Cutting-edge cross-linking biomaterials advancing ophthalmic therapeutics

Corneal cross-linking (CXL) has emerged as an important therapeutic strategy for enhancing the biomechanical stability of corneal tissues. Originally introduced to slow or halt the progression of keratoconus (KC), its indications have expanded to include a variety of corneal ectatic and infectious disorders, alongside a growing interest in scleral reinforcement for progressive myopia. Recent advances in cross-linking technologies focused on optimizing reagent formulations, refining delivery strategies, and incorporating functional biomaterials such as nanoparticles, hydrogels, and microneedle-based systems to enhance stromal penetration, achieve controlled release, and reduce procedural invasiveness. Despite these developments, key challenges remain, particularly in achieving consistent treatment depth, maintaining long-term biosafety, and ensuring stable clinical outcomes. This review summarizes the mechanisms of action and classification of contemporary ophthalmic cross-linking methods and agents, evaluating their clinical and experimental outcomes in corneal and scleral cross-linking while weighing their respective strengths and limitations. Furthermore, this review identifies key constraints of current protocols and highlights emerging strategies aimed at improving treatment precision, safety, and reproducibility, thereby providing a conceptual framework for the development of next-generation ophthalmic cross-linking therapies.