Development of acellular conduits for peripheral nerve repair and regeneration & in-vitro neuromodulation targeting microglia activity

During the time of this thesis two separate projects were followed in the area of regenerative neuroscience. The first project focused on the development of an acellular nerve graft for peripheral nerve repair and replacement. During this project, protocols were established for the decellularization of pig nerves. Most research regarding the production of acellular nerve grafts is conducted using rodent models. However, due to size and modality mismatch of rodent and human peripheral nerves, a suitable large animal donor is required for clinical application. This project was enabled by the EUROSTAR grant to PD Dr. Srinivas Madduri, the Department of Biomedicine, University of Basel and the Department of Neurosurgery, University Hospital Basel.
During the second part of this thesis, I focused on the impact of neuromodulation protocols on microglia activity and how to modulate their inflammatory response via targeted stimulation in-vitro. Neuromodulation therapies are investigated in various diseases and conditions, experimentally, such as in Alzheimer’s Disease but also clinically as in chronic pain. The beneficial outcomes of electric stimuli are mainly attributed to direct effect on neuronal cells. However, long lasting improvement following neuromodulation cannot be explained by immediate effects on neuronal excitability only. Newer developments indicate a direct impact of electric fields on glia cells. Therefore, the direct impact on glia activity was further investigated during this project. This project was enabled by the Gerbert Rüf Foundation grant to Dr. Bekim Osmani, the Department of Biomedicine, University of Basel and the Department of Neurosurgery, University Hospital Basel and Bottneuro AG.
Even though these projects are of different origins, potential future combinations are possible. First, the in-vitro electrical stimulation device, developed during the second project can be used for mesenchymal stem cell differentiation into Schwann cell-like cells used for recellularization of acellular grafts as described in the review written during the first project1.
Second, a recent study has shown enhanced peripheral nerve regeneration by providing electric pulses to the regenerating nerves2. Optimal electrical stimulation parameters for axonal elongation and nerve regeneration can be established using the in-vitro electrical stimulation device developed during this thesis. Further, during this thesis a patent was filled for soft neuronal implants on cellulose basis3. By wrapping the developed acellular grafts with these neuronal implants, electrical stimulation protocols can be applied to enhance nerve regeneration even further.
Third, to mimic the natural microenvironment present during neuroinflammation in-vivo, acellular grafts loaded with inflammatory molecules such as cytokines, growth factors and enzymes can be used as a model of neuroinflammation in-vitro. Using such a 3D system, the impact of electric fields on microglia activity can be analyzed in a system more closely resembling natural conditions without the potential paracrine effects of simultaneous stimulation of neural cells. An ongoing collaboration with Prof. Bert Müller from the department of Biomedical Engineering investigates microglia modulation in an artificial 3D scaffold made from electrospun cellulose scaffolds.