The Fabulous 3: An Exploration Of Adipose Derived Stem Cells, Neurotrophic Factors And Fibrin Hydrogel For Peripheral Nerve Repair And Regeneration

Background: Injuries to the peripheral nerve system are a common clinical problem which affect mostly young individuals. Standard treatment methods are well established, but are associated with several undeniable disadvantages that may have a long-lasting impact on the patients’ quality of life. Therefore, peripheral nerve regeneration and repair is an active field of research with a variety of treatment strategies. However, most of them fail to be translated into clinical practice.
Objective: The aim of the present thesis was to investigate translational approaches for enhancing peripheral nerve regeneration as well as for the surgical nerve repair.
Methods: The first manuscript of this thesis focused on the neurotrophic potency of adipose derived stem cells (ASC) in response to growth factors stimuli, i.e. NGF or VEGF in vitro and in vivo, and the impact of two different stem cell delivery strategies, i.e. intramural versus intraluminal loading, in fibrin nerve conduits (FNC) on early nerve regeneration. The second manuscript evaluated the neurotrophic effect of ASC after stimulation by a variety of neurotrophic factors (NTF), i.e., NGF, BDNF, NT3, NT4, GDNF and CNTF, and investigated the neuroregenerative events taking place in ASC and sensory neuronal cells upon stimulation. In the third manuscript, we conducted a prospective, randomized, two-arm-controlled phase-1 clinical trial comparing the outcome of digital nerve injuries with or without nerve gap after experimental treatment with the fibrin nerve conduit (FNC) or the epineural suture with fibrin sealant versus the standard treatment with the autologous nerve graft or the epineural suture over a period of 12 months.
Results: NTF-stimulated ASC promoted the axonal regeneration in vitro and in vivo, with NT3-stimulation revealing a specifically significant effect. Analysis of regenerative events taking place in ASC and sensory neuronal cells upon NT3-signaling resulted in up- regulation of regeneration associated genes and changing phosphorylation sites in both cell types. FNC based intramural delivery of NGF-stimulated ASC promoted better axonal regeneration in vivo than intraluminal delivery. In the clinical context, the FNC and the fibrin sealant may enhance the early nerve regeneration and performed non-inferior to standard treatments for peripheral nerve repair.
Conclusion: Ex-vivo stimulation of ASC by NTF and FNC assisted intramural delivery may offer new options for the development of effective stem cell-based therapies, while the FNC and the fibrin sealant might already present viable clinical treatment alternatives for the repair of short-gap nerve injuries.