Shanghai Fangyu Health Pharmaceutical Technology Co., Ltd.

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.

The nano/micron sized-fluticasone propionate inhalable suspension (FPs) is used for asthma treatment, and this study aimed to elucidate the effects of particle size on the absorption of FPs by various pulmonary cells and the subsequent therapeutic efficacy for asthma. FPs of 727, 1136 and 1612 nm were prepared, and an increase in diameter diminished the endocytosis and macropinocytosis of FPs by alveolar epithelial cells (A549 and Calu-3 cells) but facilitated their uptake by M2-like macrophages; results about the transport across Calu-3 monolayer showed the mucus layer was the main rate-limiting step for the uptake of FPs by epithelial cells; the animal tests showed that although a decrease in diameter improved the pulmonary absorption of FPs, the particle size did not affect the lung distribution of FPs; a further detection revealed that larger FPs were taken more effectively by alveolar macrophages and lymphocytes and exerted a better therapeutic effect on asthma than the smaller ones. This study showed that the particle size of FPs had a significant impact on their absorption, elimination and cellular distribution in the lung after inhalation and further on their effectiveness in asthma treatment, and the particle size of the nano/micron sized-FPs should be designed and optimized for asthma treatment on the premise of meeting the requirements of inhalation preparations.