In Situ Prevascularization Strategy with Three-Dimensional Porous Conduits for Neural Tissue Engineering

Neovascularization is crucial for peripheral nerve regeneration and long-term functional restoration. Previous studies have emphasized strategies that enhance axonal repair over vascularization. Here, we describe the development and application of an in situ prevascularization strategy that uses 3D porous nerve guidance conduits (NGCs) to achieve angiogenesis-mediated neural regeneration. The optimal porosity of the NGC is a critical feature for achieving neovascularization and nerve growth patency. Hollow silk fibroin/poly(L-lactic acid-co-epsilon-caprolactone) NGCs with 3D sponge-like walls were fabricated using electrospinning and freeze-drying. In vitro results showed that 3D porous NGC favored cell biocompatibility had neuroregeneration potential and, most importantly, had angiogenic activity. Results from our mechanistic studies suggest that activation of HIF-1 alpha signaling might be associated with this process. We also tested in situ prevascularized 3D porous NGCs in vivo by transplanting them into a 10 mm rat sciatic nerve defect model with the aim of regenerating the severed nerve. The prevascularized 3D porous NGCs greatly enhanced intraneural angiogenesis, resulting in demonstrable neurogenesis. Eight weeks after transplantation, the performance of the prevascularized 3D NGCs was similar to that of traditional autografts in terms of improved anatomical structure, morphology, and neural function. In conclusion, combining a reasonably fabricated 3D-pore conduit structure with in situ prevascularization promoted functional nerve regeneration, suggesting an alternative strategy for achieving functional recovery after peripheral nerve trauma.