Since its introduction as a treatment for progressive keratoconus, corneal cross-linking (CXL) has undergone sustained scientific refinement – a “corneal cross-linking evolution”. A three-part EuroTimes series published in January/February 2025 traces this evolution, with particular focus on how advances in protocol design have expanded CXL from a stabilising intervention to a tool for biomechanical and visual rehabilitation.
Authored by Farhad Hafezi, Mark Hillen, and Emilio Torres-Netto, the series examines the scientific rationale behind successive generations of CXL techniques. A central theme is the role of the corneal epithelium. While epithelium-on approaches were long pursued to improve patient comfort, the authors outline how intact epithelium limits both oxygen diffusion and ultraviolet fluence, reducing cross-linking efficacy compared with the standard epithelium-off Dresden protocol.
The series then moves beyond conventional dichotomies to discuss customised and combination approaches. In ectatic corneas, modest and variable corneal flattening following standard CXL can still provide meaningful biomechanical benefit. However, targeted delivery of higher fluence to the steepest or thinnest regions has enabled more predictable cone flattening. First-generation topography-guided CXL demonstrated the feasibility of this concept, while second-generation approaches—most notably PTK-assisted customised epi-on CXL (PACE)—introduced controlled epithelial removal to create riboflavin and oxygen gradients over the cone. Early clinical data show substantially greater flattening and reduction in corneal asymmetry, supporting a shift from pure disease stabilisation toward partial visual rehabilitation.
The EuroTimes articles also address combination strategies. When corneal stability has been achieved, subsequent procedures such as PTK, PRK, or intracorneal ring segment implantation can further improve corneal regularity. Importantly, long-term follow-up data cited in the series suggest no routine benefit of prophylactic CXL in otherwise normal corneas undergoing laser refractive surgery, reinforcing the need for careful patient selection.
Beyond ectasia, the series highlights the expanding role of CXL in infectious keratitis through PACK-CXL. By exploiting the pathogen-inactivating properties of photoactivated chromophores, CXL has demonstrated efficacy comparable to antimicrobial therapy in selected cases, with particular relevance where access to prolonged medical treatment is limited.
Taken together, the EuroTimes series illustrates how CXL has matured into a platform technology. Ongoing optimisation, protocol personalisation, and exploration of emerging concepts such as two-photon CXL suggest that its clinical applications will continue to broaden—provided development remains anchored in physiological understanding and long-term evidence.
