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Harriet Lloyd, Raksha Urs, LeeJee Suh, Ronald H Silverman; Ultrasound mediated transepithelial delivery of riboflavin for corneal cross-linking therapy. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5633.
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Corneal cross-linking therapy has emerged as a treatment option for keratoconus. This procedure uses UV light and riboflavin to augment the stromal collagen bonds, and requires epithelial debridement to achieve adequate riboflavin permeation into the stroma, which can lead to pain, potential complications and increased post-op care. Our goal was to determine the potential of ultrasound alone and in combination with gas-encapsulating, lipid shell microspheres to permeabilize the epithelium for riboflavin delivery.
33 NZW rabbits (66 eyes) were placed into three groups: epithelium on, epithelium off and sham. An unfocused 1MHz transducer was coupled to the eye at a distance of 25mm with an applicator filled with 20% Dextran T500 solution. 1-MHz tonebursts were applied at 1 msec intervals at four settings for 5 minutes: (1) 0.07 MPa,10% duty cycle, (2) 0.14 MPa,10% duty cycle, (3) 0.15 MPa, 20% duty cycle, (4) 0.3 MPa, 20% duty cycle. Targestar-P (Targeson, Inc.) 2-μm diameter microspheres were introduced into the applicator in half the cases prior to insonification. Corneas then received riboflavin drops for 30 minutes, after which aqueous riboflavin concentration was measured by spectrophotometry. Corneas were harvested and light microscopy of H&E-stained sections performed to determine if any ultrasound-induced structural changes occurred.
T-Tests showed no significant difference between control and sham groups. Anterior chamber riboflavin concentration was significantly higher (by a factor, x, of 12) in the epithelium-off group than the control (p=.001). In the ultrasound-only-treated groups, significant increases in riboflavin delivery occurred in eyes treated at a 20% duty cycle at 0.15 MPa (x=3.4, p=.05) and 0.3 MPa (x=6.1, p=.01). Ultrasound in the presence of microspheres produced an increase in riboflavin delivery at lower intensities compared to ultrasound-alone, but the increase was less than ultrasound-alone at higher intensities.
Ultrasound-alone at diagnostic levels appears effective in enhancing transepithelial delivery of riboflavin. Addition of microspheres enhanced delivery at lower ultrasound intensity, possibly thru sonoporation mediated by bubble resonance and microjects. At higher intensity, delivery was enhanced relative to controls, but less than with ultrasound alone, possibly due to absorption and bubbles rupturing at higher intensity.
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