ABSTRACT: Peripheral nerve injury (PNI) frequently progresses into chronic neuropathic pain (NP) when the early-stage regenerative microenvironment fails to stabilize, subsequently triggering peripheral and central sensitization. In this study, an autonomous, bio-instructive bilayer nerve guidance conduit (NGC) is engineered, integrating a piezoelectric PLLA inner layer (output 1151.35 mV) with a ropivacaine (RVC)-loaded PCL outer layer (83.63% release over 14 days). This dual-functional platform aims to achieve synchronized structural restoration and long-term analgesia. In vitro, the piezo-induced surface potentials triggers Ca2+ mobilization and activates the NGF, GDNF Mmp-9, Jun, Olig1, and Shh genes, promoting Schwann cells (SCs) proliferation, migration, and phenotypic reprogramming, which effectively blocked the peripheral sensitization. In vivo, using a rat chronic constriction injury (CCI) model, PLLA-PCL-RVC@NGC significantly alleviates mechanical, thermal, and cold hypersensitivity while accelerating functional recovery (SFI), thereby preventing the central sensitization. RNA-seq and serum analysis reveal that the device modulates TNF-α/NF-κB, IFN-α/γ, and IL-6 cytokines. This was evidenced by the significant downregulation of IgG, TGF-β1, S100, NF200, MMP-9, and Fcgr1A genes, alongside enhanced regenerative markers. By synergizing autonomous autonomous piezo-potentials with the sustained release of RVC, this bio-instructive NGC effectively attenuates both peripheral and central sensitization, thereby averting the onset of NP.
