Democratizing Corneal Cross-Linking to Transform Global Eye Care

Making medical devices portable and affordable opens up access to the world

Prof. Farhad Hafezi MD, PhD, FARVO, and Dr. Emilio Torres-Netto, MD, PhD, FWCRS, from the ELZA Institute in Zurich (www.elza-institute.com), spoke about how the change from sophisticated hospital-based medical equipment into more accessible, cost-effective portable devices are about to significantly change how certain eye diseases in low-to-middle income countries (LMICs) are treated.

Prof. Hafezi: “Traditionally, disorders such as keratoconus and infectious required treatment in a hospital. Keratoconus is the leading cause of preventable blindness among children and adolescents worldwide. What happens in keratoconus is that the cornea becomes increasingly weaker. Because the eye is pressurized, the weakened part starts to bulge outward into a cone shape. As the cone grows, people’s vision gets worse. Historically, the only treatment was a corneal transplant, but for the last 20 years, we’ve been able to strengthen the cornea and stop the disease from progressing using a treatment called corneal cross-linking” (CXL) [1] – and CXL has dramatically reduced the number of corneal transplant surgeries required to treat keratoconus [2].

Dr. Torres-Netto: “The problem is that until relatively recently, CXL has mostly been performed in operating theaters inside hospitals. Operating theaters need to be completely sterile, staffed, and booked weeks in advance, as surgeons compete for theater space. This makes the procedure very expensive. Often the problem is that in LMICs, most of the population lives in rural regions, whereas the hospitals are concentrated in one or two cities. In LMICs, it’s not only the cost of the procedure in the hospital that can be prohibitive, it’s also the cost of the time and travel to the hospital that stops people from receiving the procedure. In extreme cases, many cities or villages don’t even have hospitals or surgical centers, and it can often take days to get there [3]. I’ve had this experience several times traveling through riverside towns in the middle of the Amazon rainforest.”

Dr. Hillen: “How do you see us tackling the challenges of training healthcare workers and ensuring safe, high-quality CXL treatments with these portable devices, especially in remote areas of LMICs?

Prof. Hafezi: “If you think about the process, CXL was being performed with the patient lying on their back in the operating theater. In a CXL procedure, we first apply riboflavin to the cornea, then we would plug in the cross-linking device, wheel it across the room, and then use it to deliver the UV light to the patient’s cornea from above and perform the cross-linking which strengthens the cornea and treats the patient’s keratoconus.”

Dr. Torres-Netto: “We know that CXL doesn’t just strengthen the cornea – it also kills pathogens that might be there too – so much so that we also use CXL to treat corneal infections in a process called ‘photoactivated chromophore for keratitis-corneal cross-linking’ or PACK-CXL [1, 4]. If CXL sterilizes the cornea, and the patient receives antibiotic drugs and a bandage contact lens immediately at the end of the procedure, then the environment where CXL is performed suddenly doesn’t need to be an operating theater. It could be a doctor’s office or even a tent in a field.

The UV light delivered during cross-linking does not care whether it is being delivered from above with the patient lying down or sitting upright at the slit lamp. We’ve done the work to show that the riboflavin in the eye does not settle downwards when the patient is sat upright either. We’ve recently shown that CXL at the slit lamp is as effective and as safe as CXL performed in the OR [3].

Prof. Hafezi: “Indeed, we developed a portable, yet sophisticated cross-linking device that is the size of a torch, powered by batteries, and charged over USB-C. As the cross-linking device needs to be at a certain distance from the cornea, we decided to develop it so that it could be used at the slit lamp – which is ubiquitous in eye care. If a doctor or an optometrist wants to examine your eye, they’ll likely start with a slit lamp exam. But even then, our device can be attached to a portable stand and adjusted to the correct distance using a little prism device, so you don’t even need the slit lamp to perform cross-linking ‘in the field’. All this means is that you can take a cross-linking device in a backpack, and perform CXL wherever it is needed, bringing it to the people, rather than requiring the people to come to the cross-linking device, in the operating theater, in the hospital, in the city.”

Dr. Torres-Netto: “This is also a big deal with corneal infections. We refer to them as infectious keratitis (IK), and IK blinds hundreds of thousands of people worldwide each year, mostly in LMICs [1, 4]. There, the IK mostly is caused by agricultural injuries that introduce pathogens to the cornea. The traditional treatment involves an intensive regimen of antimicrobial drugs – think hourly application of several eye drops. This requires the patient to be hospitalized, and this also requires drugs that need to be refrigerated – and just like with CXL for keratoconus, the travel, the doctor costs, and the costs of the drugs are substantial.

These barriers frequently prevent follow-up care – patients often don’t turn up to follow-up visits because they simply can’t afford to, and this leads to even more preventable blindness. However PACK-CXL – in around 80% of cases – can treat the IK in a single session reduces costs and also the risk of blindness due to non-compliance with follow-up visits.”

Prof. Hafezi: “So this movement away from CXL in a hospital setting to wherever there is a slit lamp essentially ‘democratizes’ access to this critical treatment, and it truly has the potential to help so many people in LMICs, where previously the cost and access to treatment barriers were too high for most people who needed this form of treatment. Finally, we’re also trying to repeat this process, but for screening eyes for keratoconus.

Again, all of the sophisticated devices that can detect the disease developing in the cornea – known as keratographers – are large, expensive, and located in hospitals. We’re working on introducing a smartphone-based keratographer that can be used wherever a smartphone can be used. As CXL only stops the disease from progressing, whatever vision is lost before that point remains lost, so earlier screening and treatment with CXL means people will have better vision for the rest of their lives compared with CXL detected and treated later [1].

In an ideal world, everyone should have access to this form of screening and treatment, no matter where they live and how much money they have. By going portable with these devices, we’re moving the field in the right direction to achieve that.

Dr. Hillen: “Switching gears a bit, I know about another intriguing project you’re involved in, Emilio. It involves using sunlight for corneal cross-linking. Can you tell us more about that?”

Dr. Torres-Netto: “We really wanted to find a simpler way to help people with keratoconus, especially where getting to a hospital isn’t easy. So, we thought, why not see if sunlight, something everyone has access to, could work with oral riboflavin for cross-linking? Dr. John Jarstadt at the University of South Florida published three cases of people with corneal ectasias that took high dose riboflavin – up to 1.5 grams a day – and simply  spent 15 minutes daily outdoors without wearing sunglasses, exposing their eyes to natural sunlight” [5].

Dr. Hillen: “Could you walk us through the design and execution of this study?”

Dr. Torres-Netto: “Certainly. Thanks to support from the Velux Stiftung, were were able to perform this study. We utilized sixteen New Zealand White rabbits, dividing them into two groups. The treatment group received oral riboflavin and was exposed to sunlight, aiming for a cumulative light dosage reflective of therapeutic levels. The control group underwent sunlight exposure without riboflavin. Our goal was to assess the biomechanical changes in the cornea through this non-invasive method.”

Dr. Hillen: “And what were the results?”

Dr. Torres-Netto: “Interestingly, Mark, our findings didn’t show a significant increase in corneal stiffness in the treated group compared to controls. On the contrary, we observed an unexpected potential softening effect in the posterior cornea of the treated animals, highlighted by OCT elastography.”

Dr. Hillen: “How do these results shape our understanding of sunlight and oral riboflavin’s role in corneal cross-linking?”

Dr. Torres-Netto: “The outcomes suggest that this method – oral riboflavin administration and natural sunlight exposure – as conducted, may not be a viable standalone treatment for keratoconus. The lack of significant corneal stiffening and the observed softening effect raises critical questions about the effectiveness of sunlight-induced cross-linking under these specific conditions. It probably has to do with the extremely low concentration of riboflavin that can be reached in the corneal stroma after oral administration. If it were possible to improve the bioavailability of riboflavin in the cornea after oral ingestion, this would have great potential.”

Dr. Hillen: “Given these results, where do you see the future direction of research or clinical application heading?”

Dr. Torres-Netto: “The study underscores the need for further investigation into the mechanisms of corneal cross-linking, especially with non-traditional activation sources like sunlight. Future research should explore optimized riboflavin delivery methods and controlled light exposure parameters to potentially enhance treatment outcomes. It’s a reminder of the complexities involved in developing new, accessible treatments for eye conditions like keratoconus.”

Dr. Hillen: “Emilio, Farhad, thank you for sharing your findings and insights into making keratoconus treatment more accessible and cost-effective – especially in low-to-middle-income countries.”

Dr. Mark Hillen is the Director of Communications at the ELZA Institute, Zurich, and is an active member of the ELZA research team. He is ranked by Expertscape as the #5 highest-impact author in the field of corneal cross-linking and was the Chief Editor of The Ophthalmologist and currently also serves as an Editor-at-Large of the Media Mice eyecare range of publications.