Tiam Mana Saffari

43 THE ROLE OF VASCULARIZATION IN NERVE REGENERATION 2 FUTURE DIRECTIONS Although several studies have discussed the surgical techniques of VNGs 19,68,71,72 , the clinical use has been sparse. Limited availability of VNGs in patients with nerve injuries stimulates the need for alternative methods for introducing vascularity to nerve reconstructions. The number of biomedical companies involved in regenerative medicine and tissue engineering has been steadily increasing, representing future interest in off-the-shelf suitable alternatives to autografting, such as biodegradable scaffolds which maintain mechanical properties and ultrastructure. Both biomaterials and decellularized nerve grafts have been combined with growth factors or stem cells to provide options to reconstruct nerve defects 73,74 . Moreover, exosomes, extracellular vesicles carrying microRNA, derived from Schwann cells, macrophages or stem cells provide exciting prospects for future treatment as the exosomes overcome the obstacles associated with cell therapy 75,76 . Other promising techniques include the generation of capillary-like networks in scaffolds to support the growth and viability of tissue substitutes that require blood supply, mainly when nutrient demand cannot be covered by diffusion processes in the center of these three-dimensional (3D) constructs 77,78 . Future 3D printing may be able to precisely recreate the structure of the scaffold to mimic a native nerve. Apart from the design and ultrastructure of the scaffold, several different factors are important and currently studied, such as biodegradation. The slow pace of nerve regeneration necessitates the scaffold to not be a fast degrading polymer, especially when reconstructing large defects. Moreover, the acetic environment created by the degradation of biocompatible polymers needs to be addressed in order to maintain a healthy bed for nerve regeneration 79 . Other considerations may be the thickness of the outer scaffold, which should not exceed 100-200 µm which is the diffusion limit of oxygen, aforementioned 4 . The application of 3D printed nerves with or without vessels will evolve over the next decade and may be implemented and improve outcomes in peripheral nerve injuries, especially to successfully repair large segmental defects.