Kartogenin-encapsulated self-healing injectable hydrogel based on hyaluronic acid and chitosan derivative for use as viscosupplementation in knee osteoarthritis

Abstract

Early osteoarthritis treatment often relies on viscosupplementation via intra-articular injections, which are limited by inflammation risk and poor cartilage restoration. To address these issues, self-healing hydrogels provide a promising alternative because of their ability to recover structure after mechanical stress. This study reports an injectable self-healing hydrogel composed of N-succinyl chitosan (NSC) and hyaluronic dialdehyde (HAD), combined with kartogenin (KGN), synthesized under mild conditions via Schiff base reactions. Successful synthesis and properties were confirmed using H NMR, FT-IR, swelling ratio (1000-2500 %), and rheometry. The hydrogel exhibited strong self-healing even at low cross-link density, influenced by the oxidation degree of HAD. Shear-stimulated KGN release reached 20 % within 1 h, 50 % higher than static conditions, and was sustained for 28 days in phosphate-buffered saline (PBS) and culture medium at 37 °C. The hydrogel degraded gradually, maintaining integrity in PBS and retaining 50 % weight after 21 days in DMEM. KGN-loaded hydrogels were non-toxic and significantly enhanced mouse mesenchymal stem cell differentiation into chondrocytes, increasing Col2a1, Sox9, and Acan expression by 7.5-, 1.5-, and 3-fold, respectively, compared with differentiation medium supplemented with 1 μM KGN solution. These findings demonstrate that NSC-HAD hydrogels are a promising platform for osteoarthritis treatment, integrating injectability, self-healing, controlled drug release, biodegradability, and chondrogenic support.