Corneal Cross-Linking: The Science Beyond the Myths and Misconceptions

Abstract

Purpose: There has been a recent explosion in the variety of techniques used to accomplish corneal cross-linking (CXL) for the treatment of ectatic corneal diseases. To understand the success or failure of various techniques, we review the physicochemical basis of corneal CXL and re-evaluate the current principles and long-standing conventional wisdom in the light of recent, compelling, and sometimes contradictory research. Methods: Two clinicians and a medicinal chemist developed a list of current key topics, controversies, and questions in the field of corneal CXL based on information from current literature, medical conferences, and discussions with international practitioners of CXL. Results: Standard corneal CXL with removal of the corneal epithelium is a safe and efficacious procedure for the treatment of corneal ectasias. However, the necessity of epithelium removal is painful for patients, involves risk and requires significant recovery time. Attempts to move to transepithelial corneal CXL have been hindered by the lack of a coherent understanding of the physicochemistry of corneal CXL. Misconceptions about the applicability of the Bunsen–Roscoe law of reciprocity and the Lambert–Beer law in CXL hamper the ability to predict the effect of ultraviolet A energy during CXL. Improved understanding of CXL may also expand the treatment group for corneal ectasia to those with thinner corneas. Finally, it is essential to understand the role of oxygen in successful CXL. Conclusions: Improved understanding of the complex interactions of riboflavin, ultraviolet A energy and oxygen in corneal CXL may provide a successful route to transepithelial corneal CXL.

Corneal UV Protective Effects of a Topical Antioxidant Formulation: A Pilot Study on In Vivo Rabbits

“…Vizzari et al showed that topical application of the antioxidant and shielding solution significantly counteracted the UV-induced oxidative stress in both the aqueous humor and lens of exposed rabbits [40]. Furthermore, riboflavin shows an indirect antioxidant capacity because it has a shielding action (limits the damage caused by UV-A irradiation), as demonstrated in our studies on cross linking [44][45][46].…”

Corneal UV Protective Effects Of A Topical Antioxidant Formulation: A Pilot Study On In Vivo Rabbits

“…Vizzari et al showed that topical application of the antioxidant and shielding solution significantly counteracts the UV-induced oxidative stress in both aqueous humor and lens of exposed rabbits [40]. Furthermore, riboflavin shows an indirect antioxidant capacity because it has a shielding action (limits the damage caused by the UV-A irradiation) as demonstrated in our studies on cross linking [52][53][54]. The existence of ocular biochemical damages due to acute and chronic exposure to UV-B and UV-A has been widely demonstrated.…”

The Effect of Sodium Iodide on Stromal Loading, Distribution and Degradation of Riboflavin in a Rabbit Model of Transepithelial Corneal Crosslinking

“…If riboflavin degradation is inhibited in the corneal stroma during a clinically relevant time window, ie, over 20–30 min of UVA exposure, 51 then NaI may be helpful to in vivo crosslinking. The data in the present study do not reach statistical significance in showing this independent effect in terms of a decay slope, but do show significantly higher riboflavin grades at 15, 20, and 25 minutes after onset of UVA exposure during crosslinking.…”

“…After sufficient riboflavin loading, oxygen is the limiting reagent in CXL. [49][50][51] However, with insufficient oxygen UVA radiation photodegrades riboflavin, reducing CXL efficiency 52 and increasing UVA radiation exposure to corneal endothelium. In conventional CXL procedures, effective CXL and endothelial protection is achieved by repeated intraoperative application of riboflavin onto a deepithelialized stromal surface.…”