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Daniel M. Gore, David O'Brart, Paul French, Chris Dunsby, Bruce D. Allan; Transepithelial Riboflavin Absorption in an Ex Vivo Rabbit Corneal Model. Invest. Ophthalmol. Vis. Sci. 2015;56(8):5006-5011. doi: 10.1167/iovs.15-16903.
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To measure depth-specific riboflavin concentrations in corneal stroma using two-photon fluorescence microscopy and compare commercially available transepithelial corneal collagen cross-linking (CXL) protocols.
Transepithelial CXL riboflavin preparations—MedioCross TE, Ribocross TE, Paracel plus VibeX Xtra, and iontophoresis with Ricrolin+—were applied to the corneal surface of fresh postmortem rabbit eyes in accordance with manufacturers' recommendations for clinical use. Riboflavin 0.1% (VibeX Rapid) was applied after corneal epithelial debridement as a positive control. After riboflavin application, eyes were snap frozen in liquid nitrogen. Corneal cross sections 35-μm thick were cut on a cryostat, mounted on a slide, and imaged by two-photon fluorescence microscopy. Mean (SD) concentrations were calculated from five globes tested for each protocol.
Peak riboflavin concentration of 0.09% (±0.01) was observed within the most superficial stroma (stromal depth 0–10 μm) in positive controls (epithelium-off). At the same depth, peak stromal riboflavin concentrations for MedioCross TE, Ricrolin+, Paracel/Xtra, and Ribocross TE were 0.054% (±0.01), 0.031% (0.003), 0.021% (±0.001), and 0.015% (±0.004), respectively. At a depth of 300 μm (within the demarcation zone commonly seen after corneal cross-linking), the stromal concentration in epithelium-off positive controls was 0.075% (±0.006), while at the same depth MedioCross TE and Ricrolin+ achieved 0.018% (±0.006) and 0.016% (0.002), respectively. None of the remaining transepithelial protocols achieved concentrations above 0.005% at this same 300-μm depth. Overall, MedioCross TE was the best-performing transepithelial formulation.
Corneal epithelium is a significant barrier to riboflavin absorption into the stroma. Existing commercial transepithelial CXL protocols achieve relatively low riboflavin concentrations in the anterior corneal stroma when compared to gold standard epithelium-off absorption. Reduced stromal riboflavin concentration may compromise the efficacy of riboflavin/ultraviolet corneal CXL.
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