Bioinspired Multifunctional Hydrogel Microspheres with Lubricating, Anti-Inflammatory, and Piezoelectric Effects for Osteoarthritis Treatment.

Osteoarthritis (OA) is driven by a self-perpetuating cycle of cartilage wear, persistent inflammation, and lubrication dysfunction. Inspired by the natural superlubrication and piezoelectricity of healthy cartilage, we designed injectable hydrogel microspheres (HMBTLCs) that break this vicious cycle through a triple synergistic action of lubrication, anti-inflammation, and pro-regeneration. These microspheres are fabricated via a facile microfluidic strategy, integrating curcumin-loaded liposomes and barium titanate (BaTiO3, BT) nanoparticles within a single platform. The liposomes form a self-renewing boundary lubrication layer on the microsphere surface, achieving an ultralow coefficient of friction of 0.022, and provide sustained release of curcumin for over 28 days to scavenge inflammatory factors, thereby ameliorating the OA microenvironment. Concurrently, the embedded BT nanoparticles convert physiological joint loading into endogenous electrical signals (≈20 mV under 3 N load) to promote chondrogenesis. Critically, transcriptomic analysis reveals a cooperative mechanism: curcumin and piezoelectric stimulation not only synergistically upregulate chondrogenic markers (e.g., ACAN) and downregulate the catabolic enzyme MMP13 through distinct pathways, but also converge on shared anti-inflammatory signaling pathways (e.g., TNF-α, NF-κB, IL-17) to promote macrophage M2 polarization (CD206/CD86 ratio increased by 7.7-fold). By orchestrating these chemical and physical cues, HMBTLCs interrupt the pathological OA cycle under both cellular and animal conditions, reducing the OARSI score by 79.31% in a rat OA model, demonstrating their therapeutic potential for OA while also serving as a model for biomimetic material design.