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 parasurgical treatment for corneal ectasia such as keratoconus.

Corneal collagen cross-linking as of 2015 is lacking sufficient evidence to determine if it is useful in keratoconus.[2]

Medical uses[edit]

A 2015 Cochrane review that look 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[3]

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.[4]

Patients 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.,[5] 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.[6][7]

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.[8][9]

Combination with refractive eye surgeries[edit]

Cross-linking is not intended to correct vision, thus it is usually combined with refractive eye surgeries such as photorefractive keratectomy, intrastromal corneal ring segments, and mini asymmetric radial keratotomy.[10] Cross-linking can also be used to avoid post-LASIK ectasia and to improve refractive outcomes.[11]


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 USA clinical trials commenced only in 2008.


The standard protocol of Corneal Collagen Cross-linking, with epithelium removal, is approved for use throughout Europe.[12] In the United States, amid concerns about study data and labeling,[13] a FDA panel recommended approval of Avedro’s combined riboflavin ophthalmic solutions and ultraviolet light irradiation for corneal collagen cross-linking in February 2015.[14] In March 2015, FDA decided not to approve the Avedro's new drug application, identifying areas of the application concerning the device which require additional information.[15]


  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. ^ 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 2744909. PMID 19715585. 
  4. ^ 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. 
  5. ^ Kathryn M. Hatch, William B. Trattler. (16 May 2012). "Corneal Crosslinking: Epi-on or Epi-off?". Medscape. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ 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. 
  9. ^ Jacob, Soosan. "Contact Lens-Assisted CXL for Thin Corneas". Cataract & Refractive Surgery Today. 
  10. ^ Abbondanza, M; Abdolrahimzadeh, B; Guidobaldi, M (January 2016). "[Combined Corneal Collagen Cross-linking and Mini Asymmetric Radial Keratotomy for the Treatment of Keratoconus].". Acta Medica International 3 (1): 63–68. doi:10.5530/ami.2016.1.14. 
  11. ^ Stephenson, Michelle. "LASIK Xtra: Is It for Everyone?". Review of Ophthalmology. 
  12. ^ Keating, A; Pineda II, R; Colby, K (November 2010). "[Corneal Cross Linking for Keratoconus].". Seminars in Ophthalmology 25 (5-6): 249–255. doi:10.3109/08820538.2010.518503. 
  13. ^ "FDA panel recommends approval of riboflavin, UV for keratoconus, corneal ectasia". Healio. Ocular Surgery News. 24 February 2015. 
  14. ^ Lowes, Robert (27 February 2015). "Corneal Crosslinking Drug Gets Cautious Nod From FDA Panel". Medscape. 
  15. ^ "FDA Does Not Approve Avedro's Corneal Cross-Linking Platform Application, Requesting Additional Information". Eyewire Today. 31 March 2015. 

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