Neural tissue-engineered prevascularization in vivo enhances peripheral neuroregeneration via rapid vascular inosculation

Neural tissue engineering techniques typically face a significant challenge, simulating complex natural vascular systems that hinder the clinical application of tissue-engineered nerve grafts (TENGs). Here, we report a subcutaneously pre-vascularized TENG consisting of a vascular endothelial growth factor-induced host vascular network, chitosan nerve conduit, and inserted silk fibroin fibers. Contrast agent perfusion, tissue clearing, microCT scan, and blood vessel 3D reconstruction were carried out continuously to prove whether the regenerated blood vessels were functional. Moreover, histological and electrophysiological evaluations were also applied to investigate the efficacy of repairing peripheral nerve defects with pre-vascularized TENG. Rapid vascular inosculation of TENG pre-vascularized blood vessels with the host vascular system was observed at 4 d bridging the 10 mm sciatic nerve defect in rats. Transplantation of pre-vascularized TENG in vivo suppressed proliferation of vascular endothelial cells (VECs) while promoting their migration within 14 d post bridging surgery. More importantly, the early vascularization of TENG drives axonal regrowth by facilitating bidirectional migration of Schwann cells (SCs) and the bands of Bungner formation. This pre-vascularized TENG increased remyelination, promoted recovery of electrophysiological function, and prevented atrophy of the target muscles when observed 12 weeks post neural transplantation. The neural tissue-engineered pre-vascularization technique provides a potential approach to discover an individualized TENG and explore the innovative neural regenerative process.

Automated summary

In this study, a subcutaneously pre-vascularized tissue-engineered nerve graft (TENG) was developed using a vascular endothelial growth factor-induced host vascular network, chitosan nerve conduit, and inserted silk fibroin fibers. The functionality of regenerated blood vessels was confirmed through various imaging techniques and 3D reconstruction. Pre-vascularized TENG facilitated rapid vascular inosculation and enhanced the migration of vascular endothelial cells (VECs) and Schwann cells (SCs), promoting axonal regrowth and remyelination. The transplantation of pre-vascularized TENG resulted in the recovery of electrophysiological function and prevention of muscle atrophy.