Tranexamic Acid-Associated Hyaluronic Acid Exhibits Enhanced Oxidative Stability: A Comparative Rheological Study

Background: The clinical performance of intra-articular hyaluronic acid (HA) is strongly dependent on its resistance to oxidative degradation within the inflamed osteoarthritic joint. Reactive oxygen species induce HA chain scission, leading to a loss of molecular entanglement and a shift from elastic-dominant to viscous-dominant behavior. Tranexamic acid (TXA), a lysine analogue with documented anti-inflammatory and anti-proteolytic properties, has been combined with HA with the hypothesis that it may limit oxidative-induced rheological degradation. Objective: This study aims to determine whether an HA-TXA formulation preserves viscoelastic integrity under oxidative stress and how its behavior compares with linear, hybrid, and cross-linked HA viscosupplements. Methods: Four HA-based formulations were evaluated using stress-controlled rotational rheometry compliant with ISO 3219 standards. Complex modulus (G*), complex viscosity (η*), and phase angle (tan δ) were measured within the linear viscoelastic domain. Oxidative challenge was induced with hydrogen peroxide (5.4% v/v), and time-dependent rheological changes were recorded over 30 min. Resistance to degradation was defined by relative variations in rheological parameters from baseline. Results: Baseline measurements revealed distinct viscoelastic profiles among the HA formulations. After oxidative exposure, the HA-TXA formulation showed a modest decrease in η* (-17.0%) and limited increase in tan δ (+4.0%), indicating preserved viscoelastic organization. Its stability exceeded that of hybrid (-40%; +12.6%) and linear HA (-53%; +25.6%) and approached that of cross-linked HA (-25.4%; +5.6%). The magnitude of microstructural alteration remained minimal despite chemical stress. Conclusions: The association of TXA with HA confers a marked protection against oxidative-induced viscoelastic degradation, preserving macromolecular network integrity and elastic behavior. These findings suggest that TXA modulates oxidative stress-related rheological failure of HA through mechanisms distinct from chemical cross-linking.