Peripheral nerve regeneration
The Tissue Engineering laboratory of the Clinic for Plastic and Hand Surgery has decades of experience in the field of peripheral nerve regeneration.
The site of coaptation is seen to the left and the nerve regeneration can be followed from left to right. In this study we could show that an interleukin-6 inhibition leads to improved regeneration (Koulaxouzidis, 2015a).
Nerve conduit research
Our group routinely carries out projects on nerve conduits, aiming at replacement of autologous nerve grafts. We were thus able to show that bridging 15 mm defects of the ishiadicus nerve of the rat with a fibrin-filled poly-dl-lactide-ɛ-caprolactone shell loaded with interleukin 10 (Leibig et al., 2016) and C3 Toxin (Leibig et al., 2015) is fundamentally possible, but with a lower efficiency compared to the autologous nerve. A fibrin / Schwann cell matrix in a poly-dl-lactide-ɛ-caprolactone conduit showed improved regeneration compared to the sole conduit (Galla et al., 2004). In a further work, a biogenic conduit was produced and tested. A polyvinyl chloride tube was left in the rat subcutaneous tissue for four weeks, and the connective tissue that forms on the outside of the tube was used as a conduit (Penna et al., 2011; Penna et al., 2012b). If the conduit was loaded with Schwann cells, this led to improved functional results (Penna et al., 2012a). In another work we were able to show that Rho Kinase inhibitors improve the elongation of axons in Schwann cell culture and dorsal spinal ganglion culture in vivo (Fuentes et al., 2008). Furthermore, it could be shown that IL-6 inhibition or a nerve transplant from an IL-6 - / - mouse leads to improved nerve regeneration compared to the control group (Figure 1) (Koulaxouzidis et al., 2015a), while the administration of IL -10 led to improved myelination (Sakalidou et al., 2011). In a further experimental approach, we investigated the mechanisms of influencing axonal regeneration by adding propionylmannosamine (Koulaxouzidis et al., 2015b; Witzel et al., 2015).
Novel experimental models for nerve regeneration
We have developed new in vitro models and further developed the functional evaluation of existing models. A new 3D in vitro model of peripheral nerve regeneration was described in our laboratory, which is well suited for testing pharmacological substances and with which is suited for reducing the number of animal experiments, at least at the stage of a project (Kraus et al., 2015). In order to facilitate and standardize the functional evaluation of the N. ishiadicus defect model, we have developed a digital infrared system for recording the gait pattern (Fricker et al., 2016).
Future directions
At the moment, our group is working on a joint interdisciplinary project with the Department Of Microsystems Engineering to use innovative 3D bioprinting technology to improve the efficacy of nerve conduits.
El-Karabaty H, Hetzel A, Galla TJ, Horch RE, Lucking CH, Glocker FX: The effect of carpal tunnel release on median nerve flattening and nerve conduction. Electromyogr Clin Neurophysiol, 2005; 45 (4): 223-227.
Fricker, L., Penna, V., Lampert, F., Stark, G.B., Witzel, C., and Koulaxouzidis, G. A self-made, low-cost infrared system for evaluating the sciatic functional index in mice. Neural Regen Res 2016 11, 829-834.
Fuentes, E.O., Leemhuis, J., Stark, G.B., and Lang, E.M. Rho kinase inhibitors Y27632 and H1152 augment neurite extension in the presence of cultured Schwann cells. J Brachial Plex Peripher Nerve Inj 2008 3, 19.
Galla, T.J., Vedecnik, S.V., Halbgewachs, J., Steinmann, S., Friedrich, C., and Stark, G.B. Fibrin/Schwann cell matrix in poly-epsilon-caprolactone conduits enhances guided nerve regeneration. Int J Artif Organs 2004 27, 127-136.
Koulaxouzidis G, Reim G, Witzel C: Fibrin glue repair leads to enhanced axonal elongation during early peripheral nerve regeneration in an in vivo mouse model. Neural Regen Res, 2015; 10 (7): 1166-1171.
Koulaxouzidis, G., Reim, G., Fluhr, J.W., Simunovic, F., Stark, G.B., and Witzel, C. In Situ Deactivation of Interleukin-6 Enhances Early Peripheral Nerve Regeneration in a Murine Injury Model. J Reconstr Microsurg 2015 31, 508-515.
Koulaxouzidis, G., Reutter, W., Hildebrandt, H., Stark, G.B., and Witzel, C. In vivo stimulation of early peripheral axon regeneration by N-propionylmannosamine in the presence of polysialyltransferase ST8SIA2. J Neural Transm (Vienna) 2015b 122, 1211-1219.
Koulaxouzidis G, Reutter W, Witzel C: N-Propionylmannosamine: using biochemical glycoengineering to promote peripheral nerve regeneration. Neural Regen Res, 2016; 10 (12): 1947-1948.
Kraus, D., Boyle, V., Leibig, N., Stark, G.B., and Penna, V. The Neuro-spheroid--A novel 3D in vitro model for peripheral nerve regeneration. Journal of neuroscience methods 2015 246, 97-105.
Lang EM, Asan E, Plesnila N, Hofmann GO, Sendtner M: Motoneuron survival after C7 nerve root avulsion and replantation in the adult rabbit: effects of local ciliary neurotrophic factor and brain-derived neurotrophic factor application. Plast Reconstr Surg, 2005; 115 (7): 2042-2050.
Leibig, N., Boyle, V., Kraus, D., Stark, G.B., and Penna, V. C3 toxin and poly-DL-lactide-epsilon-caprolactone conduits in the critically damaged peripheral nervous system: a combined therapeutic approach. Annals of plastic surgery 2015 74, 350-353.
Leibig, N., Boyle, V., Kraus, D., Stark, G.B., and Penna, V. Il10 and poly-dl-lactide-varepsilon-caprolactone conduits in critical size nerve defect bridging-An experimental study. Microsurgery 2016 36, 410-416.
Narayanan K, Swartz WM, Stark GB, Moller A, Munger BL: Preservation of nerve function in an allogeneic hand transplant model in primates. Transpl Proc 20:335-336, 1988
Patrick CW, Zheng B, Schmidt M, Herman S, Chauvin P, Fan Z, Stark GB, Evans GRD: Dermal Fibroblasts Genetically Engineered to Release Nerve Growth Factor. Ann Plast Surg 47 (47): 660-665, 2001
Penna V, Stark GB, Leibig N, Boyle V, Sakalidou M: Rho-Inhibition by local application of C3-toxin for enhancement of axonal sprouting in a rat end-to-side nerve repair model Microsurg, 2012; 32 (3): 207-212.
Penna, V., Munder, B., Stark, G.B., and Lang, E.M. An in vivo engineered nerve conduit--fabrication and experimental study in rats. Microsurgery 2011 31, 395-400
Penna, V., Stark, G.B., Wewetzer, K., Radtke, C., and Lang, E.M. Comparison of Schwann cells and olfactory ensheathing cells for peripheral nerve gap bridging. Cells, tissues, organs 2012a 196, 534-542.
Penna, V., Wewetzer, K., Munder, B., Stark, G.B., and Lang, E.M. The long-term functional recovery of repair of sciatic nerve transection with biogenic conduits. Microsurgery 2012b 32, 377-382.
Penna V, Wewetzer K, Munder B, Stark GB, Lang E: The biogenic conduit promotes functional recover after sciatric nerve transection under long-term conditions. Muscle Nerve, 2011.
Sakalidou, M., Leibig, N., Boyle, V., Koulaxouzidis, G., and Penna, V. Interleukin-10 and regeneration in an end-to-side nerve repair model of the rat. J Peripher Nerv Syst 2011 16, 334-340.
Vedecnik S.V., Galla T.J., Halbgewachs J., Stark G.B.: Tissue Engineering bei peripheren Nerven - Dreidimensionale Fibrin/Schwann-Zellen-Matrix in Poly-epsilon-Caprolacton-Konduiten zur geführten Defektüberbrückung Chirurgisches Forum 2004, 2004; 33: 13-14
Witzel, C., Reutter, W., Stark, G.B., and Koulaxouzidis, G. N-Propionylmannosamine stimulates axonal elongation in a murine model of sciatic nerve injury. Neural Regen Res 2015 10, 976-981.
Witzel C, Brushart TM, Koulaxouzidis G, Infanger M: Electrical Nerve Stimulation Enhances Perilesional Branching after Nerve Grafting but Fails to Increase Regeneration Speed in a Murine Model. J Reconstr Microsurg, 2016; 32 (6): 491-497
Dr. D. Kraus