Tiam Mana Saffari

33 THE ROLE OF VASCULARIZATION IN NERVE REGENERATION 2 INTRODUCTION Vascularization is one of the great challenges faced in nerve reconstruction, especially in nerve autograft substitutes such as nerve allografts or conduits that do not contain living cells 1 . In these substitutes, vascularization needs to be achieved to ensure cellular survival and avoid central necrosis, which is observed in nerve grafts with large diameters and long defects 1,2 . The diffusion limit of oxygen to meet the demands of cellular metabolism is around 100-200 µm, which is an essential to recognize when evaluating the role of vascularity in neural regeneration 3,4 . There is an increased understanding of nerve regeneration and cell biology with compelling evidence for the association of arterial blood vessels and nerves, in particular the alignment of peripheral nerves with blood vessels. The nervous system forms intricate branching networks reaching every organ in the body and relies on the vascular tree to supply oxygen and nutrients to meet substantial metabolic demands supporting organ development 5 . It has been suggested that vascular endothelial cells guide the regeneration of peripheral nerve axons by producing vascular endothelial growth factor (VEGF) to induce angiogenesis preceding the repair of damaged nerves 6 (Figure 1). VEGF is a potent multifunctional cytokine that stimulates the outgrowth of Schwann cells and blood vessels, while enhancing axonal outgrowth from the dorsal root ganglia 7-10 . As a result, VEGF has become the focus of numerous investigations with regards to its effects on the peripheral nerves 7,11-14 . Clinical attempts to augment vascularization and improve nerve graft outcomes using VEGF have led to conf licting results 15,16 , suggesting that the specific molecular regulations and patterns of angiogenesis following peripheral nerve injury are broader and more complex. In this review, the role of vascularization in nerve regeneration will be discussed, including the key regulation molecules in vascularization, the vascular system of the nerve, the mechanisms of vascularization and the application of vascularized nerve grafts (VNG) in peripheral nerve reconstruction.