Therapeutic ultrasound offers a noninvasive delivery potential to enhance ocular delivery.
32,33 Anti-VEGF injection is associated with vision improvement; however, ophthalmologists have recognized the burden of poor patient compliance and tolerance of the monthly regular visit for the injection treatment.
30,34 An ultrasound approach for the delivery of anti-VEGF drugs may lead to improved patient outcomes in terms of higher treatment compliance and avoidance of side effects associated with injection treatment.
31 Our previous research findings indicated that ultrasound can be effective and safe for transcorneal delivery of various topically applied compounds into the eye, including the small hydrophilic drug-mimicking compound sodium fluorescein, steroid DEX sodium phosphate, anti-parasitic compound PHMB, and various antiglaucoma drugs.
35–41 In our previous transcorneal experiments, we observed up to 10 drug delivery enhancements with minimal and reversible changes in the eye tissues, as determined in short-term safety studies. Few studies have been conducted using therapeutic ultrasound to enhance sclera drug delivery. The most significant factors of therapeutic ultrasound in enhancing drug delivery are cavitation and acoustic streaming effects.
37,40,42 A study of ultrasound-mediated transscleral delivery of macromolecules showed that low frequency and low-intensity ultrasound (40 kHz at 0.12 W/cm
2) had significantly enhanced the transscleral penetration of fluorescent dextran (70 kDa) by 1.48 times in in vivo rabbit model.
43 Higher frequency low-intensity ultrasound application (1 MHz at 0.05 W/cm
2) also resulted in permeability increase of fluorescein isothiocyanate diffusion through the sclera.
44 A study of Fluorescent dextran of different sizes (20–150 kDa) with ultrasound frequency (40 kHz–3 MHz) at 0.05 W/cm
2 on fresh rabbit sclera ex vivo found the ultrasound application increased sclera penetration up to 20 fold for molecules ≤70 kDa and up to 3 fold for ≥70 kDa molecules.
45 Further, a commercial ultrasound drug delivery system - SonoEye with proprietary ultrasound parameters (Seagull Technology, Sydney, Australia) showed successful transscleral delivery of Avastin to the posterior segment of in vivo rabbit eye models.
46 In vitro studies of isolated human sclera showed a 7.5 enhancement in Avastin sclera delivery using iontophoretic technique.
47 However, in vitro transscleral studies also showed that Avastin has low transscleral permeability and long lag time for its molecular size and hindered diffusion (with Avastin reported lag time of 24 ± 13 hours, mean ± standard deviation).
7 Ultrasound frequency is inversely proportional to the cavitation effects that are a factor in enhancing drug delivery.
37,40,41 In our study, the ultrasound parameters used were in the medium range to generate cavitation to enhance scleral permeability while ensuring thermal safety.
37,40–42,48