• Endothelial cell damage (due to UVA irradiation). Protecting the endothelial cells requires precise knowledge of how much radiation is penetrating the stroma, and that in turn requires careful measurement of the absorption coefficient and the effects of riboflavin. Early studies into the safety of riboflavin/UVA cross-linking advised a minimum corneal thickness of 400 µm to ensure that the radiant exposure of the endothelium remained within the recommended safety limits for UVA light [1]. However, more recent studies which have suggested that this minimum thickness value may be overly cautious [2], and the introduction of modified cross-linking procedures have resulted in the safe treatment of much thinner corneas.
  • Damage to the corneal limbus (location of epithelial stem cells). As an added protection it is advised that polymethacrylate rings or other forms of masking should be used to ensure absolute limbal protection, particularly in low-compliance patients who cannot maintain fixation adequately during the 30 minute CXL procedure [3].
  • Impairment of corneal sensitivity due to nerve damage (a consequence of the epithelial removal process). Immediately after CXL the subepithelial plexus and anterior/mid-stromal nerve fibres disappear. In humans and rabbits, regeneration of nerve fibres is complete after about six months [3,4] and plexus structure after one year [3] by which time sensitivity returns to normal [5].


[1] Spoerl E, Mrochen M, Sliney D, Trokel S, Seiler T. Safety of UVA-Riboflavin Cross-Linking of the Cornea. Cornea. 2007;26(4):385-9.

[2] Seiler, T. G., Batista A,  Frueh BE, and Koenig K. “Riboflavin Concentrations at the Endothelium During Corneal Cross-Linking in Humans.” Investigative Ophthalmology and Visual Science 2019; 60: 2140-2145.

[3] Mazzotta C, Traversi C, Baiocchi S, Caporossi O, Bovone C, Sparano C, et al. Corneal healing after riboflavin ultraviolet-A collagen cross-linking determined by confocal laser scanning microscopy in vivo: Early and late modifications. American Journal of Ophthalmology. 2008;146:527-33.

[4] Xia Y, Chai X, Zhou C, Ren Q. Corneal nerve morphology and sensitivity changes after ultraviolet A/riboflavin treatment. Experimental Eye Research. 2011;93:541-7.

[5] Mazzotta C, Traversi C, Baiocchi S, Sergio P, Caporossi T, Caporossi A. Conservative treatment of keratoconus by riboflavin-uva-induced cross-linking of corneal collagen: quantitative investigation. European Journal of Ophthalmology. 2006;16:530-5.


Last updated: December 2021