Hyaluronan in Ocular Surface Health and Disease: From Biological Mechanisms to Therapeutic Applications

ABSTRACT

Hyaluronan (HA) is an ubiquitous non‐sulfated glycosaminoglycan with unique physicochemical and biological properties that underpin its essential roles in tissue homeostasis, repair, and diseases. First identified in the vitreous humor of the eye, HA has a long‐standing history in ophthalmology as a key component of ophthalmic visco‐surgical devices and topical formulations. However, beyond its well‐established biophysical functions as a highly hydrated, viscoelastic, and lubricating polymer, HA is now recognized as a dynamic regulator of cellular behavior through size‐dependent interactions with specific receptors and extracellular matrix components. In this review, we provide a comprehensive overview of HA biology at the ocular surface, spanning its local biosynthesis, turnover, structure, and physicochemical properties to its diverse physiological and pathological roles. We briefly discuss the molecular mechanisms by which size, organization, chemical modifications, and receptors of HA govern its function. We highlight recent advances demonstrating that HA is endogenously synthesized and spatially regulated across ocular surface tissues, including the cornea, limbal stem cell niche, and Meibomian glands, where it governs tissue biomechanics, wound healing, stem cell maintenance, morphogenesis, aging, and inflammation. Finally, we review current and emerging therapeutic applications of HA at the ocular surface, including eye drops, hydrogels, nanoparticles, biomaterials, and drug delivery systems, and address analytical challenges related to HA characterization. Together, this review positions HA as both a fundamental endogenous regulator of ocular surface health and disease, and a versatile therapeutic platform, bridging basic matrix biology with clinical ophthalmology.