Synergistic enhancement of chitosan/hyaluronate hydrogels via pH- triggered phase separation and Lysine crosslinking for potential biomedical applications

Non-covalent chitosan/sodium hyaluronate (CS/HA) hydrogels hold significant promise for biomedical applications due to their biocompatibility and tunable properties, yet their utility is often limited by poor mechanical strength and excessive swelling. This study proposed a synergistic multi-parameter optimization strategy to enhance these properties through matrix ratio tuning (30–60% HA), NaOH immersion (0.1–1.3 M), and Lysine (Lys) crosslinking (20%). Peak tensile strength (1.5 MPa) and strain (110%) were achieved at 30% HA, while 40% HA optimized Young’s modulus (0.77 MPa). NaOH immersion induced deprotonation-driven network densification, yielding a 4.28-fold increase in tensile stress (3.7 MPa) and 66.4% reduction in swelling. Lys crosslinking enhanced toughness by 220.8% (0.77 MJ/m³) via ε-amino/carboxyl dynamic bonds. Structural analyses revealed that NaOH and Lys transformed the hydrogel into a lamellar porous network with reduced pore size through deprotonation, deacetylation, and bridge crosslinking. The optimized hydrogel demonstrated controllable degradation (18.5% in 6 days) and high cytocompatibility (> 75% cell viability), exhibiting the potential for load-bearing scaffolds and sustained drug delivery. This work provides a universal framework for engineering robust non-covalent hydrogels, addressing critical biomechanical challenges in biomedical applications.