ABB  Vol.4 No.6 A , June 2013
Therapeutic approaches enhancing peripheral nerve regeneration
Abstract: Peripheral nerve injury is a common occurrence and represents a major economic burden for society. The development of novel strategies to enhance peripheral nerve regeneration is, therefore, of great relevance. Conventional treatments include surgical repair of the damaged nerves for minor injuries, whereas autologous nerve grafts are required to recover longer interruptions. However, despite great surgical advances, functional recovery is often poor. Although it is well known that the peripheral nervous system has a greater regenerative capacity than the central nervous system and, considering the scientific advancements and knowledge in regenerative medicine, clinical applications appears still limited. This review provides an overview of the methodological approaches currently under study, aimed at enhancing peripheral nerve regeneration. In particular, tissue engineering, cell therapy and pharmacological approaches will be discussed.
Cite this paper: Stefano, M. , Toni, F. , Orazi, V. , Ortensi, A. and Tata, A. (2013) Therapeutic approaches enhancing peripheral nerve regeneration. Advances in Bioscience and Biotechnology, 4, 53-60. doi: 10.4236/abb.2013.46A008.

[1]   Beris, A., Lykissas, M., Korompilias, A. and Mitsionis, G. (2007) End-to-side nerve repair in peripheral nerve injury. Journal of Neurotrauma, 24, 909-916. doi:10.1089/neu.2006.0165

[2]   Lundborg, G. (2002) Enhancing posttraumatic nerve regeneration. Journal of Peripheral Nervous System, 7, 139-140. doi:10.1046/j.1529-8027.2002.02019.x

[3]   Beris, A. and Lykissas M.G. (2009) Experimental results in end-to-side neurorrhapy. International Review Neurobiology, 87, 269-279. doi:10.1016/S0074-7742(09)87013-X

[4]   Harley, B.A., Leung, J.H., Silva, E.C.C.M. and Gibson, L. J. (2007) Mechanical characterization of collagenglycosaminoglycan scaffolds. Acta Biomaterials, 3, 463474. doi:10.1016/j.actbio.2006.12.009

[5]   Chiono, V., Tonda-Turo, C. and Ciardelli, G. (2009) Artificial scaffolds for peripheral nerve reconstruction. International Review Neurobiology, 87, 173-198. doi:10.1016/S0074-7742(09)87009-8

[6]   Chiono, V., Ciardelli, G., Vozzi, G., Vozzi, F., Salvadori, C., Dini, F., Carlucci, F., et al. (2009) Melt extruded guides for peripheral nerve regeneration. Biomed Microdevices, 11, 1037-1350. doi:10.1007/s10544-009-9321-9

[7]   Yan, Q.J., Li, J., Li, S.P. and Zhang, P. (2008) Synthesis and RDG peptide modifications of poly(lactic acid)-co[(glycolic acid)-alt-(L-lysine)]. ePolimers, 28, 1-12.

[8]   Magnaghi, V., Conte, V., Procacci, P., Pivato, G., Cortese, P., Cavalli, E., Pajardi, G., Ranucci, E., Fenili, F., Manfredi, A. and Ferruti, P. (2011) Biological performance of a novel biodegradable polyaminodoamine hydrogel as guide for peripheral nerve regeneration. Journal Biomedical Materials Research, 98, 19-30. doi:10.1002/jbm.a.33091

[9]   Franchini, J., Ranucci, E., Ferruti, P., Rossi, R. and Cavalli, R. (2006) Synthesis, physicochemical properties, and preliminary biological characterizations of a novel amphoteric agmatine-based poly(amidoamine) with RGDlike repeating units. Biomacromolecules, 7, 1215. doi:10.1021/bm060054m

[10]   Jacchetti, E., Emilitri, E, Rodighiero, S., Indrieri, M., Gianfelice, A., Lenardi, C., Podestà, A., Ranucci, E., Ferruti, P. and Milani, P. (2008) Biomimetic poly(amidoamine) hydrogels as synthetic materials for cell culture. Journal Nanobiotechnology, 6, 1-14. doi:10.1186/1477-3155-6-14

[11]   Mauro, N., Manfredi, A., Ranucci, E., Procacci, P., Larus, M., Antonioli, D., Mantovani, C., Magnaghi, V. and Ferruti, P. (2013) Degradable poly(aminodoamine) hydrogels as scaffolds for in vitro culturing of peripheral nervous system cells. Macromolecular Bioscience, 13, 332-347. doi:10.1002/mabi.201200354

[12]   Battiston, B., Raimondo, S., Tos, P., Goidano, V., Audisio, C., Scevola, A., Perroteau, I. and Geuna, S. (2009) Tissue engineering of peripheral nerves. International Review Neurobiology, 87, 227-249. doi:10.1016/S0074-7742(09)87011-6

[13]   Brunelli, G.A., Battiston, B., Vigasio, A., Brunelli, G. and Marocolo, D. (1993) Bridging nerve defects with combined skeletal muscle and vein conduits. Microsurgery, 14, 247-251. doi:10.1002/micr.1920140407

[14]   Battiston, B., Tos, P., Cushway, T. and Geuna, S. (2000) Nerve repair by means of vein filled with muscle grafts. I. Clinical results. Microsurgery, 20, 32-36. doi:10.1002/(SICI)1098-2752(2000)20:1<32::AID-MICR6>3.0.CO;2-D

[15]   Geuna, S., Raimondo, S., Nicolino, S., Boux, E., Fornaro, M., Tos, P., Battiston, B. and Perroteau, I. (2003) Schwann-cell proliferation in muscle-vein combined conduits for bridging rat sciatic nerve defects. Journal Reconstruction Microsurgery, 19, 119-123. doi:10.1055/s-2003-37818

[16]   Raimondo, S., Nicolino, S., Tos, P., Battiston, B., Giacobini-Robecchi, M.G., Perroteau, I., Geuna, S. (2005) Schwann cell behavior after nerve repair by means of tissue-engineered muscle-vein combined guides. Journal Comparative Neurology, 489, 249-255. doi:10.1002/cne.20625

[17]   Nicolino, S., Raimondo, S., Tos, P., Battiston, B., Fornaro, M., Geuna, S. and Perroteau, I. (2003) Expression of alpha2a-2b neuregulin-1 is associated with early peripheral nerve repair along muscle-enriched tubes. Neuroreport, 14, 1541-1545. doi:10.1097/00001756-200308060-00029

[18]   Fu, S.Y. and Gordon, T. (1997) The cellular and molecular basis of peripheral nerve regeneration. Molecular Neurobiology, 14, 67-116. doi:10.1007/BF02740621

[19]   Magnaghi, V., Procacci, P. and Tata, A.M. (2009) Novel pharmacological approaches to Schwann cells as neuroprotective agents for peripheral nerve regeneration. International Review Neurobiology, 87, 295-315. doi:10.1016/S0074-7742(09)87015-3

[20]   Frostick, S.P., Yin, Q. and Kemp, G.J. (1998) Schwann cells, neurotrophic factors and peripheral nerve regeneration. Microsurgery, 18, 397-405. doi:10.1002/(SICI)1098-2752(1998)18:7<397::AID-MICR2>3.0.CO;2-F

[21]   Hall, S. (2005) The response to injury in the peripheral nervous system. Journal of Bone & Joint Surgery, 87, 1309-1319.

[22]   Li, Q., Ping, P., Jiang, H. and Liu, K. (2006) Nerve conduit filled with GDNF gene modified Schwann cells enhances regeneration of the peripheral nerve. Microsurgery, 26, 116-121. doi:10.1002/micr.20192

[23]   Yan, Q., Yin, Y. and Binbin, L. (2012) Use new PLGLRGD-NGF nerve conduits for promoting peripheral nerve regeneration. Biomedical Engineering Online, 11, 36. doi:10.1186/1475-925X-11-36

[24]   Tohill, M. and Terenghi, G. (2004) Stem cell plasticity and therapy for injuries of the peripheral nervous system. Biotechnologies Applied Biochemistry and Biotechnology, 40, 17-24. doi:10.1042/BA20030173

[25]   Barry, E.P. and Murphy, J.M. (2004) Mesenchymal stem cells: clinical applications and biological characterization. International Journal Biochemical Cell Biology, 36, 568-584. doi:10.1016/j.biocel.2003.11.001

[26]   Strem, B.M., Icok, K.C., Zhu, M., Wulur, I., Alfonso, Z., Schreiber, R.E., Fraser, K.J. and Hedrick, M.H. (2005) Multipotential differentiation of adipose tissue derived stem cells. Keio Journal Medicine, 54, 132-141. doi:10.2302/kjm.54.132

[27]   Caddick, J., Kingham, P.J., Gardiner, N.J. Wiberg, M., Terenghi, G. (2006) Phenotypic and functional characteristic of mesenchymal stem cells differentiated along a Schwann cell lineage. Glia, 54, 840-849. doi:10.1002/glia.20421

[28]   Devon, R. and Doucette, R. (1992) Olfactory ensheathing cells myelinate dorsal root ganglion neurites. Brain Research, 589, 175-179. doi:10.1016/0006-8993(92)91182-E

[29]   Carr, V.M. and Farbman, A.I. (1992) Ablation of the olfactory bulb up-regulates the rate of neurogenesis and induces precocious cell death in olfactory epithelium. Experimental Neurology, 115, 55-59. doi:10.1016/0014-4886(92)90221-B

[30]   Li, Y., Field, P.M. and Raisman, G. (1997) Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells. Science, 277, 2000-2002. doi:10.1126/science.277.5334.2000

[31]   Radtke, C., Kocsis, J.D. and Vogt, P.M. (2009) Transplantation of oltactory ensheating cells for peripheral nerve regeneration. International Review Neurobiology, 87, 405-415. doi:10.1016/S0074-7742(09)87022-0

[32]   Marshall, C.T., Lu, C., Winstead, W., Zhang, X., Xiao, M., Harding, G., Klueber, K.M. and Roisen, F.J. (2006) The therapeutic potential of human olfactory-derived stem cells. Histology Histopathoogy, 21, 633-643.

[33]   Guntinas-Lichius, O., Angelov, D.N., Tomov, T.L., Dramiga, J., Neiss, W.F. and Wewetzer, K. (2001) Trans-plantation of olfactory ensheathing cells stimulates the collateral sprouting from axotomized adult rat facial motoneurons. Experimental Neurology, 172, 70-80. doi:10.1006/exnr.2001.7774

[34]   Deumens, R., Koopmans, G.C., Lemmens, M., Mollers, S., Honig, W.M., Steinbusch, H.W., Brook, G. and Joosten, E.A. (2006) Neurite outgrowth promoting effects of enriched and mixed OEC/ONF cultures. Neuroscience Letters, 397, 20-24. doi:10.1016/j.neulet.2005.11.063

[35]   Richardson, P.M. (1991) Neurotrophic factors in regeneration. Current Opinion Neurobiology, 1, 401-406. doi:10.1016/0959-4388(91)90061-B

[36]   Levi Montalcini, R. (1987) The nerve growth factor 35 years later. Science, 237, 1154-1162. doi:10.1126/science.3306916

[37]   Tuszynski, M.H. and Blesch, A. (2004) Nerve growth factor: From animal models of cholinergic neuronal degeneration to gene therapy in Alzheimer’s disease. Progress Brain Research, 146, 441-449. doi:10.1016/S0079-6123(03)46028-7

[38]   Hempstead, B.L. (2006) Dissecting the diverse actions of pro-and mature neurotrophins. Current Alzheimer Research, 3, 19-24. doi:10.2174/156720506775697061

[39]   Sun, W., Sun, C., Lin, H., Zhao, H., Wang, J., Ma, H., Chen, B., Xiao, Z. and Dai, J. (2009) The effect of collagen-binding NGF-beta on the promotion of sciatic nerve regeneration in a rat sciatic nerve crush injury model. Biomaterials, 30, 4649-4656. doi:10.1016/j.biomaterials.2009.05.037

[40]   Rutkowski, G.E., Miller, C.A., Jeftinija, S. and Mallapragada, S.K. (2004) Synergistic effects of micropatterned biodegradable conduits and Schwann cells on sciatic nerve regeneration. Journal of Neural Engineering, 1, 151-157. doi:10.1088/1741-2560/1/3/004

[41]   Xu, X., Yu, H., Gao, S., Mao, H.Q., Leong, K.W. and Wang, S. (2002) Polyphosphoester microspheres for sustained release of biologically active nerve growth factor. Biomaterials, 23, 3765-3772. doi:10.1016/S0142-9612(02)00116-3

[42]   Terenghi, G. (1999) Peripheral nerve regeneration and neurotrophic factors. Journal of Anatomy, 194, 1-14. doi:10.1046/j.1469-7580.1999.19410001.x

[43]   Mohanna, P.N., Terenghi, G. and Wiberg, M. (2005) Composite PHB-GGF conduit for long nerve gap repair: A long-term evaluation. Scandinavian Journal of Plastic and Reconstructive Surgery and Hand Surgery, 39, 129137. doi:10.1080/02844310510006295

[44]   Nguyen, L., Rigo, J.M., Roche, V., Belachew, S., Malgrange, B., Rogister, B., et al. (2001) Neurotransmitters as early signals for central nervous system development. Cell and Tissue Research, 301, 187-202. doi:10.1007/s004410000343

[45]   Zheng, J.Q., Felder, M., Connor, J.A. and Poo, M. (1994) Turning of nerve growth cones induced by neurotransmitters. Nature, 368, 140-144. doi:10.1038/368140a0

[46]   Kuffler, D.P. (1996) Chemioattraction of sensory growth cones by diffusible concentration gradients of acetylcholine. Molecular Chemical Neuropathology, 28, 199-208. doi:10.1007/BF02815223

[47]   Tata, A.M., Cursi, S., Biagioni, S. and Augusti, T.G. (2003) Cholinergic modulation of neurite outgrowth and neurofilament expression in developing chick sensory neurons. Journal Neuroscience Research, 73, 227-234. doi:10.1002/jnr.10650

[48]   Bernardini, N., Srubek, T.G., Tata, A.M., Augusti-Tocco, G. and Biagioni, S. (2004) Detection of basal and potassium-evoked acetylcholine release from embryonic DRG explants. Journal Neurochemistry, 88, 1533-1539. doi:10.1046/j.1471-4159.2003.02292.x

[49]   Loreti, S., Vilaró, M.T., Visentin, S., Rees, H., Levey, A.I. and Tata, A.M. (2006) Rat Schwann cells express M1-M4 muscarinic receptor subtypes. Journal Neuroscience Research, 84, 97-105. doi:10.1002/jnr.20874

[50]   Loreti, S., Ricordy, R., De Stefano, M.E., Augusti-Tocco, G. and Tata, A.M (2007) Acetylcholine inhibits cell cycle progression in cultured rat Schwann cells by activation of M2 receptor subtype. Neuron Glia Biology, 3, 269-279. doi:10.1017/S1740925X08000045

[51]   Gumera, C.B. and Wang, Y. (2007) Modulating neuronal responses by controlled integration of acetylcholine-like functionalities in biomimetic polymers. Advances Materials, 19, 4404-4409. doi:10.1002/adma.200701747

[52]   Tu, Q., Li, L., Zhang, Y., Wang, J., Liu, R., Li, M., Liu, W. and Wang, X. (2011) The effect of acetylcholine-like biomimetic polymers on neuronal growth. Biomaterials, 32, 3253-3264. doi:10.1016/j.biomaterials.2011.01.044