Deciphering UVA/Riboflavin Collagen Crosslinking: A Pathway to Improve Biomedical Materials

Abstract Collagen crosslinking employing ultraviolet A rays and riboflavin (UVA/R) has emerged as a pivotal technique in clinical therapies, especially in ophthalmology since the 1990s. Despite its clinical adoption, the lack of clarity of the detailed mechanism and the imperative for a refined manufacturing process necessitates further investigation. This study advances the understanding of UVA/R crosslinked collagen, concentrating on identifying the primary crosslinking sites using seven synthetic peptides and exploring the pathways of riboflavin‐mediated crosslinking. The results demonstrate that tyrosine residues are key crosslinking sites, and riboflavin plays a dual role as both a catalyst and a competitive inhibitor in the crosslinking process. Furthermore, the UVA/R crosslinked collagen matrix exhibits a more harmonious balance between stability and degradability compared with chemically crosslinked collagen matrices, coupled with superior mechanical properties and augmented biocompatibility. In vivo experiments further validate its excellent biocompatibility, reduced tissue inflammation, and promotion of tissue regeneration. The research provides crucial insights into collagen crosslinking mechanisms, paving the way for the development of sophisticated collagen‐based biomaterials tailored for biomedical applications.