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Corneal collagen cross-linking

File:Cross-linking procedure, UV light source.jpg
Cross-linking procedure, UV light source[1]

Corneal collagen cross-linking[2] with riboflavin (vitamin B2) and UV-A light (also known as CXL, C3-R,[3] CCL[4] and KXL[5] ), better known as Cross-linking, is a parasurgical treatment for corneal ectasia such as keratoconus.

It 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 procedure, with epithelium removed, is approved for use throughout Europe and Canada.

On 24 February 2015, amid concerns about study data and labeling,[6] a joint panel of the FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee (DODAC) and Ophthalmic Devices Panel (OP-MDAC) recommended approval of Avedro’s combined riboflavin ophthalmic solutions (Photrexa and Photrexa Viscous) and ultraviolet light irradiation (KXL system) for corneal collagen cross-linking.[7] 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.[8]

The procedure

The 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.[10]

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

Epithelium-Off (Dresden protocol)

The standard cross-linking technique, also called Dresden protocol[11] (CXL) requires the removal of central 9 nm of corneal epithelium layer (epi-off), followed by 30 minutes of riboflavin administration, subsequently, UVA light is applied for 30 minutes.

Transepithelial Cross-linking

In transepithelial or epithelium-on (epi-on) cross-linking technique, the corneal epithelium layer is left intact. Brian Boxer Wachler was the first to perform transepithelial crosslinking in 2004.[12] in this technique, because the epithelium is not removed, riboflavin loading requires more time than with epi-off techniques.

Pocket Cross-linking

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.[13][14] Therefore, the treatment is both, effective and painless. In conventional epi-off technique the epithelium is removed which makes the procedure effective but painful. Transepithelial cross-linking, where the epithelium, which is a significant barrier for Riboflavin administration, is not removed and the Riboflavin has to pass through the epithelium in order to get it into the target tissue (corneal stroma) is painful but the effectiveness is discussed controversially.

Accelerated Cross-linking

In accelerated cross-linking (also known as ACXL, KXL[15][16] ), UVA exposure time is reduced to less than 3 minutes, this is achieved by increasing the UVA power and reducing the exposure time, thereby maintaining the same energy on the eye as standard cross-linking while reducing cross-linking time.[17]

Combination with refractive eye surgeries

Cross-linking is not intended to correct vision, thus it is usually combined with refractive eye surgeries such as photorefractive keratectomy and intrastromal corneal ring segments. Cross-linking can also be used to avoid post-LASIK ectasia and to improve refractive outcomes.[18]

Cross-linking and LASIK

File:Applying riboflavin for LASIK Xtra.png
Applying riboflavin on the stromal bed just after excimer laser ablation

Corneas normally become thinner after LASIK because the excimer laser used removes tissue. This effect is more marked when higher degrees of spectacle power or larger optical zones are treated.[19] In a small percentage of cases, this thinning causes the cornea to bulge forwards and become distorted in a condition called corneal ectasia.[20] In a similar manner to keratoconus, corneal collagen cross-linking has been found to benefit patients with post-LASIK corneal ectasia as well.[21] However, when cross-linking is performed only after the cornea becomes distorted, vision remains blurry even though the disease is stabilised. Simultaneously crosslinking corneal collagen with LASIK ('LASIK Xtra') aims to strengthen the cornea at the point of surgery and may be useful in cases where a very thin cornea is expected after the LASIK procedure. This would include cases of high spectacle power and patients with thin corneas before surgery. By strengthening the cornea and preventing its distortion, the patient avoids the risk of blurred vision which is experienced if ectasia is treated only after it happens. Definitive evidence that the procedure can reduce the risk of corneal ectasia will only become available a number of years later as corneal ectasia, if it happens, usually occurs in the late post-operative period. Some have also questioned the cost effectiveness of this procedure for preventing corneal ectasia, since corneal ectasia is a very rare complication and there may be many cases treated unnecessarily.[22] Recently, it has been found that LASIK Xtra adds stability to hyperopic treatments[23] and may also do the same for very high myopic treatments. As a result, some centers outside the USA are already performing LASIK Xtra routinely in such cases.[24]

Corneal Collagen Cross-linking may also be combined with other treatments to improve corneal strength or optical refraction. Successful treatment methods include Mini Asymmetric Radial Keratotomy (MARK),[25] corneal ring segment inserts (Intacs or Ferrara rings), topography-guided laser, or Keraflex.[26][27][28] Corrective lenses are normally required after these treatments, but with smaller, more normalized prescriptions. Increased corneal symmetry allows for more comfortable contact lens wear, often of daily disposable lenses. These newer methods have an important role in limiting deterioration of vision, increasing unaided and uncorrected vision, and strongly reducing the case for corneal transplantation.[29]


  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. PMID 21670914. doi:10.1590/s0004-27492011000100017. 
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  5. ^ "KXL, Accelerated Crosslinking". Avedro. 
  6. ^ "FDA panel recommends approval of riboflavin, UV for keratoconus, corneal ectasia". Healio. Ocular Surgery News. 24 February 2015. 
  7. ^ Lowes, Robert (27 February 2015). "Corneal Crosslinking Drug Gets Cautious Nod From FDA Panel". Medscape. 
  8. ^ "FDA Does Not Approve Avedro's Corneal Cross-Linking Platform Application, Requesting Additional Information". Eyewire Today. 31 March 2015. 
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  10. ^ Spoerl E, Wollensak G, Dittert DD, Seiler T (2004). "Thermomechanical behavior of collagen-cross-linked porcine cornea". Ophthalmologica 218 (2): 136–40. PMID 15004504. doi:10.1159/000076150. 
  11. ^ Spoerl, E (2003). "Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus.". Am J Ophthalmol 135 (5): 620–7. PMID 12719068. Retrieved 13 February 2015. 
  12. ^ Kathryn M. Hatch, William B. Trattler. (16 May 2012). "Corneal Crosslinking: Epi-on or Epi-off?". Medscape. 
  13. ^ Daxer A, Mahmoud H and Venkateswaran RS. Corneal Crosslinking and Visual Rehabilitation in Keratoconus in One Session without epithelial debridement: New Technique. Cornea 2010;29:1176-1179.
  14. ^ 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.
  15. ^ "Accelerated Cross-linking". Avedro. 
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  17. ^ Bethke, Walter. "A Cross Section of Cross-Linking". Review of Ophthalmology. 
  18. ^ Stephenson, Michelle. "LASIK Xtra: Is It for Everyone?". Review of Ophthalmology. 
  19. ^ Munnerlyn, CR, Koons, SJ, Marshall, J. "Photorefractive keratectomy: a technique for laser refractive surgery," J. Refract. Surg., 1988, 14, 46-52
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  21. ^ Vincigeurra P,Camesasca FI,Albe E,Trazza S.Corneal collagen cross-linking for ectasia after excimer laser refractive surgery:1-year results. J Refract Surg 2009; 22:1–12.
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  27. ^ Straub, Laura (March 2010). "Thermo-Biomechanics for Treating Keratoconus and Refractive Errors" (PDF). Cataract and Refractive Surgery Today. Retrieved 15 December 2012. 
  28. ^ "Thermo-biomechanical system gets CE mark | OphthalmologyTimes". 2010-05-07. Retrieved 2013-04-02. 
  29. ^ Hersch, Peter S. (1 June 2010). "Keratoconus approach is promising". Ophthalmology Times Europe. Retrieved 2 April 2013. 

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