Femke Mathot

8 Stem cells on nerve graft substitutes 129 INTRODUCTION Peripheral nerve discontinuities that cannot be restored by direct end-to-end coaptation of nerve ends remain a clinical challenge. Despite many efforts to find an equivalent replacement, autologous nerve graft, which results in donor site morbidity, remains the gold standard in peripheral nerve reconstruction. To minimize donor site morbidity, increase the number of reconstructive options and improve the outcomes of peripheral nerve repair, further improvement of the commercially available ‘off-the-shelf’ nerve graft substitutes is essential. Two commercially available nerve autograft substitutes are the NeuraGen® Nerve Guide (approved by the Food and Drug Administration in 2001) and the Avance® Nerve Graft (approved by the FDA in 2007). The NeuraGen® Nerve Guide is an artificial bioabsorbable hollow conduit made of purified bovine type I collagen. It has demonstrated effective nerve regeneration in small diameter, short (<3cm) sensory nerves defects, but evidence for its effective use in sensory nerve defects of longer size and/or larger diameter, or in motor nerve defects, remains scarce and inconsistent. 1-3 The Avance® Nerve Graft is a decellularized human nerve allograft that has been processed to remove cellular debris. This process includes decellularization with chondroitinase and gamma-irradiation, leading to a natural human product with a remaining ultrastructure that does not necessitate the use of immunosuppression. While clinical outcomes have been mostly with case reports and series 1, 4-6 , there has been a lack of prospective clinical trials and valid comparisons to autografts. Their application in large motor-nerve defects remains controversial. 1, 4, 7, 8 The hypothesis that the addition of a cells that deliver growth factors at the nerve regeneration site could result in enhanced nerve regeneration has been confirmed by studies reporting a synergistic effect of mesenchymal stromal/stem cells (MSCs) added to a nerve conduit, leading to improved functional outcomes in various types of nerve gaps. 9-14 Similarly, the enhancing effect of added MSCs or Schwann cells to processed nerve allografts has also been demonstrated on a gene expression and functional outcome level. 15-20 A variety of non-validated delivery methods have been reported. Micro-injection has been extensively described to deliver the MSCs. Acute micro-injection is known to be traumatic to MSCs even though cells remain metabolically active. 21 Micro-injection also damages the ultrastructure of the allograft and when placed in the center of a hollow conduit, leakage occurs which may alter the effective dose of MSCs in an unpredictable manner. 22-27 Dynamic seeding is a novel, recently described delivery method that successfully adheres MSCs in a uniform matter on the surface of processed nerve grafts. 27, 28 Application and validation of this dynamic seeding strategy when applied to commercially available products like the Avance® Nerve Graft and the NeuraGen® Nerve Guide could enhance the clinical applicability of the described method and would enable a valid comparison of the two products and their capability to enhance nerve regeneration when