Controversies in Corneal Collagen Crosslinking: A Review of Investigational Crosslinking Protocols and Its Off-label Application.

Corneal collagen crosslinking is a pharmacological treatment aimed at strengthening the corneal stroma using riboflavin combined with ultraviolet (UV) A irradiation.1 In 1998, Spoerl et al2 first described the strengthening effect of crosslinking with riboflavin and UV light on corneal tissue using porcine eyes. The photochemical reaction between riboflavin and UVA radiation produces additional chemical bonds that stiffens the stromal collagen fibers.3 In 2003, Wollensak et al3 showed in a pivotal study that corneal collagen crosslinking, using the “Dresden protocol,” halted the progression of keratoconus in all treated eyes, and even showed signs of regression in 16 of the 23 eyes. Subsequent studies have confirmed the efficacy of this protocol in halting the progression of keratoconus and its relative safety.4 However, it was not until 2017 that corneal collagen crosslinking was approved by the US Food and Drug Administration (FDA) for the treatment of progressive keratoconus and corneal ectasia after refractive surgery.5 Currently in the United States, there is only 1 standard crosslinking procedure that is approved by the FDA, which follows the Dresden protocol described in the study by Wollensak et al.5 The protocol involves removal of 8mm of central corneal epithelium, followed by instillation of riboflavin 0.1% with 20% dextran on the cornea for 30 minutes, and then UVA radiation at a wavelength of 370 nm and an irradiance of 3mW/cm for 30 minutes to deliver a total energy of 5.4 J/cm. Despite the general safety of this procedure, modifications to the standard protocol have been investigated