Ultrasound-responsive CPS piezoelectric hydrogel synergistically repairs annulus fibrosus defects through immune reprogramming and cell recruitment

As a globally prevalent cause of disability, lumbar disc herniation has structural disruption of the annulus fibrosus (AF) as its pathological core. To address three critical bottlenecks in AF repair-microenvironmental imbalance (excessive inflammation/oxidative stress), inadequate cellular regeneration (low cell density), and mechanical instability-this study developed an ultrasound-responsive piezoelectric hydrogel scaffold (CPS gel) composed of cerium dioxide, poly-L-lactic acid fibers, and sodium alginate. The core mechanisms include: 1) Immune Reprogramming: Ceria nanoparticles exert dual superoxide dismutase/catalase-mimetic catalytic activity to scavenge reactive oxygen species, inhibit the NF-κB signaling pathway, downregulate IKKα/IκBα phosphorylation, and thereby drive macrophage polarization toward the M2 phenotype; 2) Directed Cellular Regeneration: Ultrasound-activated piezoelectric effects from PLLA fibers facilitate cell migration and proliferation via the ITGβ1/PI3K/AKT/ERK pathway, promoting collagen secretion; 3) Mechanical Reconstruction: The sodium alginate 'egg-box' network provides physiologically matched compressive modulus, and <i>in vivo</i> experiments confirm the restoration of intervertebral disc compressive stiffness. Employing a triple synergistic strategy-immunomodulation, cell recruitment, and mechanical restoration-this study proposes a promising solution for structural regeneration of the annulus fibrosus.