Harnessing piezoelectric stimulation to modulate PI3K-AKT signaling for intervertebral disc regeneration.

Low back pain affects 70-85 % of adults globally, with intervertebral disc degeneration (IVDD) driving nearly half of cases. Integrating human genetic evidence from a large-scale genome-wide association study in up to 829,699 participants along with immunofluorescence staining of nucleus pulposus in patients with varying degrees of IVDD, we identified PI3K-Akt signaling as a central pathway in lumbar disc herniation. Guided by this genetic blueprint, we engineered a piezoelectric scaffold GelMA-FF (GF) which can transform physiological loading into regenerative bioelectrical signals, and regulate PI3K-Akt pathway. The GF system synergizes gelatin methacryloyl's biomechanical compatibility with diphenylalanine crystals' piezoelectric capacity, directly targeting fixed charge density restoration-the electrophysiological hallmark of IVDD. The results reveal that GF-generated electrical signals could change the pathogenic PI3K-Akt/NF-κB axis, shifting disc metabolism from inflammatory catabolism to anabolic regeneration. This GF system also enhances mitochondrial energetics and extracellular matrix synthesis, achieving structural and functional recovery in preclinical models. This study proposes a novel strategy-a paradigm where genetic risk architectures guide physiology-matched biomaterials to transduce endogenous mechanical microenvironment cues into regeneration signals.