Updates on Corneal Collagen Cross-Linking for Keratoconus: A 10-Year Review of Techniques, Clinical Outcomes, and Future Directions.

AIM: To synthesize major advances in corneal collagen cross-linking (CXL) for keratoconus over the past decade (2015-2025), with emphasis on protocol evolution, comparative effectiveness (epithelium-off vs. epithelium-on; conventional vs. accelerated), pediatric outcomes, repeat and customized approaches, adjunctive therapies, biomechanical assessment, safety, and emerging strategies, including oxygen supplementation and topography-guided CXL.

DESIGN: Structured narrative review.

MATERIALS AND METHODS: A systematic literature survey of randomized controlled trials, prospective cohort studies, registry analyses (including the Save Sight Keratoconus Registry), meta-analyses, and long-term follow-up studies published between 2015 and early 2025 was conducted. Extracted outcomes included maximum keratometry (Kmax), mean keratometry (Kmean), corrected distance visual acuity (CDVA), corneal thickness, progression and re-treatment rates, and complication profiles across protocols (standard epithelium-off, accelerated, transepithelial/epithelium-on, repeat CXL, and combination procedures).

RESULTS: Long-term evidence supports standard epithelium-off (Dresden) CXL as the reference protocol for biomechanical stabilization, with durable arrest of progression in most treated eyes and sustained improvements in corneal shape and CDVA through 5-10 years in several large cohorts. Accelerated protocols provide comparable short-term stabilization and reduce operative time, but may show shallower demarcation lines and less consistent long-term flattening in some series, particularly when pulsed delivery or oxygen enhancement is not used. Transepithelial (epithelium-on) techniques reduce postoperative pain and epithelial complications but, in meta-analyses, generally yield less keratometric flattening than epithelium-off CXL; newer riboflavin formulations, iontophoresis, oxygen supplementation, and pulsed UVA delivery have narrowed this efficacy gap. Pediatric keratoconus benefits from early CXL but has higher rates of late progression and retreatment than adult cohorts. Combined strategies (intracorneal ring segments and/or topography-guided surface ablation with CXL) can improve optical quality in selected eyes with adequate stromal reserve. PACK-CXL remains investigational as an adjunctive therapy for infectious keratitis. Overall complication rates are low; transient haze is the most common complication, and serious adverse events are rare when pachymetric safety thresholds are respected.

DISCUSSIONS: Over the past decade, CXL has evolved from a single Dresden protocol to a spectrum of approaches that balance efficacy, safety, comfort, and practicality. Long-term cohort evidence continues to support epithelium-off Dresden CXL as the reference standard for robust biomechanical stabilization.

CONCLUSIONS: CXL has evolved from a single protocol into a versatile therapeutic platform. The Dresden epithelium-off technique remains the efficacy benchmark for robust biomechanical reinforcement, while optimized accelerated and epithelium-on approaches expand treatment options. Key future directions include oxygen-enhanced photochemistry, personalized/topography-guided CXL, and integration of biomechanical imaging into patient-specific planning and long-term monitoring.