Peripheral Nerve Regeneration Using a Nerve Conduit with Olfactory Ensheathing Cells in a Rat Model

Abstract

BACKGROUND:

Autologous nerve grafts are the gold standard treatment for peripheral nerve injury treatment. However, this procedure cannot avoid sacrificing other nerves as a major limitation. The aim of the present study was to evaluate the potential of olfactory ensheathing cells (OECs) embedded in a nerve conduit.

METHODS:

A 10-mm segment of the sciatic nerve was resected in 21 rats, and the nerve injury was repaired with one of the following (n = 7 per group): autologous nerve graft, poly (ε-caprolactone) (PCL) conduit and OECs, and PCL conduit only. The consequent effect on nerve regeneration was measured based on the nerve conduction velocity (NCV), amplitude of the compound muscle action potential (ACMAP), wet muscle weight, histomorphometric analysis, and nerve density quantification.

RESULTS:

Histomorphometric analysis revealed nerve regeneration and angiogenesis in all groups. However, there were significant differences (p < 0.05) in the ACMAP nerve regeneration rate of the gastrocnemius and tibialis anterior muscles between the autologous graft (37.9 ± 14.3% and 39.1% ± 20.4%) and PCL only (17.8 ± 8.6% and 13.6 ± 5.8%) groups, and between the PCL only and PCL + OECs (46.3 ± 20.0% and 34.5 ± 14.6%) groups, with no differences between the autologous nerve and PCL + OEC groups (p > 0.05). No significant results in NCV, wet muscle weight, and nerve density quantification were observed among the 3 groups.

CONCLUSION:

A PCL conduit with OECs enhances the regeneration of injured peripheral nerves, offering a good alternative to autologous nerve grafts.

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References

  1. 1.

    Im JH, Lee JY, Lee S, Lee MG, Chung YG, Kim KW. Comparison of the regeneration induced by acellular nerve allografts processed with or without chondroitinase in a rat model. Cell Tissue Bank. 2019;20:307–19.

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Dalamagkas K, Tsintou M, Seifalian A. Advances in peripheral nervous system regenerative therapeutic strategies: a biomaterials approach. Mater Sci Eng C Mater Biol Appl. 2016;65:425–32.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Nikolaev SI, Gallyamov AR, Mamin GV, Chelyshev YA. Poly(epsilon-caprolactone) nerve conduit and local delivery of vegf and fgf2 genes stimulate neuroregeneration. Bull Exp Biol Med. 2014;157:155–8.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    You H, Wei L, Liu Y, Oudega M, Jiao SS, Feng SN, et al. Olfactory ensheathing cells enhance Schwann cell-mediated anatomical and functional repair after sciatic nerve injury in adult rats. Exp Neurol. 2011;229:158–67.

    PubMed  Article  Google Scholar 

  5. 5.

    Ramón-Cueto A, Valverde F. Olfactory bulb ensheathing glia: a unique cell type with axonal growth-promoting properties. Glia. 1995;14:163–73.

    PubMed  Article  Google Scholar 

  6. 6.

    Dombrowski MA, Sasaki M, Lankford KL, Kocsis JD, Radtke C. Myelination and nodal formation of regenerated peripheral nerve fibers following transplantation of acutely prepared olfactory ensheathing cells. Brain Res. 2006;1125:1–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Cheng SY, Ruan HZ, Wu XG. Olfactory ensheathing cells enhance functional recovery of injured sciatic nerve. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2003;17:18–21.

    PubMed  Google Scholar 

  8. 8.

    Wang C, Shi Z, Wang K. Effect of olfactory ensheathing cells transplantation on protecting spinal cord and neurons after peripheral nerve injury. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2005;19:875–8.

    PubMed  Google Scholar 

  9. 9.

    Delaviz H, Joghataie MT, Mehdizadeh M, Bakhtiyari M, Nobakht M, Khoei S. Transplantation of olfactory mucosa improve functional recovery and axonal regeneration following sciatic nerve repair in rats. Iran Biomed J. 2008;12:197–202.

    PubMed  Google Scholar 

  10. 10.

    Radtke C, Aizer AA, Agulian SK, Lankford KL, Vogt PM, Kocsis JD. Transplantation of olfactory ensheathing cells enhances peripheral nerve regeneration after microsurgical nerve repair. Brain Res. 2009;1254:10–7.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Verdú E, Navarro X, Gudiño-Cabrera G, Rodríguez FJ, Ceballos D, Valero A, et al. Olfactory bulb ensheathing cells enhance peripheral nerve regeneration. NeuroReport. 1999;10:1097–101.

    PubMed  Article  Google Scholar 

  12. 12.

    Li BC, Jiao SS, Xu C, You H, Chen JM. PLGA conduit seeded with olfactory ensheathing cells for bridging sciatic nerve defect of rats. J Biomed Mater Res A. 2010;94:769–80.

    PubMed  Google Scholar 

  13. 13.

    Brandes G, Khayami M, Peck CT, Baumgärtner W, Bugday H, Wewetzer K. Cell surface expression of 27C7 by neonatal rat olfactory ensheathing cells in situ and in vitro is independent of axonal contact. Histochem Cell Biol. 2011;135:397–408.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Guntinas-Lichius O, Angelov DN, Tomov TL, Dramiga J, Neiss WF, Wewetzer K. Transplantation of olfactory ensheathing cells stimulates the collateral sprouting from axotomized adult rat facial motoneurons. Exp Neurol. 2001;172:70–80.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Tisay KT, Key B. The extracellular matrix modulates olfactory neurite outgrowth on ensheathing cells. J Neurosci. 1999;19:9890–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Richter M, Westendorf K, Roskams AJ. Culturing olfactory ensheathing cells from the mouse olfactory epithelium. Methods Mol Biol. 2008;438:95–102.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Vincent AJ, West AK, Chuah MI. Morphological plasticity of olfactory ensheathing cells is regulated by cAMP and endothelin-1. Glia. 2003;41:393–403.

    PubMed  Article  Google Scholar 

  18. 18.

    Goulart CO, Ângelo Durço DF, de Carvalho LA, Oliveira JT, Alves L, Cavalcante LA, et al. Olfactory ensheathing glia cell therapy and tubular conduit enhance nerve regeneration after mouse sciatic nerve transection. Brain Res. 2016;1650:243–51.

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Gu J, Xu H, Xu YP, Liu HH, Lang JT, Chen XP, et al. Olfactory ensheathing cells promote nerve regeneration and functional recovery after facial nerve defects. Neural Regen Res. 2019;14:124–31.

    PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Morrissey TK, Kleitman N, Bunge RP. Isolation and functional characterization of Schwann cells derived from adult peripheral nerve. J Neurosci. 1991;11:2433–42.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Takami T, Oudega M, Bates ML, Wood PM, Kleitman N, Bunge MB. Schwann cell but not olfactory ensheathing glia transplants improve hindlimb locomotor performance in the moderately contused adult rat thoracic spinal cord. J Neurosci. 2002;22:6670–81.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Pearse DD, Sanchez AR, Pereira FC, Andrade CM, Puzis R, Pressman Y, et al. Transplantation of schwann cells and/or olfactory ensheathing glia into the contused spinal cord: survival, migration, axon association, and functional recovery. Glia. 2007;55:976–1000.

    PubMed  Article  Google Scholar 

  23. 23.

    Yang Q, Peng J, Guo Q, Huang J, Zhang L, Yao J, et al. A cartilage ECM-derived 3-D porous acellular matrix scaffold for in vivo cartilage tissue engineering with PKH26-labeled chondrogenic bone marrow-derived mesenchymal stem cells. Biomaterials. 2008;29:2378–87.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Radtke C, Kocsis JD. Peripheral nerve injuries and transplantation of olfactory ensheathing cells for axonal regeneration and remyelination: fact or fiction? Int J Mol Sci. 2012;13:12911–24.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Boruch AV, Conners JJ, Pipitone M, Deadwyler G, Storer PD, Devries GH, et al. Neurotrophic and migratory properties of an olfactory ensheathing cell line. Glia. 2001;33:225–9.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Woodhall E, West AK, Chuah MI. Cultured olfactory ensheathing cells express nerve growth factor, brain-derived neurotrophic factor, glia cell line-derived neurotrophic factor and their receptors. Brain Res Mol Brain Res. 2001;88:203–13.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Nazareth L, Tello Velasquez J, Lineburg KE, Chehrehasa F, St John JA, Ekberg JA. Differing phagocytic capacities of accessory and main olfactory ensheathing cells and the implication for olfactory glia transplantation therapies. Mol Cell Neurosci. 2015;65:92–101.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Su Z, Chen J, Qiu Y, Yuan Y, Zhu F, Zhu Y, et al. Olfactory ensheathing cells: The primary innate immunocytes in the olfactory pathway to engulf apoptotic olfactory nerve debris. Glia. 2013;61:490–503.

    PubMed  Article  Google Scholar 

  29. 29.

    Barton MJ, John JS, Clarke M, Wright A, Ekberg J. The glia response after peripheral nerve injury: a comparison between schwann cells and olfactory ensheathing cells and their uses for neural regenerative therapies. Int J Mol Sci. 2017;18:287.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  30. 30.

    Guérout N, Duclos C, Drouot L, Abramovici O, Bon-Mardion N, Lacoume Y, et al. Transplantation of olfactory ensheathing cells promotes axonal regeneration and functional recovery of peripheral nerve lesion in rats. Muscle Nerve. 2011;43:534–51.

    Article  CAS  Google Scholar 

  31. 31.

    Penna V, Stark GB, Wewetzer K, Radtke C, Lang EM. Comparison of schwann cells and olfactory ensheathing cells for peripheral nerve gap bridging. Cells Tissues Organs. 2012;196:534–42.

    PubMed  Article  Google Scholar 

  32. 32.

    Makadia HK, Siegel SJ. Poly lactic-co-glycolic acid (plga) as biodegradable controlled drug delivery carrier. Polymers (Basel). 2011;3:1377–97.

    CAS  Article  Google Scholar 

  33. 33.

    Fu K, Pack DW, Klibanov AM, Langer R. Visual evidence of acidic environment within degrading poly (lactic-co-glycolic acid) (PLGA) microspheres. Pharm Res. 2000;17:100–6.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Di W, Czarny RS, Fletcher NA, Krebs MD, Clark HA. Comparative study of poly (ε-Caprolactone) and poly (lactic-co-glycolic acid)-based nanofiber scaffolds for pH-sensing. Pharm Res. 2016;33:2433–44.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Vishwakarma A, Sharpe P, Shi S, Ramalingam M. Stem cell biology and tissue engineering in dental sciences. In: 1st ed. USA: Academic Press; 2014.

  36. 36.

    Leong NL, Kabir N, Arshi A, Nazemi A, Jiang J, Wu BM, et al. Use of ultra-high molecular weight polycaprolactone scaffolds for ACL reconstruction. J Orthop Res. 2016;34:828–35.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Navarro X, Udina E. Methods and protocols in peripheral nerve regeneration experimental research: part III-electrophysiological evaluation. Int Rev Neurobiol. 2009;87:105–26.

    PubMed  Article  Google Scholar 

  38. 38.

    Ahn SW, Yoon BN, Kim JE, Seok JM, Kim KK, Lim YM, et al. Nerve conduction studies: basic principal and clinical usefulness. Ann Clin Neurophysiol. 2018;20:71–8.

    Article  Google Scholar 

  39. 39.

    Kimura J. Electrodiagnosis in diseases of nerve and muscles: principles and practice. 4th ed. USA: Oxford University Press; 2013.

    Google Scholar 

  40. 40.

    Misra UK, Kalita J. Clinical neurophysiology: nerve conduction, electromyography, evoked potentials. 3rd ed. Amsterdam: Elsevier; 2013.

    Google Scholar 

  41. 41.

    Lauretani F, Bandinelli S, Bartali B, Di Iorio A, Giacomini V, Corsi AM, et al. Axonal degeneration affects muscle density in older men and women. Neurobiol Aging. 2006;27:1145–54.

    PubMed  Article  Google Scholar 

  42. 42.

    Chamberlain LJ, Yannas IV, Hsu HP, Strichartz G, Spector M. Collagen-GAG substrate enhances the quality of nerve regeneration through collagen tubes up to level of autograft. Exp Neurol. 1998;154:315–29.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Xu JG, Gu YD. Experimental Study of Morphology and Electrophysiology on Denervated Skeletal Muscle. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 1999;13:202–5.

    CAS  PubMed  Google Scholar 

  44. 44.

    Wu JX, Chen L, Ding F, Gu YD. A rat model study of atrophy of denervated musculature of the hand being faster than that of denervated muscles of the arm. J Muscle Res Cell Motil. 2013;34:15–22.

    PubMed  Article  Google Scholar 

  45. 45.

    Wu P, Chawla A, Spinner RJ, Yu C, Yaszemski MJ, Windebank AJ, et al. Key changes in denervated muscles and their impact on regeneration and reinnervation. Neural Regen Res. 2014;9:1796–809.

    PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

This research was supported by a Grant of Translational R&D Project through Institute for Bio-Medical convergence, Incheon St. Mary’s Hospital, The Catholic University of Korea. The authors wish to acknowledge the financial support of the Catholic Medical Center Research Foundation made in the program year of 2017.

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Correspondence to Sang-Uk Lee.

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The animal studies were performed after receiving approval from the Institutional Animal Care and Use Committee of The Catholic University of Korea. (IACUC approval No. CIMH-2017-005). All procedures on animals were performed in accordance with the rules recommended by the Ethics Review Committee for Animal Experimentation.

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Lee, JY., Kim, YH., Kim, BY. et al. Peripheral Nerve Regeneration Using a Nerve Conduit with Olfactory Ensheathing Cells in a Rat Model. Tissue Eng Regen Med (2021). https://doi.org/10.1007/s13770-020-00326-9

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Keywords

  • Peripheral nerve injury
  • Olfactory ensheathing cells
  • Poly (ε-caprolactone) conduit
  • Nerve conduction study