Tiam Mana Saffari

175 STEM CELLS, VASCULARITY, AND NERVE 8 The regenerative potential of cell-based therapy The regenerative potential of cell-based therapy following nerve injury is particularly relevant for large diameter and long nerve defects 87 . In rodent models, extensive research using stem cells in peripheral nerve repair suggests that the application of stem cells enhances functional motor outcomes. It has been shown that stem cells elevate expression of neurotrophic factors, angiogenic growth factors and contribute to angiogenesis 46,52,63,88 . The exact survivability of stem cells in vivo, however, is difficult to investigate and remains largely unknown. When MSCs were dynamically seeded on nerve allografts, in vivo survivability up to 29 days was found using luciferase- based bioluminescence imaging 89 . This suggests that survivability of stem cells may be hampered by rejection, inflammation, or migration. Larger animal models are also investigating augmentation of nerve repair outcomes by the provision of BMSCs to nerve grafts 90,91 . Tissue-engineered nerve grafts enhanced with autologous BMSCs have been used to repair 50 mm-long median nerve defects in rhesus monkeys. After one year, histological and morphometric analyses of regenerative nerves found results comparable to autograft repair. Blood samples and histopathological examination of nerve found no immune rejection, confirming that tissue-engineered nerve grafts augmented with BMSCs were safe to use in monkeys 92 . Extensive investigations of safety in preceding pre-clinical trials have provided the data necessary to proceeding evaluation of MSCs in clinical trials 93 . Clinical stem cell application is novel and has been applied to several fields including treatment for cardiovascular diseases with promising results 19 . Several clinical trials investigating central nervous system diseases, including spinal cord injury and traumatic brain injury, have proven the safety of MSC application. Ongoing trials suggest that MSCs prepare the environment of injury for axonal ingrowth and stimulate angiogenesis. While this is promising, more studies are needed to assess the time and route of administration to obtain more consistent data 94 . In the field of PNI, most clinical trials related to stem cell treatment focus on hemifacial spasm, burn wound healing and diabetic peripheral neuropathy 4 and are still in the early phases. Although the application of Schwann cells is not desired due to the aforementioned limitations, the first FDA-regulated dose phase I trial on human Schwann cell transplantation in spinal cord injuries has found promising results with no adverse effects 95 . Currently, little pre-clinical or clinical research has addressed the interaction of stem cells and