BlueCross BlueShield of Tennessee Medical Policy Manual

Corneal Collagen Cross-Linking


Corneal collagen cross-linking (CXL) is a photochemical procedure being evaluated as a method to stabilize the cornea in individuals with progressive keratectasia such as keratoconus and pellucid marginal degeneration.  CXL may also have anti-edematous and antimicrobial properties.

Keratoconus is a bilateral dystrophy characterized by progressive ectasia (paracentral steepening and stromal thinning) that impairs visual acuity.  Keratoconus can be idiopathic or iatrogenic and may be seen as a result of laser in situ keratomileusis (LASIK).  Pellucid marginal degeneration is a noninflammatory progressive degenerative disease, typically characterized by bilateral peripheral thinning (ectasia) of the inferior cornea. 

CXL is performed with the photosensitizer riboflavin (vitamin B2) and ultraviolet-A (UVA) irradiation. A common CXL protocol removes about 8 mm of the central corneal epithelium 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.


See also:  Intrastromal Corneal Ring Segments (ICRS) for Vision Correction



No CXL devices have received FDA approval for the treatment of keratoconus in the U.S. Phase III clinical trials evaluating safety and efficacy are on-going.


BlueCross BlueShield Association. Medical Policy Reference Manual. (3:2016). Corneal collagen cross-linking (9.03.28). Retrieved July 21, 2016 from BlueWeb. (21 articles and/or guidelines reviewed)

Kanellopoulos, A. (2012). Long term results of a prospective randomized bilateral eye comparison trial of higher fluence, shorter duration ultraviolet A radiation, and riboflavin collagen cross linking for progressive keratoconus. Clinical Ophthalmology, 2012 (96), 97-101. (Level 3 evidence)

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

National Institute of Health. (2016).Facts about the cornea and corneal disease. Retrieved July 22, 2016 from

Padmanabhan, P., & Abhishek, D. (2013). Collagen cross-linking in thin corneas. Indian Journal of Ophthalmology, 61 (8), 422-424. Abstract retrieved September 10, 2015 from PubMed database.

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




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