In situ piezoelectricity induces M2 polarization of macrophages to regulate Schwann cells for alleviating neuropathic pain of CCI rats

Peripheral nerve injuries often lead to neuropathic pain (NP), which is influenced by macrophage polarization, impacting Schwann cell function. Bioelectric signals, particularly from piezoelectric materials like polyvinylidene fluoride (PVDF), play a pivotal role in modulating macrophage polarization. In this study, we demonstrate that PVDF's piezoelectric properties enhance M2 polarization during hypoxia macrophage model, as indicated by increased CD206 (M2 marker) expression and decreased CD8 (M1 marker). This shift in polarization is linked to enhanced secretion of Arg-1 and IL-10 from M2 macrophages, and reduced levels of ROS, iNOS, and TNF-α from M1 macrophages. The underlying mechanism driving this polarization shift involves the activation of the AMPK signaling pathway. In vitro, M2-conditioned medium significantly promoted Schwann cell proliferation and migration. In a chronic sciatic nerve constriction (CCI) rat model, PVDF treatment improved pain sensitivity, as shown by increased mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL). Additionally, PVDF treatment reduced the CD80/CD206 (M1/M2) ratio, promoting an anti-inflammatory environment, and increased the NF200/S100 ratio, indicating enhanced axonal regeneration. RNA sequencing revealed that Schwann cells co-cultured with M2-conditioned medium upregulated Cell Adhesion Molecule (CAM), Ca⁺ signaling pathway, and Mitogen Activated Protein Kinases (MAPK), critical signal pathway for Schwann cell regeneration and nerve repair. Our findings suggest that PVDF's piezoelectric properties offer a novel strategy for modulating macrophage polarization and enhancing Schwann cell activity, providing a potential therapeutic approach for NP.