Corneal collagen cross-linking

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Cross-linking procedure, UV light source[1]

Corneal collagen cross-linking with riboflavin (vitamin B2) and UV-A light (also known as CXL, C3-R, CCL and KXL), better known as cross-linking, is a surgical treatment for corneal ectasia such as keratoconus.

It is used in an attempt to make the cornea stronger. According to a 2015 Cochrane review, there is insufficient evidence to determine if it is useful in keratoconus.[2] In 2016, the US Food and Drug Administration approved riboflavin ophthalmic solution crosslinking based on three 12-month clinical trials.[3]

Medical uses[edit]

A 2015 Cochrane review that looked at all high quality evidence on corneal collagen cross-linking found that it was insufficient to determine if it is useful in keratoconus.[2]


Removed corneal epithelium during CCR operation on an eye with post-LASIK complication, from Kymionis et al., 2009[4]

Corneal cross-linking involves a one-time application of riboflavin solution to the eye that is activated by illumination with UV-A light for approximately 30 or less minutes. The riboflavin causes new bonds to form across adjacent collagen strands in the stromal layer of the cornea, which recovers and preserves some of the cornea's mechanical strength. The corneal epithelial layer is generally removed to increase penetration of the riboflavin into the stroma, a procedure known as the standard protocol.[5]

People that are considered for treatment must undergo an extensive clinical workup, including corneal tomography, computerized corneal topography, endothelial microscopy, ultrasound pachymetry, b-scan sonography, keratometry and biomicroscopy.

Transepithelial cross-linking[edit]

In transepithelial or epithelium-on (epi-on) cross-linking technique which was first performed in 2004 in the U.S.,[6] the corneal epithelium layer is left intact. in this technique, because the epithelium is not removed, riboflavin loading requires more time than with epi-off techniques.

Pocket cross-linking[edit]

In Pocket Cross-linking Riboflavin is injected directly into the target tissue (corneal stroma) via a corneal pocket in order to bypass the epithelium, which is left intact.[7][8]

Contact lens-assisted collagen cross-linking[edit]

Contact lens-assisted cross-linking (CACXL) may be performed for patients with corneal stromal thickness between 350 µm to 400 µm after epithelial removal. in this method a pre-corneal riboflavin film, a riboflavin-soaked UV barrier-free soft contact lens of negligible power and a pre-contact lens riboflavin film are used to decrease UV irradiance to safe levels at the level of the endothelium.[9][10]


The technique was first developed in Germany in 1998 and clinical trials have been in course since the same year; in Italy routine interventions have been successfully performed since 2005, while in the United States clinical trials commenced only in 2008.


The standard protocol of Corneal Collagen Cross-linking, with epithelium removal, is approved for use throughout Europe.

In the United States, the US Food and Drug Administration approved riboflavin ophthalmic solution and KXL system for crosslinking for the treatment of keratoconus on April 18, 2016, based on three 12-month clinical trials, making them the first FDA approved treatment for progressive keratoconus.[3] The KXL system and two photoenhancers for the treatment of corneal ectasia following refractive surgery also received approval in 2016.[11]


  1. ^ Renesto Ada, C; Sartori, M; Campos, M (Jan–Feb 2011). "[Cross-linking and intrastromal corneal ring segment].". Arquivos brasileiros de oftalmologia. 74 (1): 67–74. doi:10.1590/s0004-27492011000100017. PMID 21670914. 
  2. ^ a b Sykakis, E; Karim, R; Evans, JR; Bunce, C; Amissah-Arthur, KN; Patwary, S; McDonnell, PJ; Hamada, S (24 March 2015). "Corneal collagen cross-linking for treating keratoconus.". The Cochrane database of systematic reviews. 3: CD010621. doi:10.1002/14651858.CD010621.pub2. PMID 25803325. 
  3. ^ a b Lowes, Robert (April 18, 2016). "FDA Approves Photrexa for Corneal Crosslinking in Keratoconus". 
  4. ^ Kymionis GD, Diakonis VF, Coskunseven E, Jankov M, Yoo SH, Pallikaris IG (2009). "Customized pachymetric guided epithelial debridement for corneal collagen cross linking". BMC Ophthalmology. 9: 10. doi:10.1186/1471-2415-9-10. PMC 2744909free to read. PMID 19715585. 
  5. ^ Spoerl E, Wollensak G, Dittert DD, Seiler T (2004). "Thermomechanical behavior of collagen-cross-linked porcine cornea". Ophthalmologica. 218 (2): 136–40. doi:10.1159/000076150. PMID 15004504. 
  6. ^ Kathryn M. Hatch; William B. Trattler. (16 May 2012). "Corneal Crosslinking: Epi-on or Epi-off?". Medscape. 
  7. ^ Daxer A, Mahmoud H, Venkateswaran RS (2010). "Corneal Crosslinking and Visual Rehabilitation in Keratoconus in One Session without epithelial debridement: New Technique". Cornea. 29: 1176–1179. doi:10.1097/ico.0b013e3181d2c644. 
  8. ^ Studeny P, Krizova D, Stranak Z. "Clinical outcomes after Complete Intracorneal Ring Implantation and Corneal Crosslinking in an Intrastromal Pocket in One Session for Keratoconus". Journal of Ophthalmology. 2014: S1. doi:10.1155/2014/568128. 
  9. ^ Agarwal, Amar; Jacob, Soosan (August 10, 2014). "Contact lens-assisted cross-linking treats corneal ectatic disorders in thin corneas". Ocular Surgery News U.S. Edition. 
  10. ^ Jacob, Soosan. "Contact Lens-Assisted CXL for Thin Corneas". Cataract & Refractive Surgery Today. 
  11. ^ "Highlights of Prescribing Information: PHOTREXA VISCOUS (riboflavin 5'-phosphate in 20% dextran ophthalmic solution) 0.146% for topical ophthalmic use PHOTREXA (riboflavin 5'-phosphate ophthalmic solution) 0.146% for topical ophthalmic use For use with the KXL® System" (PDF). U.S. Food and Drug Administration. pp. 5–14. 

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