Riboflavin for corneal cross-linking

Abstract

Corneal collagen cross-linking (CXL) with riboflavin and ultraviolet A (UVA) radiation is the first therapeutic modality that appears to arrest the progression of keratoconus and other corneal ectasias. Riboflavin is central to the process, acting as a photosensitizer for the production of oxygen singlets and riboflavin triplets. These free radicals drive the CXL process within the proteins of the corneal stroma, altering its biomechanical properties. Riboflavin also absorbs the majority of the UVA radiation, which is potentially cytotoxic and mutagenic, within the anterior stroma, preventing damage to internal ocular structures, such as the corneal endothelium, lens and retina. Clinical studies report cessation of ectatic progression in over 90% of cases and the majority document significant improvements in visual, keratometric and topographic parameters. Clinical follow-up is limited to 5-10 years, but suggests sustained stability and enhancement in corneal shape. Sight-threatening complications are rare. The optimal stromal riboflavin dosage for CXL is as yet undetermined.

An Investigation of the Effects of Riboflavin Concentration on the Efficacy of Corneal Cross-Linking Using an Enzymatic Resistance Model in Porcine Corneas

“…Although numerous modifications of the epithelium-off CXL technique have been postulated, these have almost universally focused on variation in the UVA protocol and additives to the standard riboflavin 0.1% solution 21. Indeed, except for some epithelium-on CXL formulations that utilize 0.25% riboflavin concentrations,32 virtually all currently used epithelium-off protocols use a riboflavin concentration of 0.1% 21,22. Despite the passage of almost two decades since the first human clinical CXL treatments,7 the optimum riboflavin dosage for CXL is undetermined,22 but to fully evaluate the efficacy and safety of any drug, it is vital to determine its dose-response curve 35…”

“…Finally, in the CXL process riboflavin has two basic functions. As well as acting as a photosensitizer to produce both oxygen singlets and riboflavin triplets to drive the CXL process,22 it also absorbs the UVA photons within the anterior corneal stromal to reduce UVA toxicity and potential damage to internal ocular structures such as the endothelium 48. The use of higher-strength riboflavin solutions resulting in increased stromal riboflavin concentrations and therefore increased UVA absorption within the anterior stroma, should theoretically reduce the amount of UVA radiation reaching deeper layers of the cornea, reducing the risk of endothelial toxicity as well as allowing for the possible treatment of thinner corneas 49.…”

“…The precise reasons for the reduced efficacy of ACXL protocols are unclear, and the exact mode of action of CXL at a molecular level is undetermined 21. It is postulated that riboflavin acts as a photosensitizer to produce both oxygen singlets and riboflavin triplets,22 which then drive the CXL process within the corneal stroma 23. What is understood is that oxygen is essential to drive the process, and in the absence of oxygen, CXL is impaired 24.…”

“…Indeed, except for some transepithelial CXL protocols,32 published CXL research, including those with varying riboflavin formulations, has almost universally maintained a riboflavin concentration of 0.1%. Almost 15 years after publication of the first clinical paper,7 the optimal stromal riboflavin dosage for CXL is yet to be determined 22. This present study aims to investigate this issue by determining the efficacy of CXL using an enzymatic (pepsin) resistance model in ex vivo porcine corneas with varying concentrations of riboflavin (0.05%, 0.1%, 0.2%, and 0.3%).…”

Biomedical applications of electrical stimulation

“…A recent study showed that efective ocular iontophoresis could also be achieved when both working and counter electrodes were placed on the same eye [157]. Trans-corneal iontophoresis has been frequently used to deliver ribolavin, which is a chemical used in combination with ultraviolet (UV) irradiation to crosslink and stifen the cornea [158]. In a clinical trial published in 2014, transcorneal iontophoresis was performed in 19 patients (22 eyes) to deliver ribolavin into the cornea, which was subsequently used to crosslink the cornea by UV irradiation to treat progressive keratoconus [159].…”