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In the standard corneal collagen crosslinking procedure for keratoconus, the surface epithelial cells are first removed.  The epithelial cells are similar to the tiles on a floor.  We remove the cells in order to allow better penetration of the riboflavin drops into the cornea.  This is followed by exposure to ultraviolet light which interacts with the riboflavin in the cornea to produce the crosslinking reaction occurs.  Some people refer to this as an epi-off procedure.  This technique is the only FDA-approved method of CXL in the U.S. today.   

In the trans-epithelial crosslinking procedure, or the epi-on technique, the treatment is similar;  however, we do not remove the surface epithelial cells.  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.   

There are some disadvantages also to the trans-epithelial technique.  Most of these relate to its relative efficacy 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.  There are methods to achieve good riboflavin saturation with the epithelium intact and new riboflavin formulations which are being studied, however. 

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 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 as with other techniques. 

4)      Although there does appear to be less transient corneal haze formation with the epi-on technique, it’s not yet clear whether this haze is an unwanted side effect of crosslinking or really represents the crosslinking effect as can be seen when we look at the cornea with the microscope. 

Here at the CLEI Center for Keratoconus, we have been studying trans-epithelial crosslinking in a formal clinical trial.  We have looked at 82 treatments thus far over the course of the year.  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.  It can’t be directly compared to the result that we have with standard crosslinking techniques because of study designs, but it does appear that, although effective, the results may be less robust using the epi-on approach.

Remember, 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, this will remain a question until further clinical trial results become available. 


We are pleased to announce a new clinical trial of transepithelial corneal collagen crosslinking (CXL) for keratoconus and corneal ectasia after previous refractive surgery. This study compares two variants of transepithelial crosslinking, otherwise know as “epi-on” crosslinking. All subjects will undergo pre-treatment with a topical anesthetic (to improve riboflavin absorption) and riboflavin 0.1% for 60 minutes. During UV irradiation, subjects will be randomized to 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.

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