A kneading-responsive hyaluronic acid-based hydrogel for on-demand local anesthesia in osteoarthritis

An intelligent hydrogel system that can rapidly release local anesthetics in response to simple mechanical kneading offers a patient-friendly solution for managing osteoarthritis (OA) pain during acute flare-ups. Conventional stimuli-responsive hydrogels often require specialized devices (e.g., near-infrared emitters and ultrasound generators), limiting their accessibility in real-world settings. A kneading-responsive hydrogel composed of oxidized hyaluronic acid (OHA) and carboxymethyl chitosan, incorporating pressure-sensitive multivesicular liposomes (pMVLs) loaded with phosphoric acid and benzocaine covalently linked to OHA, was developed in this study. Mechanical kneading (0.25 ± 0.03 kg/cm²) ruptured the pMVLs, releasing acid to lower the gel pH from 7.4 to 6.7, thereby cleaving Schiff base bonds and accelerating benzocaine release by 2.26-fold in vitro. In OA-rat models, periarticular injection of the hydrogel significantly increased pain thresholds, and kneading raised benzocaine accumulation in the synovial fluid by 3.88-fold, improving locomotor activity and joint function. The release was gated by a predefined pressure threshold: the hydrogel remained quiescent under physiological interstitial pressures but was activated by conscious kneading (0.25 ± 0.03 kg/cm²), allowing for patient-controlled, on-demand analgesia. This kneading-responsive hydrogel enables self-controlled, on-demand analgesia without the need for specialized equipment, providing a convenient strategy for precision pain management in OA. STATEMENT OF SIGNIFICANCE: Many pain-relief options rely on clinic devices or fixed depots that patients cannot control. We report an equipment-free, kneading-responsive hyaluronic-acid hydrogel that converts gentle finger pressure (0.25 kg·cm⁻², measured) into on-demand local anesthesia for osteoarthritis flares. The reservoir combines a pH-sensitive OHA/CMS network with pressure-sensitive multivesicular liposomes that release phosphoric acid, transiently lowering the pH to cleave imine (Schiff-base) bonds and accelerate benzocaine release. In OA rats, a single kneading produced ∼48 h of drug elevation, while the depot persisted for up to 14 days; once-daily kneading maintained effective analgesia for up to 6 days, improving pain, mobility, and cartilage preservation. Benchmarking versus NIR/ultrasound highlights the trade-off between remote triggering and simple, patient-directed use. This self-managed platform enables localized, repeat-dosing pain control.