Stem cells in nerve reconstruction: Hype, hope or reality?

The overarching goal of this thesis is to further improve outcomes after nerve reconstruction by individualizing nerve allograft repair with the addition of adipose-derived MSCs. The aim of the first part was to investigate the clinical problem. In chapter 2, an evidencebased overview of the effectiveness of nerve conduits and allografts in motor and mixed sensory/motor nerve reconstruction is provided. In chapter 3, the outcomes of digital nerve gap reconstruction with the NeuraGen type 1 collagen nerve conduit and the Avance Nerve Graft are reported in a retrospective observational study.
The second part of this thesis focuses on the addition of adipose derived MSCs to decellularized nerve allografts and the in-vitro characteristics on human tissue, as well as the in-vivo characteristics in a rat-model. An adequate, reliable and validated cell seeding technique is an essential step for evaluating the translational utility of MSC-enhanced decellularized nerve grafts. Therefore in chapter 4, a new method to effectively seed decellularized nerve allografts with MSCs is described and validated. To understand how the functions of MSCs can be leveraged for peripheral nerve repair, in chapter 5, we investigated whether interactions of MSCs with decellularized nerve allografts can improve mRNA and protein expression of growth factors that may support nerve regeneration. After in-vitro testing, the MSC seeded nerve allograft was implemented in a rat model. As there is a paucity of information regarding the ultimate survivorship of implanted MSCs or if these cells remain where they are placed, in chapter 6, the in-vivo distribution and survival of MSCs seeded on a decellularized nerve allograft was tracked using luciferase based bioluminescent imaging (BLI). In chapter 7, the molecular mechanisms underlying nerve repair by a decelullarized nerve allograft preseeded with autologous, undifferentiated, adipose derived MSCs are studied and compared to the unseeded allograft and autograft nerve.
In the general discussion (chapter 8) the results of this thesis are put into a broader perspective and compared to other recent publications. Furthermore, the implications of this research for future perspectives are discussed.