Corneal Cross-Linking

Corneal Cross-Linking

Keratoconus and other corneal ectasias are often described as non-inflammatory, progressive disorders that are characterized by thinning and steepening of the inferior or central cornea, irregular astigmatism, and loss of best-corrected visual acuity

Treatment was once limited to spectacles and rigid contact lenses or invasive treatments such as penetrating keratoplasty. Other treatments options available to patients include photorefractive keratectomy, intrastromal corneal ring segments, and phakic intraocular lenses.  With the recent FDA approval of Photrexa, Photrexa Viscous, and KXL System (Avedro, see below) corneal collagen cross-linking (CXL) can be added to that list in the United States.

How It Started

Spoerl et al first studied CXL in 1998, when they treated porcine eyes with riboflavin and UV-irradiation and weak glutaraldehyde.  They found increased biomechanical stiffening of the cornea when compared with untreated corneas. [1]

Wollensak et al then performed a prospective, non-randomized clinical pilot study in 23 eyes with moderate or advanced progressive keratoconus. Their data showed that treatment with riboflavin drops and ultraviolet-A (UVA) irradiation (370 nm, 3 mW/cm2 for 30 minutes) was able to halt the progression of keratoconus in all eyes and caused disease regression in 16 eyes. [2]

A number of clinical studies have confirmed the ability of CXL to stabilize and regularize the cornea, in turn helping to improve visual acuity in patients with keratoconus [3-9] and postoperative LASIK ectasia. [10,11] Given such positive results, CXL has become a welcomed option for ophthalmologists. 

How It Works

To perform the procedure, the epithelium is debrided and then the photosensitizer (riboflavin) is placed topically every two minutes for 30 minutes.  The cornea is then examined for proper penetration of the riboflavin, usually at least 400 microns.  The eye is then irradiated for 30 continuous minutes. 

The combination of the riboflavin and UV light induces the photooxidative cross-links.  The generation of collagen crosslinks is largely determined by the concentration of riboflavin and wavelength, time, and energy dose of the light source.

The standard CXL treatment protocol for a patient with progressive keratoconus is exposure to UVA light (3 mW/cm2) for 30 minutes and is termed the Dresden protocol.  Multiple other treatment protocols have been attempted with increased intensity and shortened duration.  It is thought that by increasing the irradiation intensity but keeping the illumination dose at 5.4 J/cm2, it may be possible to reduce CXL treatment time. Reduced treatment time could help to improve practice efficiency and throughput volumes, increase patient comfort, and reduce the risk of corneal dehydration.

Avedro’s CXL Technology

As mentioned above, Photrexa Viscous, Photrexa and the KXL System — all produced by Avedro Inc., an ophthalmic pharmaceutical and medical device company based in Waltham, MA — received FDA approval on April 18, 2016 for the treatment of progressive keratoconus and represent a first-in-class therapeutic treatment for keratoconus.

The Photrexa Viscous is composed of 1.46 mg/mL riboflavin 5’-phosphate in 20 percent dextran ophthalmic solution, while the Photrexa does not contain the dextran solution.  Photrexa Viscous and Photrexa are photoenhancers indicated for use with the KXL System in corneal collagen cross-linking for the treatment of progressive keratoconus.   

The FDA approval was based on Avedro’s NDA submission, which encompassed data from two prospective, randomized, parallel-group, open-label, placebo-controlled, 12-month trials conducted in the United States to determine the safety and effectiveness of Photrexa Viscous and Photrexa when used for performing corneal cross-linking in eyes with progressive keratoconus.  In the studies, patients had one eye designated as the study eye and were randomized to receive one of two study treatments (CXL or sham) in their study eye.

According to Avedro’s website, the cross-linked eyes showed increasing improvement in Kmax from Month 3 through Month 12 with an average Kmax reduction of 1.4 D in Study 1 and 1.7 D in Study 2 at Month 12 in the cross-linked eyes, while the untreated eyes had an average increase of 0.5 D in Study 1 and 0.6 D in Study 2 at Month 12. Complications from the treatment can include ulcerative keratitis, corneal opacity (haze), punctate keratitis, corneal striae, corneal epithelium defect, eye pain, reduced visual acuity, and blurred vision. 

The company's corneal crosslinking technology is already available in Asia and Europe.  It is anticipated that orders for the KXL System should be available in the near future, with plans to begin shipment of the Photrexa products in the upcoming months.


  1. Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal tissue. Exp Eye Res. 1998;66:97–103.
  2. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-A-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135:620–627.
  3. Toprak I, Yildirim C. Effects of corneal collagen crosslinking on corneal topographic indices in patients with keratoconus. Eye Contact Lens. 2013;39:385–387.
  4. Steinberg J, Ahmadiyar M, Rost A, et al. Anterior and posterior corneal changes after crosslinking for keratoconus. Optom Vis Sci. 2014;91: 178–186.
  5. Ghanem RC, Santhiago MR, Berti T, et al. Topographic, corneal wavefront, and refractive outcomes 2 years after collagen crosslinking for progressive keratoconus. Cornea. 2014;33:43–48.
  6. Sloot F, Soeters N, van der Valk R, et al. Effective corneal collagen crosslinking in advanced cases of progressive keratoconus. J Cataract Refract Surg. 2013;39:1141–1145.
  7. Guber I, Guber J, Kaufmann C, et al. Visual recovery after corneal crosslinking for keratoconus: a 1-year follow-up study. Graefes Arch Clin Exp Ophthalmol. 2013;251:803–807.
  8. Caporossi A, Mazzotta C, Baiocchi S, et al. Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study. Am J Ophthalmol. 2010;149:585–593.
  9. Wittig-Silva C, Whiting M, Lamoureux E, et al. A randomized controlled trial of corneal collagen cross-linking in progressive keratoconus: preliminary results. J Refract Surg. 2008;24:S720–S725.
  10. Hafezi F, Kanellopoulos J, Wiltfang R, et al. Corneal collagen cross- linking with riboflavin and ultraviolet A to treat induced keratectasia after laser in situ keratomileusis. J Cataract Refract Surg. 2007;33:2035– 2040.
  11. Kanellopoulos AJ. Post-LASIK ectasia. Ophthalmology. 2007;114:1230 
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