Corneal cross-linking (CXL) is a technique that combines UV light (UV-A) and riboflavin (vitamin B2) to create a photochemical reaction in the main structural layer of the cornea, the stroma. This reaction results in the creation of chemical cross-links between molecules in the stroma, binding them together, and mechanically stiffening and strengthening the cornea.
The effect of CXL is almost immediate and leads to a mechanical stiffening of the cornea – by about 450 percent. The effect is detectable just hours after CXL. The success rate of CXL, according to the medical literature, is well over 90 percent.
After several years of basic research in Dresden, Germany, CXL was first used in patients’ eyes in 1999. The procedure they developed, called the “Dresden protocol,” involved the removal of epithelial cells at the surface of the cornea, in order to let riboflavin penetrate into the stroma underneath. This made the Dresden protocol an epithelium-off, or “epi-off” protocol.
By 2004, CXL was ready for the clinic. Prof. Farhad Hafezi, MD, PhD, FARVO, was part of the Zurich team that developed the first UV irradiation lamp, also known as a “cross-linking device”.
Since then, CXL has become the worldwide gold standard for the treatment of keratoconus and other corneal ectasias, with an estimated 200,000 treatments being performed each year.
CXL’s safety has been demonstrated time and time again in many studies. Currently (as of May 2025), more than 3,000 peer-reviewed scientific articles can be found in the medical database, and our group has contributed over 160 of them. This represents about 5 percent of the world’s scientific literature on CXL alone.
The biggest concern when CXL was being developed was protecting the endothelial cells at the base of the cornea. These function to nourish the rest of the cornea and keep it transparent. Unlike epithelial cells at the top of the cornea, once damaged or killed, these cells do not grow back.
CXL involves the use of ultraviolet light, but it also involves a chemical that absorbs UV light and acts as a shield to the tissue below it: riboflavin. Riboflavin is consumed during UV irradiation from the top-down, and when the Dresden protocol was being developed, it was calculated that, to protect corneal endothelial cells from UV-caused damage, an effective safety margin would be 70 µm of uncross-linked, riboflavin-soaked cornea at the base of the stroma.
As the Dresden protocol effectively cross-links the top 330 µm of the cornea (from the top, down), this meant that the minimum corneal thickness before irradiation was limited to 400 µm.
While the biomechanical stiffening of the cornea is the primary and most well-known effect of CXL, the procedure has several other clinically important benefits:
UV-A activated riboflavin generates “reactive oxygen species” (ROS) that can destroy bacteria, fungi, and several other microorganisms. This antimicrobial effect is the basis for the use of CXL in infectious keratitis treatment (PACK-CXL [link to PACK-CXL page]), offering a promising adjunct or alternative to antibiotics and helping combat antimicrobial resistance.
Pathogens produce enzymes to digest tissue in the organisms they infect, as what’s produced by these enzymes acts as their food source. The stroma is composed mostly of collagen molecules, and so during infections of the cornea (“infectious keratitis”), it’s typically pathogen-produced collagenases that digest the cornea. This manifests as corneal ulcers, which when eventually healed, result in corneal scarring.
However, when PACK-CXL is performed and binds these molecules together, it not only strengthens the cornea, but it also hides a proportion of binding sites for these proteases. In biochemistry, this process is called “steric hindrance”, and in practice, this means it’s harder for pathogens to digest the cornea, and it should slow down the formation and reduce the size of any corneal ulcers (and the ultimate scar size). All this is in addition to the procedure’s pathogen-killing properties.
The final beneficial side-effect of the corneal strengthening that CXL achieves is that it can reduce corneal edema, helping the cornea to maintain its shape and clarity, and ultimately, patients’ visual acuity.
Cross-Linking (CXL)
Cross-Linking (CXL)
Cross-Linking (CXL)
As you will read below, CXL for keratoconus and other corneal ectasias has also evolved since the first days of the Dresden protocol. The treating ophthalmologist not only needs to be familiar with all these new techniques but also needs to assess which technique is scientifically sound enough to be used on a case-by-case basis.
Here are the CXL-for-ectasia treatment approaches available today:
The epithelium is removed to allow riboflavin to penetrate fully before UV-A irradiation. This is suitable for patients with progressive keratoconus or ectasia and sufficient corneal thickness (≥400 µm). It is considered the gold standard with the most extensive long-term data supporting its efficacy, however, this procedure may cause some discomfort and requires a longer healing period as the epithelial cells regrow and recover the cornea. It’s also slow. To deliver the dose (or “fluence” of UV energy required, 5.4 J/cm², it requires 30 minutes of UV light being delivered at an intensity of 3 mW/cm².
Today, this procedure has been reserved for patients requiring the absolute maximum cross-linking effect, such as children with particularly aggressive forms of the disease.
Uses higher intensity UV-A over a shorter time to reduce procedure duration, although the more the procedure is accelerated, the less effective it becomes. However, the trade-off in efficacy is relatively minor, when, for example, the Dresden protocol’s 5.4 J/cm² UV energy is delivered at 9 mW/cm² for 10 minutes in an epi-off manner.
This has led to this accelerated CXL protocol becoming the default treatment option for many ophthalmologists performing CXL today, unless there is a good reason not to.
The epithelium layer of the cornea consists of epithelial cells that are tightly bound together with “tight junctions,” and this forms a very effective barrier from the outside world from entering the eye any further. This also includes riboflavin. Epithelium-on (epi-on) CXL, therefore, requires an extra step to have the riboflavin pass through and into the stroma.
One approach is to use penetration enhancers, which temporarily degrade the tight junctions binding the epithelial cells together, enabling riboflavin to pass through the gaps. The alternative approach is to use ionotophoresis, which involves using a special apparatus that applies an electrical charge to the riboflavin to electrostatically pass through the epithelium and into the stroma. This requires a riboflavin-filled chamber to be placed above the cornea, with one electrode, and another electrode attached to your head elsewhere to complete the circuit.
Both methods are less invasive than epi-off CXL and have faster recovery times
This method is less invasive and better suited for patients with thinner corneas or ocular surface disease. It typically has faster recovery but may provide less biomechanical stiffening than epi-off – but ELZA has been working on eliminating this effectiveness gap… [link to epi-on vs epi-off page]
ELZA-PACE is a second-generation customized CXL protocol that is aimed at delivering a strong flattening effect on the cornea, in order to rehabilitate the vision of people with keratoconus and other related corneal ectasias. ELZA-PACE involves the SCHWIND AMARIS excimer laser to selectively remove epithelial cells over the cone based on epithelial cell maps from the CSO MS-39. The AMARIS performs this with such precision that absolutely no stromal tissue is removed, meaning that the cornea retains all of its structural integrity. This also creates a partial epi-on and epi-off cross-linking procedure, and the difference in cross-linking effect between the two regions is what underpins this impressive corneal flattening effect.
The ELZA-sub400 protocol is the most modern method of performing CXL in thin corneas. Older thin cornea protocols (like swelling the cornea with hypoosmolar riboflavin, or using a riboflavin-soaked contact lens to bulk the cornea) came with drawbacks such as, respectively, unpredictable swelling responses, or significantly worse cross-linking efficacy. The ELZA-sub400 protocol is the result of years of work modelling the CXL reaction between corneal tissue, riboflavin, UV light, and oxygen, and enables surgeons to safely perform CXL in corneas as thin as ~200 µm while retaining the ~70 µm uncross-linked safety margin at the base of the stroma to protect the endothelium. Its principle is simple: each cornea is measured at its thinnest point just before UV irradiation, and the customized UV fluence is calculated to achieve the desired cross-linking depth. In practice, this is simple: all that needs to be adjusted is the duration of irradiation.
At ELZA, every patient receives a detailed assessment including corneal imaging with advanced corneal biometers, such as the Pentacam and the MS-39, as well as a comprehensive biomechanical evaluation with the CorVis ST.
This information guides our experts in recommending the safest and most effective CXL protocol tailored to the patient’s unique condition and needs. Our goal is to maximize treatment benefit and minimize risks, and this detailed imaging and corneal assessments enables us to achieve that.
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