duration of 5 minutes. The aqueous humor concentration of a topically applied hydrophilic dye, sodium fluorescein, was determined quantitatively in ultrasound- and sham-treated rabbit eyes in vivo. Gross and light microscopic examinations were used to observe structural changes in the cornea 0 to 24 hours after ultrasound exposure. Cavitation activity was measured with a passive cavitation detector. Results. Most cells with an appearance different from that of the normal cells were present in the surface layer of the corneal epithelium. No structural changes were observed in the stroma. The increase in dye concentration in the aqueous humor (relative to sham treatment), after the simultaneous application of ultrasound and the dye solution, was 2.4 times at 0.19 W/cm², 3.8 times at 0.34 W/cm², and 10.6 times at 0.56 W/cm² (P < .05). Dye delivery was found to increase with increasing ultrasound intensity, which corresponded to an increase in cavitation activity. Corneal pits, observed in the ultrasound-treated epithelium, completely disappeared within 90 minutes. Conclusions. Application of 880-kHz ultrasound provided up to 10-fold enhancement in the delivery of a hydrophilic compound through the cornea while producing minor changes in the corneal epithelium.

Key Words: cornea • drug delivery • phonophoresis • sonophoresis • ultrasound

Abbreviations: DPBS, Dulbecco’s phosphate-buffered saline