Femke Mathot

9 MSC gene expression on nerve substitutes 145 INTRODUCTION Peripheral nerve injuries result in a major social and economic burden by causing loss of function of target muscles. 1-3 In order to restore nerve function when the nerve gap is not suitable for direct end to end coaptation, (sensory) autografts, allografts and artificial guides can be used to bridge the gap. While resulting in optimal recovery rates, autograft nerve options are limited in diameter and length and associated with donor side morbidity. 4 Avance® Nerve Grafts and NeuraGen® Nerve Guides are commercially available nerve substitutes, approved for clinical use and are theoretically unlimited in supply. If their clinical outcome would be similar to autografts, these nerve graft substitutes may supplant autograft nerves. Sensory nerve gaps (<2.5cm) can be effectively restored by either nerve conduits or processed nerve allografts 5 , but their application in mixed or motor nerve defects with greater defect length and larger diameters results in varying outcomes. 6-9 In daily clinical practice, processed nerve grafts are described to only lead to good outcomes in mixed/ motor nerves with maximal gap lengths of 6mm and diameters between 3 and 7mm. 10 In cases that exceed these dimensions, autograft nerves remain the gold standard by surpassing the results of nerve conduits and allografts. 10-12 However, particularly in nerve injuries with large gaps or multiple nerve injuries (i.e. brachial plexus injuries) there are often not enough autologous nerve graft sources to optimally reconstruct the defects. 13 Seeding of mesenchymal stem cells (MSCs) on nerve graft substitutes may potentially reduce the outcome differences between nerve substitutes and nerve autografts. MSCs can interact with the extracellular matrix (ECM) of the nerve graft substitute to produce trophic factors necessary for tissue regeneration that supplement endogenous trophic sources. 14-18 To benefit from these trophic properties, dynamic seeding of MSCs is beneficial as it permits atraumatic introduction of MSCs to the ECM of graft substitutes prior to implantation while preventing damage to both the cells and the graft substitutes. In peripheral nerve injury, a defined process occurs commencing fromWallerian degeneration to axonal regeneration and muscle reinnervation. This includes a nine step process from injury to regeneration: 1. response to stimulus (Schwann cells and neurons change their state and become activated, 3-7 days), 2. regional inflammation (macrophage infiltration, 3-7 days), 3. immune response (7 days), 4. cell proliferation (formation of Bunger bands, 3-7 days), 5. cell migration (Schwann cell migration, 7-14 days), 6. axon guidance (7-14 days), 7. myelination (initiated by Schwann Cells, 14 days), 8. extracellular matrix (7-14 days), 9. growth factor activity for axonal regeneration (3-14 days). 19 To determine the exact potential of MSC-seeding in clinical practice and to understand its mode of action within the described regeneration process, it is essential to elucidate the interaction between human MSCs and the ECM of clinically available nerve substitutes. The purpose of this study was to examine this interaction by measuring expression of mRNA biomarkers for myelination, neurotrophic and angiogenic processes, ECM deposition