BlueCross BlueShield of Tennessee Medical Policy Manual

Corneal Collagen Cross-Linking


Corneal collagen cross-linking (CXL) is a photochemical procedure used in the treatment of progressive keratoconus and corneal ectasia. Keratoconus is a naturally occurring dystrophy of the cornea characterized by progressive deformation (steepening) of the cornea while corneal ectasia is keratoconus that occurs after refractive surgery. Both lead to functional loss of vision and need for corneal transplantation. The goal of keratoconus treatment is to reshape the abnormal cornea into a normal dome-like shape, which allows light entering the eye to focus on the retina, improving current visual function and preventing additional vision loss.

CXL is performed with the photosensitizer riboflavin (vitamin B2) and ultraviolet-A (UVA) irradiation. Currently the only CXL method approved by the Food and Drug Administration (FDA) is the epithelium-off method. Using this method, about 8 mm of the central corneal epithelium is removed under topical anesthesia to allow better diffusion of the photosensitizer riboflavin into the stroma. Following de-epithelialization, a solution with riboflavin is applied to the cornea (every 1-3 minutes for 30 minutes) until the stroma is completely penetrated. The cornea is then irradiated with UVA at a maximal wavelength to allow for absorption by riboflavin. The interaction of riboflavin and UVA causes the formation of reactive oxygen species, leading to additional covalent bonds (cross-linking) between collagen molecules that results in stiffening of the cornea.

Another method being evaluated is the epithelium-on method (also known as epi-on or transepithelial). With this method, the corneal epithelial surface is left intact or is partially disrupted and a longer riboflavin loading time is required. This method is still under investigation.





In 2016, riboflavin 5’-phospate in 20% dextran ophthalmic solution (Photrexa Viscous®; Avedro) and riboflavin 5’-phosphate ophthalmic solution (Photrexa®; Avedro) were approved by the U.S. Food and Drug Administration for use with KXL System in corneal collagen cross-linking for the treatment of progressive keratoconus and corneal ectasia after refractive surgery.


American Academy of Ophthalmology (AAO). Preferred Practice Pattern. (2018). Corneal ectasia. Retrieved March 1, 2019 from

BlueCross BlueShield Association. Evidence Positioning System. (4:2021). Corneal collagen cross-linking (9.03.28). Retrieved August 10, 2021 from (22 articles and/or guidelines reviewed)

Henriquez, M.A., Villegas, S., Rincon, M., Maldonado, C., & Izquierdo, L. (2018). Long-term efficacy and safety after corneal collagen crosslinking in pediatric patients: three-year follow-up. European Journal of Ophthalmology, 28 (4), 415-418. Abstract retrieved February 25, 2020 from PubMed database.

Khattak, A., Nakhli, F., & Cheema, H. (2015). Corneal collagen crosslinking for progressive keratoconus in Saudi Arabia: one-year controlled clinical trial analysis. Saudi Journal of Ophthalmology, 29, 249-254. (Level 2 evidence)

Lang, S., Messmer, E., Geerling, G., Mackert, M., Brunner, T., et al. (2015). Prospective, randomized, double-blind trial to investigate the efficacy and safety of corneal cross-linking to halt the progression of keratoconus. BMC Ophthalmology, 15, 78. (Level 2 evidence)

McAnena, L., Doyle, F., & O’Keefe, M. (2016). Cross-linking in children with keratoconus: a systematic review and meta-analysis. Acta Ophthalmologica, 95 (3), 229-239. Abstract retrieved March 10, 2017 from PubMed database.

Meiri, Z., Keren, S., Rosenblatt, A., Sarig, T., Shenhav, L., & Varssano, D. (2016). Efficacy of corneal collagen cross-linking for the treatment of keratoconus: a systematic review and meta-analysis. Cornea, 35 (3), 417-428. Abstract retrieved March 10, 2017 from PubMed database.

National Institute for Health and Clinical Excellence. (2013, September). Photochemical corneal collagen cross-linkage using riboflavin and ultraviolet A for keratoconus and keratectasia. Retrieved July 21, 2016 from

O’Brart, D.P. (2017). Corneal collagen crosslinking for corneal ectasias: a review. European Journal of Ophthalmology, 27 (3), 253-269. Abstract retrieved March 10, 2017 from PubMed database.

Padmanabhan, P, Reddi, S.R., Rajagopal, R., Natarajan, R., Iyer, G., Srinivasan, B., et al. (2016). Corneal collagen cross-linking for keratoconus in pediatric patients- long term results. Cornea, 36 (2), 138-143. Abstract retrieved March 10, 2017 from PubMed database.

Papaioannou, L., Miligkos, M., & Papathanassiou, M. (2016). Corneal collagen cross-linking for infectious keratitis: a systematic review and meta-analysis. Cornea, 35 (1), 62-71. Abstract retrieved March 10, 2017 from PubMed database.

Poli, M., Lefevre, A., Auxenfans, C., & Burillon, C. (2015). Corneal collagen cross-linking for the treatment of progressive corneal ectasia: 6-year prospective outcome in a french population. American Journal of Ophthalmology, 160 (4), 654-662. Abstract retrieved November 4, 2016 from PubMed database.

Rush, W.W., & Rush, R.B. (2016). Epithelium-off versus transepithelial corneal collagen crosslinking for progressive corneal ectasia: a randomized and controlled trial. The British Journal of Ophthalmology, 101 (4), 503-508. Abstract retrieved March 10, 2017 from PubMed database.

Sorkine, N., & Varssanoe, D. (2014). Corneal collagen crosslinking: A systematic review. Ophthalmologica, 232 (1), 1-60. (Level 1 evidence)

U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Summary review, application number 203324Orig2s000. Retrieved March 10, 2017 from

Winifred S. Hayes, Inc. Medical Technology Directory. (2018, December; last update search April 2021). Conventional corneal collagen cross-linking for treatment of LASIK-related ectasia. Retrieved August 11, 2021 from (42 articles and/or guidelines reviewed)

Winifred S. Hayes, Inc. Medical Technology Directory. (2018, February; last update search May 2020). Corneal cross-linking for treatment of keratoconus. Retrieved December 7, 2020 from (66 articles and/or guidelines reviewed)




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