Neurovascularization strategy: pathfinder and interlocutor for peripheral nerve tissue engineering in a sequential process

Neurovascularization serves as the prerequisite and assurance for fostering neurogenesis after peripheral nerve injury (PNI), not only contributing to the reconstruction of the regenerative neurovascular niche but also providing a surface and directionality for Schwann cell (SC) cords migration and axons elongation. Despite the development of nerve tissue engineering techniques has drawn increasing attention to the intervention approach for repairing nerve defects, systematic generalization summary of the efficient intervention to expedite nerve angiogenesis is still scarce. This review delves into the mechanisms by which macrophages within the nerve defect trigger angiogenesis after PNI and elucidates how the newborn vessels support nerve regeneration, and then extracts three major categories of strategies for producing vascularized nerves in vitro and in vivo from them, encompassing (1) in vitro prevascularization, (2) in vivo prevascularization, and (3) stimulation of neurovascularization in situ. Furthermore, we emphasize that the lack of accuracy for structure and spatiotemporal regulation, as well as the operational inconvenience and delayed connection to the host’s nerve stumps, have stuck the existing neurovascularization technology in the preclinical stage. The successful design of a future prospective clinical vascularized nerve scaffold should be guided by a comprehensive consideration of these aspects.