Vascularization plays a significant role in treating nerve injury, especially to avoid the central necrosis observed in nerve grafts for large and long nerve defects. It is known that sufficient vascularization can sustain cell survival and maintain cell integration within tissue‐engineered constructs. Several studies have also shown that vascularization affects nerve regeneration. Motivated by these studies, vascularized nerve grafts have been developed using various different techniques, although donor site morbidity and limited nerve supply remain significant drawbacks. Tissue engineering provides an exciting alternative approach to prefabricate vascularized nerve constructs which could overcome the limitations of grafts. In this review article, we focus on the role of vascularization in nerve regeneration, discussing various approaches to generate vascularized nerve constructs and the contribution of tissue engineering and mathematical modeling to aid in developing vascularized engineered nerve constructs, illustrating these aspects with examples from our research experience. Anat Rec, 301:1657–1667, 2018. © 2018 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.

Objective. Gel aspiration-ejection (GAE) has recently been developed for the rapid production of dense, anisotropic collagen gel scaffolds with adjustable collagen fibrillar densities. In this study, a GAE system was applied to produce aligned Schwann cells within a type-1 collagen matrix to generate GAE-engineered neural tissues (GAE-EngNT) for potential nerve tissue engineering applications. Approach. The stability and mechanical properties of the constructs were investigated along with the viability, morphology and distribution of Schwann cells. Having established the methodology to construct stable robust Schwann cell-loaded engineered neural tissues using GAE (GAE-EngNTs), the potential of these constructs in supporting and guiding neuronal regeneration, was assessed both in vitro and in vivo. Main results. Dynamic mechanical analysis strain and frequency sweeps revealed that the GAE-EngNT produced via cannula gauge number 16G (~1.2 mm diameter) exhibited similar linear viscoelastic behaviors to rat sciatic nerves. The viability and alignment of seeded Schwann cell in GAE-EngNT were maintained over time post GAE, supporting and guiding neuronal growth in vitro with an optimal cell density of 2.0×10 6 cells/ml. An in vivo test of the GAE-EngNTs implanted within silicone conduits to bridge a 10 mm gap in rat sciatic nerves for 4 weeks revealed that the constructs significantly promoted axonal regeneration and vascularization across the gap, as compared to the empty conduits although less effective regeneration compared to the autograft groups. Significance. Therefore, this is a promising approach for generating anisotropic and robust engineered tissue which can be used with Schwann cells for peripheral nerve repair.