The Science and Clinical Evolution of Corneal Cross-Linking: Mechanism of Action, Ultra-Structural Changes, Clinical Indications, and Emerging Treatment Strategies.

Keratoconus is the most common corneal ectatic disorder worldwide. Typically manifesting in adolescence, it imposes a substantial burden on quality of life and, if untreated, may progress to advanced stages requiring corneal transplantation. Riboflavin/UV-A corneal cross-linking (CXL) has become the cornerstone therapy for stabilizing corneal biomechanics and halting disease progression. CXL acts through UV-A photo-activated riboflavin-driven photochemistry that induces covalent cross-links within stromal proteins. Extensive theoretical, experimental, and clinical evidence has clarified its mechanism of action, demonstrating ultrastructural stromal reorganization, resulting in biomechanical stiffening and a sustained long-term effect. Over time, riboflavin ophthalmic formulations for CXL, delivery strategies, and treatment protocols have progressed and expanded beyond the epithelium-off approach to include safer and comparably effective transepithelial techniques. In addition, novel chemical cross-linkers are being investigated as non-light-based alternatives for corneal stabilization. Beyond corneal ectatic disorders, CXL is increasingly being explored for additional clinical indications, including infectious keratitis, bullous keratopathy, and inflammatory dry eye. This systematic review describes the most recent advances in understanding the mechanism of action of CXL and associated ultrastructural changes and synthesizes current evidence on the evolution of treatment protocols and their expanding clinical indications. By critically appraising available data, we aim to guide clinical decision-making and identify priorities toward safer, more effective, and individualized CXL therapies.