{Reference Type}: Journal Article
{Title}: Metformin-grafted polycaprolactone nanoscaffold targeting sensory nerve controlled fibroblasts reprograming to alleviate epidural fibrosis.
{Author}: Xu Z;Hu B;Zheng G;Yu W;Yang C;Wang H;Chen K;He S;Liang L;Xu C;Wu X;Zang F;Yuan WE;Chen H;
{Journal}: J Control Release
{Volume}: 367
{Issue}: 0
{Year}: 2024 Mar 13
{Factor}: 11.467
{DOI}: 10.1016/j.jconrel.2024.02.001
{Abstract}: Epidural fibrosis (EF), associated with various biological factors, is still a major troublesome clinical problem after laminectomy. In the present study, we initially demonstrate that sensory nerves can attenuate fibrogenic progression in EF animal models via the secretion of calcitonin gene-related peptide (CGRP), suggesting a new potential therapeutic target. Further studies showed that CGRP could inhibit the reprograming activation of fibroblasts through PI3K/AKT signal pathway. We subsequently identified metformin (MET), the most widely prescribed medication for obesity-associated type 2 diabetes, as a potent stimulator of sensory neurons to release more CGRP via activating CREB signal way. We copolymerized MET with innovative polycaprolactone (PCL) nanofibers to develop a metformin-grafted PCL nanoscaffold (METG-PCLN), which could ensure stable long-term drug release and serve as favorable physical barriers. In vivo results demonstrated that local implantation of METG-PCLN could penetrate into dorsal root ganglion cells (DRGs) to promote the CGRP synthesis, thus continuously inhibit the fibroblast activation and EF progress for 8 weeks after laminectomy, significantly better than conventional drug loading method. In conclusion, this study reveals the unprecedented potential of sensory neurons to counteract EF through CGRP signaling and introduces a novel strategy employing METG-PCLN to obstruct EF by fine-tuning sensory nerve-regulated fibrogenesis.