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Ji Liu, Marjan Nabili, Sankaranarayana P. Mahesh, Hetal Patel, Craig E. Geist, Vesna Zderic; Corneal Changes After Ultrasound-enhanced Drug Delivery - An Ex Vivo And In Vitro Study. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3211.
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Topical drug delivery of lipophilic drugs through intact ocular surface to the anterior chamber (AC) is a well-known challenge and limits the use of these drugs in the treatment of ocular diseases. Ultrasound-facilitated delivery has been in vogue for enhancing drug penetration into the AC. We have previously shown that therapeutic ultrasound at 0.9 MHz led to 4 times more delivery of sodium fluorescein through rabbit corneas. In addition, using ultrasound assisted delivery at 3MHz, tobramycin concentrations increased 3 times in the AC. The purpose of this study was to evaluate and establish the ocular safety parameters associated with an ultrasound-enhanced drug delivery system in rabbit corneas.
Rabbit corneas were placed in a standard diffusion cell chamber at physiological temperature of 34 ºC in a circulation water bath and exposed to ultrasound (1W/cm2) at a frequency of 3 MHz for 2 min. In additional ex vivo experiments, corneas from intact eyes were exposed to ultrasound at intensities ranging from 0.2-2.2 W/cm2 and frequencies 1 MHz and 3 MHz for 2 min. Corneas were observed for surface damages with a stereomicroscope after each experiment. Standard histological techniques were used for processing and assessing any cell damages. Damages observed in epithelium were quantified in four different groups based on the depth and geometrical width of epithelium layers.
Stereomicroscopic evaluation showed pit formation in the cornea at the intensities of 0.6 W/cm2 or higher at both 1 MHz and 3 MHz. At the same level of intensity, the extent of pitting was greater at 1 MHz as compared to 3 MHz. Histologically, ultrasound application at different frequencies led to 3-4.4 times more damage in the epithelial cells as compared to control samples, with the damage being most pronounced at 3 MHz. The damage was localized in the first several layers of the epithelium with deeper layers typically intact. The most common changes observed included swelling and cell edema as compared to control cells. Cell membrane rupture was observed in more severely damaged epithelial cells. At times, epithelial cells were absent in addition to damages, especially in the surface layers. No structural changes were observed in the stroma or endothelium.
Ultrasound has the potential to provide a minimally invasive, efficient method for controlled drug delivery into the eye. Careful selection of optimal ultrasound parameters will minimize corneal damages while maximize intraocular drug delivery to therapeutic levels.
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