Corneal collagen cross-linking (CXL) is a technique that was first described in 1996 by Theo Seiler, M.D., Ph.D., and Eberhard Spoerl, Ph.D.1,2 Ultraviolet light and similar energy sources have been used in dentistry and other medical specialties, such as cardiology and orthopedics, for decades to structurally strengthen biological materials.2 This novel approach in eye care, however, was first used to arrest the progression of corneal ectasia due to keratoconus as well as to treat other causes of corneal ectasia.

The induced photochemical reaction (oxidative deamination) reinforces the cornea and significantly enhances its elasticity.3 In fact, CXL may even reduce the need for corneal transplantation in patients with ectasia.1

Other applications of CXL include treatment of corneal infection via formation of free oxygen radicals, and reduction of corneal edema and stromal melting from endothelial dysfunction. CXL is also being performed in combination with other surgical procedures, including photorefractive keratectomy (PRK), phakic IOL implantation, and insertion of corneal inlays and Intacs (Addition Technology).

The CXL procedure is minimally invasive and requires the surgeon to topically administer a solution of riboflavin to the cornea, which is then activated by ultraviolet-A for 30 minutes.1 Because riboflavin does not effectively penetrate an intact epithelium, most surgeons first remove it. Those who advocate not removing the epithelium suggest using preservatives or a 20% alcohol solution before applying riboflavin in order to loosen the tight junctions and enhance corneal penetration.1 Currently, European researchers are examining a new riboflavin preparation with modified penetration properties that would eliminate the epithelial removal step.3 CXL is contraindicated in patients with exceedingly steep corneas (>58.00D), significant corneal apical scarring and/or severe corneal thinning (<300µm). 

Combined Procedures
CXL only seems to halt disease progression by providing biochemical stability, so combining the procedure with corneal Intacs is needed to improve visual acuity.3 Many surgeons who combine the two procedures will not perform simultaneous surgery, but rather insert Intacs first and perform CXL approximately eight to 12 weeks later.4 Additionally, the literature describes a combination PRK and CXL technique, in which the surgeon first performs a partial PRK with mitomycin C, then performs CXL.4 Finally, other surgeons have performed phakic IOL implantation combined with CXL.4

FDA Approval
Unfortunately, there may be some impediments to FDA approval of CXL. Most recently, two large-scale studies of CXL were halted in the United States. The major reasons for stopping appear to be related to inadequate funding for a procedure that lacks solid intellectual property protection and low profit yield, rather than any major safety or efficacy issues.1 Whether CXL approval will take place may partially depend on practitioner acceptance and continued scrutiny of study data. Currently, several small, physician-sponsored studies are underway at various locations.1 In the meantime, the procedure is readily available in Europe and Canada.

The jury is still out on whether CXL is really ready for prime time in the United States. Some questions still remain: What lasting effects are there after the procedure is done? At what age is the procedure no longer advisable? What is the best way to deliver riboflavin to the cornea? In what order and how far apart do we schedule combined procedures? And, are there different substances that may work better than riboflavin?

These are just a few of the important questions that will have to be answered before CXL gains full acceptance here.  

1. Karmel M. Collagen cross-linking. EyeNet. 2010 Feb:39-43.
2. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet A induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003 May;135(5):620-7.
3. Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg. 2008 May;34(5):796-801.
4. Cimberle M. Corneal cross-linking shows increasingly good results, gains popularity, stimulates research. Ocular Surgery News Europe Edition. Available at: (Accessed May 28, 2010).