Corneal Collagen Crosslinking (CXL)

corneal collagen crosslinking treatment     Peter S. Hersh, M.D.

We are happy to announce FDA approval of collagen crosslinking for the treatment of progressive keratoconus as well as corneal ectasia. As lead author of the two studies leading to approval and medical monitor of the U.S. clinical trials of crosslinking , Dr. Peter Hersh and CLEI are gratified that this important new keratoconus treatment will now be more widely available. At the CLEI Center for Keratoconus, we started the crosslinking procedure in February 2008 and thank our many patients who participated in the study. If you have any questions, please contact us at 201-883-0505 or email To read the actual clinical study, click on the title above. The video below, summarizes our results.

How Corneal Collagen Crosslinking Works

In short, corneal crosslinking makes the cornea stronger.  Keratoconus is a progressive process in which the cornea (the clear dome-shaped front of the eye, like a watch crystal) deforms in association with thinning and biomechanical weakening. This is much like a bulge that can form on a thin area of a car tire or balloon. This progressive distortion and bowing out (coning) of the normal cornea creates optical aberrations, which can be thought of as static in your eye (like static on an old TV), resulting in a decrease in visual function. Because of the corneal distortion in keratoconus, patients usually require rigid or complex curvature contact lenses to achieve good functional vision; spectacle correction frequently does not result in acceptable quality of vision. Given the distortion of the cornea, contact lens fitting may be challenging in many patients. Also, since keratoconus tends to progress over the second to fifth decades of life, it can lead to intolerance of contact lenses and, ultimately, necessitate corneal transplantation. So, a treatment to slow or stop keratoconic progression would be very important to the KC patient.

Corneal Crosslinking

Since we began treating patients with crosslinking nearly a decade ago in our clinical studies, CXL has emerged as an important advancement in KC treatment to slow or stop the progression of keratoconus. In this procedure, riboflavin (Vitamin B2) is administered in conjunction with ultraviolet A (UVA – 365nm) light. The interaction of riboflavin and UV causes a photobiologic reaction in the corneal leading to the formation of additional molecular bonds between collagen molecules as well as their supporting biologic sugars. This results in stiffening of the cornea, much a placing additional cables on a bridge will help to support it.

The Corneal Collagen Crosslinking Procedure

Corneal collagen cross-linking involves the following steps:

  • After numbing drops are applied, your eyelids will be held open with a small instrument to avoid blinking during the procedure.
  • The outer layer of cells of the cornea (clear covering of the eye) will be removed by either a manual or laser technique. Sometimes we will leave this layer in place, depending on your individual situation.
  • The lid holder is removed and riboflavin (vitamin B2 eyedrops) will be applied to your eye until there is full uptake into the cornea.
  • The ultraviolet (UV-A) light source is then aligned and then you will look up at it for administration of the crosslinking treatment.
  • At the end of procedure, a bandage soft contact lens will be placed on your eye, to protect the surface of the cornea during the healing process.


What to Expect after Crosslinking

The first phase of healing is the early period 1-5 days when the surface epithelial cells heal. Generally, a bandage contact lens will protect the cornea and make it comfortable during this time. However, there may be some discomfort for which we will give you appropiate medication. You will be able to see through the lens, but vision will be hazy during this time (like driving with a foggy windshield). In some patients, vision may continue to be mildly hazy for several months, but, in general, most patients note a return to their baseline vision over the first few weeks. Contact lenses can be restarted after we are satified with the early healing, usually around 1 month after the procedure. Remember, collagen crosslinking is designed to decrease the progression of keratoconus and corneal ectasia. It is not meant to improve your vision. There are other procedures that can be used to further improve your vision. It is important to know that, although crosslinking has been shown to be successful in most patients, it may not work in all cases and keratoconus may still continue to progress.

Crosslinking Results

Corneal collagen crosslinking is a very successful procedure, with over a 90% success rate of decreasing progression of keratoconus. Here at CLEI we have been working on crosslinking for 10 years. The following abstract of results is taken from Dr. Hersh’s paper on the U.S. clinical trial which led to FDA approval.

Purpose: To evaluate the safety and efficacy of corneal collagen crosslinking (CXL) for the treatment of progressive keratoconus.

Design: Prospective, randomized, multicenter, controlled clinical trial. Participants: Patients with progressive keratoconus(n=205).

Methods: The treatment group underwent standard CXL and the sham control group received riboflavin alone without removal of the epithelium.

Main Outcome Measures: The primary efficacy criterion was the change over 1 year of topography-derived maximum keratometry value (ie the topographic height of the keratoconic cone), comparing treatment with control group. Secondary outcomes evaluated were corrected distance visual acuity (CDVA), uncorrected distance visual acuity (UDVA), manifest refraction spherical equivalent, endothelial cell count, and adverse events.

Results: In the CXL treatment group, the maximum keratometry value decreased (improved), on average, by 1.6 diopters (D) from baseline to 1 year, whereas keratoconus continued to progress in the control group. In the treatment group, the maximum keratometry value decreased by 2.0 D or more in 28 eyes (31.4%) and increased by 2.0 D or more in 5 eyes (5.6%). The CDVA improved by an average of a little over one line on the vision chart.   Twenty-three eyes (27.7%) gained and 5 eyes lost (6.0%) 2 lines or more. The UDVA improved by nearly one line on the vision chart.  Corneal haze was the most frequently reported CXL-related adverse finding. There were no significant changes in endothelial cell count 1 year after treatment.

Conclusions: Corneal collagen crosslinking was effective in improving the maximum keratometry value, CDVA, and UCVA in eyes with progressive keratoconus 1 year after treatment, with an excellent safety profile. Corneal collagen crosslinking affords the keratoconic patient an important new option to decrease progression of this ectatic corneal process.

Who Should Get Crosslinking?

Crosslinking is designed specifically to decrease the progression of keratoconus, to prevent worsening of vision. Some patients tend to respond better while others don’t require treatment. We have done a study to determine who are the best candidates as described in the video below.

Epi-on Transepithelial Crosslinking

Recently, there has been much discussion regarding transepithelial crosslinking, or the epi-on technique. In epi-on crosslinking approach, the treatment is similar to standard CXL; however, we do not remove the surface epithelial cells (which are analogous to the tiles on a floor). Because those cells remain in place and don’t need to replicate and heal, there are a few potential advantages of the epi-on technique. First, leaving the cells in place may lead to faster visual recovery and earlier return to contact lenses. Also, since there is less disruption to the surface cells, the potential for infection and the potential for corneal haze may be somewhat less.

However, there are some disadvantages. Most of these relate to the efficacy of the epi-on procedure compared to the standard technique.

  1. With the epithelial intact, it is more difficult to get complete riboflavin saturation into the cornea. Remember, the cornea absorbs riboflavin much like a sponge absorbs water. With the epithelium in place, riboflavin, a very large molecule, finds it more difficult to diffuse into the corneal tissue.
  2. The epithelium itself can act as a mask absorbing some of the incoming ultraviolet light. This may attenuate ultraviolet light energy deeper in the cornea and make the treatment effect more superficial and less deep and, thus, potentially less effective or longlasting.
  3. Oxygen from the air is required in order to perform a complete crosslinking reaction. With the epithelium intact, oxygen diffusion may be more difficult, and thus we may not get as much of a crosslinking effect.
  4. Although there may be less transient corneal haze formation with the epi-on technique, it’s not yet clear whether this haze really is an unwanted side effect of crosslinking or simply indicates an adequate crosslinking effect.

Here at the CLEI Center for Keratoconus, we have been studying trans-epithelial crosslinking in a formal clinical trial for several years (see below). Using the techniques of the study we are able to adequately achieve good riboflavin saturation into the cornea. As in the standard crosslinking technique, we see a generalized improvement of the height of the keratoconic cone one year after epi-on crosslinking. Although It can’t be directly compared to the results that we have with standard crosslinking techniques because of study designs, it does appear that the results may be less robust using the epi-on approach.  Different crosslinking approaches may be suggested based on your particular problem.  A careful assessment of your ocular situation will allow us to make the best recommendation for your care.

It is important to know that only the standard crosslinking technique is FDA-approved. Epi-on is not an FDA approved technique. It can be done in a formal clinical trial or on an off-label basis after discussion of its risks and benefits. There are a number of clinical trials in the U.S. and internationally looking at other methods of epi-on crosslinking. These include new riboflavin formulations to improve uptake, methods which the ultraviolet power or adjust the ultraviolet dose, and ways to facilitate oxygen diffusion, such as intermittently pulsing the ultraviolet light or using supplemental oxygen around the eye during the procedure. We certainly look forward to results of these number of clinical trials and the evolution of crosslinking as time goes on. Certainly, the advantages and disadvantages of various crosslinking techniques will remain unclear until further clinical trial results become available.

Clinical Trials of Corneal Collagen Crosslinking (CXL) for Keratoconus and Ectasia

CXLAt the CLEI Center for Keratoconus, we are working on new techniques to improve keratoconus treatment. We continue to conduct clinical trials of corneal collagen crosslinking (CXL). The clinical trials are designed to study the benefits and safety of corneal collagen crosslinking in patients with either keratoconus or corneal ectasia after previous refractive surgery.

We have been participating in CXL treatments in formal clinical trials for four years and have performed more than 300 procedures to date. See for general information regarding clinical trials and see CXL and CXL/Intacs and Transepithelial CXL for specific information on the crosslinking studies available at the CLEI Center for Keratoconus.

For further information and inquiries regarding your candidacy for CXL, call 201-883-0505 or email

CXL Clinical Trials – Enrollment Closed


Dr. Hersh and the CLEI Center for Keratoconus are pleased to announce a new clinical trial of transepithelial corneal collagen crosslinking (CXL) for keratoconus and corneal ectasia after previous surgery. Transepithelial crosslinking is sometimes known as the “epi-on” crosslinking technique. This study compares two variants of transepithelial crosslinking. All subjects will undergo pre-treatment with a topical anesthetic (to improve riboflavin absorption) and riboflavin 0.1% for 60 minutes or more. During UV light application, patients will receive one of two treatments – administration of riboflavin every 1 minute with UV light or administration of riboflavin every 2 minutes with UV light. The primary goal is to evaluate efficacy of the two transepithelial procedures. The second goal is to determine if there is equivalency between groups. Transepithelial crosslinking, in which the epithelium is not removed, has been proposed to offer a number of advantages over traditional crosslinking including an increased safety profile by reducing the risk of infection as no epithelial barrier will be broken, faster visual recover, and improved patient comfort in the early postoperative healing period since re-epithelialization is not required.


Dr. Hersh and the CLEI Center for Keratoconus are currently enrolling patients in a clinical study looking at the use of combined Intacs and corneal collagen crosslinking (CXL) in patients with either keratoconus or corneal ectasia after previous refractive surgery. The clinical trials will evaluate the benefits and safety of a combined Intacs and CXL procedure. The second objective of the study is to compare timing of the 2 interventions on clinical outcomes.

For further information and inquiries, call 201-883-0505 or email

For further qualifications and information, please click below:




Dr. Hersh and the CLEI Center for Keratoconus are currently enrolling patients in a clinical trial of corneal collagen crosslinking (CXL) for keratoconus and corneal ectasia after previous refractive surgery. The objective of this study is to investigate any difference between 2 riboflavin reparations during UV administration. The first preparation contains riboflavin in a dextran solution, which may tend to draw water out of the cornea and keep it thinner. The second preparation contains riboflavin in a hypotonic (low salt) solution without dextran, which may tend to keep the cornea more swollen. The primary goal of the study is to see if the use of hypotonic riboflavin (rather than riboflavin with dextran) better maintains consistent corneal thickness during UV administration. The second goal of the study is to determine if better maintenance of corneal thickness potentially could have benefits of better consistency of the procedure, decrease in corneal haze formation, and improved safety of the endothelial cells.

For further information about the trial call 201-883-0505 or email

For further qualifications, please click below:



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Thank you so much Doc! When I first came to you I was 20/50 now I'm 20/10. I'm ready to have a great year!

Randy Foye
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My experience at The Cornea and Laser Eye Institute has been amazing. All of the staff have been helpful and courteous...

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Dr. Hersh and his staff were excellent. I was comfortable from the time I walked in until the time I left after the procedure.

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