A Tear Film-Inspired Biomimetic Strategy with Enhanced Lubrication, Anchoring, and Antioxidative Properties for Dry Eye Disease.

Abstract

Dry eye disease (DED) is a multifactorial ocular surface disorder driven by tear film instability, excessive evaporation, frictional damage, oxidative stress, and epithelial injury. Current artificial tears mainly replenish aqueous volume and provide lubrication, but they may not adequately reproduce the coordinated interfacial functions of the native tear film that contribute to ocular surface stability. Here, we reported a tear film-inspired biomimetic strategy based on two complementary hyaluronic acid (HA) derivatives for the treatment of DED. HP was engineered by grafting zwitterionic poly(2-methacryloyloxyethyl phosphorylcholine) side chains onto HA to generate a highly hydrated, anti-evaporative, and low friction interface. Whereas HD was constructed by conjugating dopamine to HA to enhance ocular surface anchoring and provide intrinsic antioxidant activity. The integrated HP/HD system exhibited enhanced water retention, favorable shear-thinning behavior, and superior lubrication performance. Transverse relaxation (T₂) NMR analysis further supported the key role of the zwitterionic hydration layer in interfacial lubrication. While quartz crystal microbalance with dissipation monitoring, fluorescence quenching, FTIR, in vitro and in vivo retention studies showed that HD strengthened mucin interaction and prolonged ocular surface residence. In addition, the catechol-containing component endowed the system with effective free radical scavenging capacity and intracellular reactive oxygen species suppression. In a benzalkonium chloride induced guinea pig model of DED, topical administration of HP/HD significantly improved tear secretion, accelerated corneal epithelial repair, promoted goblet cell recovery, and reduced corneal oxidative stress compared with the commercial lubricant control. Collectively, this work establishes a tear film-inspired biomimetic strategy that integrates anti-evaporation, hydration lubrication, surface anchoring, and antioxidation within a system, offering a promising material approach for DED therapy. STATEMENT OF SIGNIFICANCE: Dry eye disease (DED) causes severe discomfort and surface damage. Current treatments for DED primarily rely on transient aqueous supplementation, which inherently fails to reconstruct the hierarchical architecture of the native tear film and suffers from rapid precorneal clearance. To overcome this fundamental limitation, we proposed a tear film inspired Biomimetic Strategy. By integrating zwitterionic hydration lubrication (via PMPC-grafted hyaluronic acid) with catechol-mediated mucoadhesion and active antioxidant defense, our system synergistically reconstructs the physiological "mucin-aqueous-lipid" interface. Functionally, this system integrates functions such as anti-evaporation, moisturizing lubrication, surface anchoring and antioxidant protection, effectively breaking the vicious cycle of DED self-reinforcement. This work provides a physiologically informed biomaterial strategy that shifts the paradigm of DED management from passive moisture supplementation to Overall tear film reconstruction.