## 3 Post-Injury Scenario--A Short Overview  
Following the cutting of a nerve (axotomy), a series of molecular and cellular mechanisms, including the activation of cell survival pathways and up-regulation of regeneration-associated genes, happen in temporal and spatial coordination to encourage peripheral nerve regeneration in the injured site [38]. The main signaling pathways involved in peripheral nerve regeneration include phosphoinositide-3-kinase (PI3K)/protein kinase B (PKB or Akt) (PI3K/Akt) signaling (increasing survival, growth, and differentiation of cells), Ras-mitogen-activated protein kinase (Ras/MAPK) signaling (enhancing neurite outgrowth and Schwann cell differentiation and myelination), cyclic AMP (cAMP) signaling (improving guidance, differentiation, neurite outgrowth, and neuronal survival), and Rho/Rho-associated coiled-coil containing protein kinase (Rho/ROCK) signaling (modulating neurite outgrowth) [39; 40]. Moreover, some studies emphasize the critical role of angiogenic signaling pathways in improving the quality of peripheral nerve repair [41]. Figure 1: Schematic representation of a peripheral spinal nerve (cross-sectional view) showing its layers and components. Reproduced with permission from ref [31]. Experimental evidence suggests that all these biomolecular events may result in axon regeneration at a rate of 1-3 mm/day, which significantly reduces with increasing time and distance from injury [42; 43; 44]. Therefore, peripheral nerves have no adequate regenerative capacity to rebuild their structure and function after severe injuries causing nerve gaps longer than 2 cm [45]. The use of autografts and allografts has a long history in the repair and regeneration of peripheral nerves; however, there are limitations in case of their extensive usage, including the shortage of donors, immune rejection, and the transfer of pathogens [46; 47; 48]. With the advent of the tissue engineering concept, polymers have achieved great success in peripheral nerve regeneration; however, other types of materials (ceramics and glasses) have also been examined for accelerating the healing process [49; 50; 51; 23]. Specifically, bioactive materials could be applied alone or in combination with polymers; constructs containing cells (e.g., mesenchymal stem cells) and growth factors (e.g., vascular endothelial growth factor (VEGF)) facilitate the restoration of nerve structure and function via distinct approaches such as increased cell growth, improved angiogenesis, and providing tissue attachment possibilities in either bare or modified types [52; 53; 54; 55]. Moreover, the use of materials capable of reducing inflammation and oxidative stress, such as nanoceria, gives further added value to peripheral nerve injury strategies [56; 57]. The applicability of different types of BGs, including silicate-, phosphate-, and borosilicate-based glasses, has been assessed through a series of experimental studies [58; 59; 60; 61]. To date, various forms and shapes of BGs have been produced and assessed in vitro and in vivo for nerve repair and regeneration, including glass tubes, glass powder/polymer tubes, and glass fiber/polymer warps. The concept behind the use of BGs in neurodegeneration relies on their ability to (1) improve cell growth and proliferation, (2) promote angiogenesis, (3) reduce inflammation, and (4) increase mechanical strength [62; 63; 64; 65; 66; 23; 62; 63; 64; 24; 25; 26; 27; 28; 29; 30; 31; 32; 33; 34; 35; 36; 37; 38; 39; 40; 41; 42; 43; 44; 45; 46; 47; 48;  
Figure 2: **(A)** SEM micrographs of the nano 45S5 Bioglass/gelatin conduits; cross-sectional view of the composites (200\(\times\)) (a), outer layer of the conduit wall (500\(\times\)) (b), and its inner layer (300\(\times\)) (c). **(B)** The illustration (a1) shows the implantation process of nerve conduits made of 45S5 nano-Bioglass/gelatin into a 10 mm long gap defect in the sciatic nerve in rats and (a2) and a macroscopic image of the regenerated nerve at 3 months post-surgery.