Shell-core structured nanofibers mediate staged anti-inflammatory and pro-neurogenic activities to repair peripheral nerve

Abstract

The inflammatory reaction significantly impedes the neurogenic process during the restoration of peripheral nerve injury (PNI). Therefore, establishing a non-inflammatory environment is crucial for effective nerve regeneration. This study proposes the use of shell-core structured nanofibers with sequential anti-inflammatory and pro-neurogenic activities to repair PNI. Icariin (ICA), known for its anti-inflammatory effects, was blended with poly(lactic-co-glycolic acid) (PLGA) to form the shell layer's spinning solution. Concurrently, glial cell-derived neurotrophic factor (GDNF) was combined with graphene oxide (GO) to create the core layer's spinning solution. These solutions were then subjected to co-axial electrospinning, resulting in shell-core structured GDNF@GO-ICA@PLGA nanofibers. Additionally, a control group of unordered GDNF/GO/ICA/PLGA nanofibers was prepared using conventional electrospinning. The resulting GDNF@GO-ICA@PLGA nanofibers exhibited distinct fibrous structures with a clear shell-core architecture and demonstrated mechanical properties similar to the control group. Notably, the shell-core structured GDNF@GO-ICA@PLGA nanofibers displayed unique staged release kinetics: over 90% ICA was released priorly within the first 0 to 13 days, followed by GDNF release from days 9 to 31. Furthermore, the GDNF@GO-ICA@PLGA nanofibers showed excellent biocompatibility with Schwann cells. In vitro results highlighted the potent anti-inflammatory capabilities of ICA released from the shell layer, while GDNF released from the core layer effectively induced neurogenic differentiation of Schwann cells. The GDNF@GO-ICA@PLGA nanofibers were then processed into a nerve conduit and applied to a 10 mm rat sciatic PNI model. The staged release of ICA and GDNF facilitated by the GDNF@GO-ICA@PLGA nanofibers created a non-inflammatory environment before initiating nerve regeneration, leading to improved PNI restoration. This study underscores the importance of shell-core structured nanofibers in sequentially mediating anti-inflammation and neurogenesis, offering a novel approach for addressing PNI.