Biomimetic Core–Sheath GelMA/PCL Nanofibers for Enhanced Peripheral Nerve Regeneration

Artificial nerve guidance conduits (NGCs) have gained significant attention in the field of peripheral nerve regeneration for the treatment of critically sized nerve defects. Nanotechnology-based NGCs are being explored as potential solutions for repairing and reconstructing peripheral nerve injuries due to their unique structure and topography. In this study, we present a novel core–sheath GelMA/PCL nanofiber construct fabricated through electrospinning and phase separation methods. The core–sheath GelMA/PCL nanofibers replicate the topological morphology of the native extracellular matrix (ECM). The outer layer, composed of GelMA, serves as an “adhesion domain” facilitating direct interaction with surrounding cells and tissues while improving wettability, integrin-mediated cell adhesion/attachment, and degradation. PCL, acting as the “elastic domain” within the nanofibers, enhances mechanical properties, maintains long-term stability of the NGCs, and enables controlled release of GelMA. Histomorphometric analysis along with electrophysiological and behavioral assessments demonstrate that these core–sheath GelMA/PCL nanofiber-based NGCs can activate endogenous mechanisms for peripheral nerve repair while promoting sensory/motor nerve regeneration and functional recovery. Overall, our findings demonstrate that GelMA/PCL nanofibers within the nuclear sheath can effectively remodel the nerve regeneration microenvironment by integrating “mechanical- biochemical” signals, thereby offering a novel strategy for addressing critical-size nerve defects.