Tiam Mana Saffari

189 FUNCTIONAL MOTOR RECOVERY OF STEM CELLS DELIVERED TO NERVE GRAFTS 9 INTRODUCTION Peripheral nerve defects not amendable to direct end-to-end neurorrhaphy require reconstruction with interposition nerve graft which could be accomplished with autograft, allograft or synthetic bioabsorbable conduits, each with their benefits and controversies 1-3 . Decellularized nerve allografts have been proposed as an ideal alternative to overcome donor site morbidity and limited supply of autografts 1,4-7 . Improvement of outcomes of decellularized allografts by addition of host derived mesenchymal stem cells (MSCs) has been proposed to overcome the limitations of decellularized allograft nerves by producing trophic factors resulting in a favorable micro-environment for tissue regeneration 8-14 . MSCs are hypothesized to not only stimulate tissue regeneration, but potentially form extracellular matrix components, enhance angiogenesis, inhibit scar formation and control immune responses 15 . Adipose derived MSCs are easily accessible and proliferate faster than bone marrow derived MSCs, while having a similar effect on nerve regeneration and are thus ideal for translation to clinical use 16-18 . In comparison to undifferentiated MSCs, MSCs differentiated into Schwann cell- like cells express neurotrophic and angiogenic genes to a greater extent than undifferentiated MSCs in vitro 16,19-21 . Several in vivo studies using different MSC- delivery strategies did not demonstrate clear differences between the outcomes of undifferentiated and differentiatedMSCs 22,23 . Others reported that differentiatedMSCs led to longer regenerating axon distance in vivo 19,21,24,25 , without resulting in improved functional outcomes 21 . The differentiation process of MSCs requires additional preparation time and expensive differentiation factors, which should be considered in translating bench work to clinical application 16 . Recent studies have reported a non-traumatic strategy to adhere undifferentiated and differentiated MSCs to the surface of decellularized allografts, leading to a 29-day in vivo survival of seeded MSCs 26-28 . The adherence of MSCs to the decellularized allograft has demonstrated an interaction between MSCs and the extracellularly matrix leading to enhanced expression of neurotrophic, angiogenic, extracellular matrix and regulatory cell cycle genes in the first three (differentiated MSCs) to seven (undifferentiated MSCs) days after seeding in vitro , implying a direct effect of