Is Epi-On the Way Forward?

Epi-on corneal cross-linking (CXL) may not yet be the gold standard for the treatment of keratoconus, but it is heading in that direction, according to Cosimo Mazzotta MD, PhD.

“Epi-on is still struggling to win trust amongst ophthalmologists around the world, and many of the protocols that are available today are still broadly unfamiliar,” he said.

Epi-off protocols remain the gold standard for keratoconus treatment, a position reinforced by the Second Global Consensus on Keratoconus and Ectatic Diseases of 2026, in which Professor Mazzotta participated as Group 3 coordinator with Prof Michael Belin and Dr Emilio Torres.

The consensus helped define new best practices and a new understanding of keratoconus as a multifactorial disease, while paving the way to a more multimodal diagnostic approach.

At the same time, Prof Mazzotta observed that accelerated epi-off is likely to remain the dominant procedure, although there is still no majority agreement on the optimal protocol.

However, Prof Mazzotta believes recent advances in epi-on protocols could change this balance. The first step, he said, is to rebuild confidence in the technique by making its mechanisms and potential benefits better understood.

One reason for the lack of popularity of epi-on can be traced back to its early development. Original protocols attempted to reproduce epi-off conditions without adequately compensating for the presence of the epithelium. Low oxygen availability, insufficient stromal riboflavin penetration, and inadequate photochemical energy resulted in disappointing outcomes and, in some cases, retreatment.

Translational research paved the way to a different approach, Prof Mazzotta explained. The introduction of Iontophoresis Plus, for example, combined enhanced riboflavin delivery with higher fluence and pulsed light. A study Prof Mazzotta and colleagues conducted, published in the Journal of Refractive Surgery, demonstrated a consistent demarcation line on optical coherence tomography (OCT) at a meaningful stromal depth, Kmax flattening close to epi-off, and stable keratoconus over time.

The findings suggested that epi-on required a different energy balance from epi-off. Higher fluence, pulsed illumination, and active riboflavin delivery appeared to address some of the limitations of the earlier protocols.

These results were a huge step forward, Prof Mazzotta said. Findings demonstrated that the limitations of epi-on were not necessarily intrinsic to the technique but could be addressed by understanding and modifying its underlying photochemical and pharmacokinetic mechanisms. Oxygen then became another important piece of the puzzle. In a prospective clinical study published in the Journal of Cataract and Refractive Surgery, Prof Mazzotta and colleagues evaluated customised transepithelial CXL with supplemental oxygen, reporting clinical and OCT outcomes with an epi-on approach.

Oxygen is not simply an accessory to the treatment but a fundamental component of the photochemical reaction, particularly when the epithelium remains intact.

This research has gained new relevance following the FDA approval of Epioxa (Glaukos) in the United States in October 2025. Epioxa is approved for epithelium-on corneal collagen cross-linking in adults and paediatric patients aged 13 years and older, in conjunction with the O₂n System and Boost Goggles. The treatment combines riboflavin photoenhancers with an oxygen-enriched environment.

For Prof Mazzotta, the development represents an important validation of the scientific rationale behind oxygen-enriched epi-on CXL.

“I am honoured to have been among the pioneers exploring oxygen supplementation in transepithelial cross-linking,” he said. “Our early clinical work helped demonstrate the importance of controlling oxygen availability during the photochemical reaction.”

His more recent work has moved towards high-fluence, pulsed-light epi-on protocols at around 10 joules, using either iontophoresis or new-generation riboflavin formulations. The aim is to narrow the remaining efficacy gap with epi-off while preserving the potential advantages of leaving the epithelium intact.

The challenge now is to make these advances better known among ophthalmologists, explain the mechanisms behind them, and establish which patients may benefit most.

Prof Mazzotta’s involvement in keratoconus extends beyond CXL research. In 2026, he served as president of the third World Keratoconus Congress in Florence. He was also among the authors of the first European Reference Network for Rare Eye Diseases (ERN-EYE) clinical consensus statement on paediatric keratoconus, providing recommendations for diagnosis, monitoring, and management within the European ERN-EYE.

The next frontier may be paediatric treatment. “It’s important to be bold but cautious,” he said. In his clinical practice, Prof Mazzotta already uses epi-on in selected paediatric patients, particularly in the better eye, where a less aggressive approach may be desirable.

Prof Mazzotta believes the transition towards epi-on can ultimately succeed, provided it never comes at the expense of early diagnosis, eliminating eye-rubbing, timely treatment, and safe retreatment when necessary.

“Working together, we can make epi-on the future of corneal cross-linking,” he said. “The goal is not simply to replace epi-off, but to develop a safer, repeatable, and increasingly effective treatment strategy that can be adapted to the patient and to the stage of disease.”

Cosimo Mazzotta MD, PhD, FWCRS is Associate Professor of Ophthalmology at University Kore of Enna, Italy.