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Riboflavin delivery methods advance as techniques evolve


Techniques for performing corneal collagen crosslink (CXL) are being evaluated and adapted, and at the same time, new applications are being developed.


Take-home message: Techniques for performing corneal collagen crosslink (CXL) are being evaluated and adapted, and at the same time, new applications are being developed.



By Nancy Groves; Reviewed by George O. Waring IV, MD, FACS

Charleston, SC-The classic paradigm for corneal collagen crosslinking (CXL) is evolving as researchers learn more about the role of oxygen and investigate alternative methods for delivering riboflavin.

The expansion of CXL beyond treatment of keratoconus and into primary refractive correction is also on the horizon, according to George O. Waring IV, MD, FACS.

The standard approach to CXL has been to deliver riboflavin to the corneal stroma and activate it with ultraviolet light, which biomechanically strengthens weak ectatic corneal tissue. Classically riboflavin was delivered into the stroma by removing the corneal epithelium, which acts as a natural barrier, and allowing it to be absorbed by passive imbibition. In passive imbibition, the riboflavin is allowed to diffuse naturally, with the epithelium off or with use of bioenhancers to loosen the epithelial tight junctions.

The relative merits of the epi-on and epi-off techniques have been debated for years, said Dr. Waring, assistant professor of ophthalmology and director of refractive surgery at Medical University of South Carolina Magill Vision Center, Charleston.

Although both are effective, “there is a reasonable amount of data to support that epithelium-off may work better,” Dr. Waring said. “The conventional thinking was always that it works better because we’re getting more riboflavin into the stroma.”

However, recent work in Dr. Waring’s lab and elsewhere suggests that the picture is more complex and that oxygen also plays a significant role in CXL. Dr. Waring explained that the oxygen is used fairly quickly in the crosslinking process, and once the levels are sufficiently depleted, the crosslinking effect is also reduced.

“It’s possible that by leaving the epithelium on we’re not so much blocking the riboflavin but limiting the oxygen diffusion. So the thinking has changed a little bit,” he said. “It may be as or more important that the epithelium is a barrier to oxygen, and that may be why we’re seeing a better effect with the epithelium off.”

Nonetheless, both the epithelium-on and epithelium-off techniques have advantages and disadvantages, Dr. Waring said.


“Epi-off may work better, as data suggests,” he said,  “but we feel that epi-on can also work, although perhaps not as well, but we can avoid the rare but potential side effects associated with epithelium removal such as prolonged surgical time, risk of infection, sterile infiltrates, prolonged healing time, and discomfort during healing. We’re trying to figure out how we can get the benefits of both.”

Altering classic CXL paradigm

The quest for improved CXL techniques has included development of active imbibition methods, such as iontophoresis, to accelerate riboflavin delivery, Dr. Waring said.

“Riboflavin can be turned into a prodrug form and have a charge delivered to it, then you can drive it through the epithelium actively,” he said. “You’re leaving the epithelium in place, but you're still getting the drug through.”

Preclinical studies performed by Sooft Italia several years ago demonstrated that the company’s device and method for corneal delivery of riboflavin by iontophoresis were effective, and early clinical use has begun.

Other developments also are likely to alter the classic CXL paradigm.

“More and more we’re realizing the potential of corneal crosslinking,” Dr. Waring said. “We may be able to use it for more advanced topographic-guided treatments, which may give us better effectiveness.”

As one example, William (B.J.) Dupps, MD, has tested crosslinking just the cone of a select area of the ectatic cornea, treating only the weakened area to achieve compensatory regularization of the corneal curvature.

Selective topographic-guided crosslinking potentially opens the way for refractive treatments in normal eyes for low amounts of myopia, hyperopia, or astigmatism. This work is being done by Avedro, which has introduced a photorefractive intrastromal crosslinking procedure (PiXL) and technology (not for sale in the United States).

“A number of patients have been treated outside the U.S. with promising results,” Dr. Waring said.

“If we put all this together, there might be a role for combined LASIK and crosslinking for some of our borderline candidates, for limited crosslinking or for hyperopic treatments that have a higher chance of regression,” he continued.


Dr. Waring was co-author with Tomita et al. of a study of simultaneous LASIK and CXL in patients with bilateral myopia. (J Cataract Refract Surg. 2014;40:981-990.)

“We found safety and stability in the refractive outcomes in a large group of patients,” he said.

“We’re still learning about the mechanisms of corneal crosslinking-they’re much more complex than we originally thought-and how to optimize treatment,” Dr. Waring said. “The focus is really going to be on the role of oxygen in the future, but there’s widespread potential application for this technology.”



George O. Waring IV, MD, FACS

P: 843/792-1414

E: georgewaring@me.com

This article was adapted from Dr. Waring’s presentation during the 2015 meeting of the American Society of Cataract and Refractive Surgery. Dr. Waring serves as an investigator and member of the scientific advisory board for Avedro Inc.






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