Tiam Mana Saffari

173 STEM CELLS, VASCULARITY, AND NERVE 8 contain fewer membrane-bound proteins. These characteristics present MSC exosomes with lower immunogenicity, the ability to cross biological barriers, and to be more stable over time 74,83 . The primary limitation of exosomes application is the limited scientific support and lack of standardized techniques for its isolation, quantification and purification. The efficacy of injected MSC exosomes and the effect of MSC exosomes travelling through the body remains unknown and to be explored 84 . Additionally, no guidelines for ethical safety assessment exists yet. MSC exosomes have great potential to be utilized for future therapeutic strategies in clinical practice following PNI if these challenges can be addressed 74 . Mode of stem cell delivery Stem cells can be delivered to the nerve reconstruction site by a variety of methods (Table 2). The selection of the delivery method depends on the intended mechanism of action of the stem cells. The process of microinjection (either intra-neural, around the nerve, intramuscular or intravenous) decreases the viability of stem cells due to the traumatic damage secondary to the pressure build-up in the syringe and flow through the needle during injection. Furthermore, intra-neural microinjection of stem cells is associated with damage of the nerve ultrastructure with unpredictable cell distributions, obstruction of axonal ingrowth, and leakage of cells 12,17,53,85,86 . Dynamic seeding has been a successful technique in delivering stem cells and results in an efficient and uniform distribution of stem cells. When cells are dynamically seeded on the surface of a decellularized nerve allograft, these cells remain viable on the nerve surface allowing for interaction with the nerve ultrastructure and resulting in the upregulation of neurotrophic factors 17,22 . According to Mathot et al., an efficiency of at least 1 x 10 6 MSCs on a 10-mm nerve graft is needed to generate noticeable outcomes. Induced differentiation of MSCs may have an effect on the final efficiency, as delivery methods have only been tested on undifferentiated MSCs, however, its effect remains unknown 17 . Controversy remains on the optimal method of delivery and requires further evaluation.