We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Animal models in peripheral nerve transection studies: a systematic review on study design and outcomes assessment

    Bruna Lopes‡

    Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, Porto, 4051-401, Portugal

    Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, Porto, 4050-313,  Portugal

    Associate Laboratory for Animal & Veterinary Science (AL4AnimalS), Lisboa, 1300-477, Portugal

    ‡Authors contributed equally

    Search for more papers by this author

    ,
    André Coelho‡

    Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, Porto, 4051-401, Portugal

    Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, Porto, 4050-313,  Portugal

    Associate Laboratory for Animal & Veterinary Science (AL4AnimalS), Lisboa, 1300-477, Portugal

    ‡Authors contributed equally

    Search for more papers by this author

    ,
    Rui Alvites

    Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, Porto, 4051-401, Portugal

    Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, Porto, 4050-313,  Portugal

    Associate Laboratory for Animal & Veterinary Science (AL4AnimalS), Lisboa, 1300-477, Portugal

    Instituto Universitário de Ciências da Saúde (CESPU), Avenida Central de Gandra 1317, Gandra, Paredes, 4585-116, Portugal

    ,
    Ana Catarina Sousa

    Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, Porto, 4051-401, Portugal

    Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, Porto, 4050-313,  Portugal

    Associate Laboratory for Animal & Veterinary Science (AL4AnimalS), Lisboa, 1300-477, Portugal

    ,
    Patrícia Sousa

    Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, Porto, 4051-401, Portugal

    Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, Porto, 4050-313,  Portugal

    Associate Laboratory for Animal & Veterinary Science (AL4AnimalS), Lisboa, 1300-477, Portugal

    ,
    Alícia Moreira

    Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, Porto, 4051-401, Portugal

    Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, Porto, 4050-313,  Portugal

    Associate Laboratory for Animal & Veterinary Science (AL4AnimalS), Lisboa, 1300-477, Portugal

    ,
    Luís Atayde

    Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, Porto, 4051-401, Portugal

    Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, Porto, 4050-313,  Portugal

    Associate Laboratory for Animal & Veterinary Science (AL4AnimalS), Lisboa, 1300-477, Portugal

    ,
    António Salgado

    Life & Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal

    ICVS/3B's e PT Government Associate Laboratory, Braga/Guimarães, Portugal

    ,
    Stefano Geuna

    Department of Clinical & Biological Sciences, & Cavalieri Ottolenghi Neuroscience Institute, University of Turin, Ospedale San Luigi, Orbassano, Turin, 10043, Italy

    &
    Ana Colette Maurício

    *Author for correspondence:

    E-mail Address: acmauricio@icbas.up.pt

    Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, Porto, 4051-401, Portugal

    Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, Porto, 4050-313,  Portugal

    Associate Laboratory for Animal & Veterinary Science (AL4AnimalS), Lisboa, 1300-477, Portugal

    Published Online:https://doi.org/10.2217/rme-2023-0102

    Aim: Peripheral nerve injury regeneration studies using animal models are crucial to different pre-clinical therapeutic approaches efficacy evaluation whatever the surgical technique explored. Materials & methods: A 944 articles systematic review on ‘peripheral nerve injury in animal models’ over the last 9 years was carried out. Results: It was found that 91% used rodents, and only 9% employed large animals. Different nerves are studied, with generated gaps (10,78 mm) and methods applied for regeneration evaluation uniformed. Sciatic nerve was the most used (88%), followed by median and facial nerves (2.6%), significantly different. Conclusion: There has not been a significant scale-up of the in vivo testing to large animal models (anatomically/physiologically closer to humans), allowing an improvement in translational medicine for clinical cases.

    References

    • 1. Lopes B, Sousa P, Alvites R et al. Peripheral nerve injury treatments and advances: one health perspective. Int. J. Mol. Sci. 23(2), 918 (2022).
    • 2. Zhang M, LiL, AnH, ZhangP, Liu P. Repair of peripheral nerve injury using hydrogels based on self-assembled peptides. Gels 7(4), 152 (2021).
    • 3. AlvitesR, Rita Caseiro A, Santos Pedrosa S et al. Peripheral nerve injury and axonotmesis: state of the art and recent advances. Cogent Medicine 5(1), 1466404 (2018).
    • 4. WangML, Rivlin M, Graham JG, Beredjiklian PK.Peripheral nerve injury, scarring, and recovery. Connect. Tissue Res. 60(1), 3–9 (2019).
    • 5. ChhabraA, Ahlawat S, Belzberg A, Andreseik G.Peripheral nerve injury grading simplified on MR neurography: as referenced to Seddon and Sunderland classifications. Indian J. Radiol. Imaging. 24(3), 217–224 (2014).
    • 6. ShenX, Qu F, Pei Y et al. Repairing sciatic nerve injury with self-assembling peptide nanofiber scaffold-containing chitosan conduit. Front. Neurol. 13, doi: 10.3389/fneur.2022.867711 (2022).
    • 7. Takaoka S, UchidaF, Ishikawa H et al. Transplanted neural lineage cells derived from dental pulp stem cells promote peripheral nerve regeneration. Hum. Cell 35(2), 462–471 (2022).
    • 8. Ma X, ElsnerE, CaiJ, Smith TL, LiZ . Peripheral nerve regeneration with acellular nerve allografts seeded with amniotic fluid-derived stem cells. Stem Cells Int. 2022, doi: 10.1155/2022/5240204 (2022).
    • 9. LiuYJ, Chen XF, Zhou LP et al. A nerve conduit filled with Wnt5a-loaded fibrin hydrogels promotes peripheral nerve regeneration. CNS Neurosci. Ther. 28(1), 145–157 (2022).
    • 10. Ray WZ, Mackinnon SE. Management of nerve gaps: autografts, allografts, nerve transfers, and end-to-side neurorrhaphy. Exp. Neurol. 223(1), 77–85 (2010).
    • 11. Campbell WW. Evaluation and management of peripheral nerve injury. Clin. Neurophysiol. 119(9), 1951–1965 (2008).
    • 12. Nuelle JAV, Bozynski C, Stoker A. Innovations in peripheral nerve injury: current concepts and emerging techniques to improve recovery. Sci. Med. 119(2), 129–135 (2022).
    • 13. Zhu J, FuQ, SongL et al. Advances in peripheral nerve injury repair with the application of nanomaterials. J. Nanomat. 2022, 1–22 (2022).
    • 14. LiA, Pereira C, Hill EE, Vukcevich O, Wang A.In Vitro, In Vivo and Ex Vivo Models for Peripheral Nerve Injury and Regeneration. Curr. Neuropharmacol. 20(2), 344–361 (2022).
    • 15. Kaplan HM, Mishra P, Kohn J. The overwhelming use of rat models in nerve regeneration research may compromise designs of nerve guidance conduits for humans. J. Mater. Sci. Mater. Med. 26(8), 226 (2015).
    • 16. LiuK, Yan L, Li R et al. 3D printed personalized nerve guide conduits for precision repair of peripheral nerve defects. Adv. Sci. (Weinh). 9(12), e2103875 (2022).
    • 17. Kaplan B, Levenberg S. The role of biomaterials in peripheral nerve and spinal cord injury: a review. Int. J. Mol. Sci. 23(3), 1244 (2022).
    • 18. NiL, Yao Z, Zhao Y et al. Electrical stimulation therapy for peripheral nerve injury. Front. Neurol. 14, doi: 10.3389/fneur.2023.1081458 (2023).
    • 19. Abd-Elsayed A, D'Souza RS. Peripheral nerve stimulation: the evolution in pain medicine. Biomedicine 10(1), 18 (2021).
    • 20. Ortiz AC, Fideles SOM, Pomini KT et al. Potential of fibrin glue and mesenchymal stem cells (MSCs) to regenerate nerve injuries: a systematic review. Cells. 11(2), 221 (2022).
    • 21. KlimovichP, Rubina K, Sysoeva V, Semina E.New frontiers in peripheral nerve regeneration: concerns and remedies. Int. J. Mol. Sci. 22(24), 13380 (2021).
    • 22. LuzhanskyID, Sudlow LC, Brogan DM, Wood MD, Berezin MY. Imaging in the repair of peripheral nerve injury. Nanomed. (Lond). 14(20), 2659–2677 (2019).
    • 23. Krarup C, Archibald SJ, Madison RD. Factors that influence peripheral nerve regeneration: an electrophysiological study of the monkey median nerve. Ann. Neurol. 51(1), 69–81 (2002).
    • 24. UdinaE, Cobianchi S, Allodi I, Navarro X. Effects of activity-dependent strategies on regeneration and plasticity after peripheral nerve injuries. Ann. Anat. 193(4), 347–353 (2011).
    • 25. Martinez de Albornoz P, Delgado PJ, Forriol F, MaffulliN . Non-surgical therapies for peripheral nerve injury. Br. Med. Bull. 100, 73–100 (2011).
    • 26. GriffinJW, Hogan MV, Chhabra AB, Deal DN. Peripheral nerve repair and reconstruction. J. Bone Joint Surg. Am. 95(23), 2144–2151 (2013).
    • 27. Sondekoppam RV, Tsui BC. Factors associated with risk of neurologic complications after peripheral nerve blocks: a systematic review. Anesth. Analg. 124(2), 645–660 (2017).
    • 28. Vela FJ, Martinez-ChaconG, Ballestin A et al. Animal models used to study direct peripheral nerve repair: a systematic review. Neural Regen. Res. 15(3), 491–502 (2020).
    • 29. Navarro X, Vivo M, Valero-Cabre A. Neural plasticity after peripheral nerve injury and regeneration. Prog. Neurobiol. 82(4), 163–201 (2007).
    • 30. Gordon T, Borschel GH. The use of the rat as a model for studying peripheral nerve regeneration and sprouting after complete and partial nerve injuries. Exp. Neurol. 287(Pt 3), 331–347 (2017).
    • 31. MaT, Hao Y, Li S et al. Sequential oxygen supply system promotes peripheral nerve regeneration by enhancing Schwann cells survival and angiogenesis. Biomaterials 289, doi: 10.1016/j.biomaterials.2022.121755 (2022).
    • 32. KimSM, Lee MS, Jeon J et al. Biodegradable nerve guidance conduit with microporous and micropatterned poly(lactic-co-glycolic acid)-accelerated sciatic nerve regeneration. Macromol. Biosci. 18(12), e1800290 (2018).
    • 33. AngiusD, Wang H, Spinner RJ et al. A systematic review of animal models used to study nerve regeneration in tissue-engineered scaffolds. Biomaterials 33(32), 8034–8039 (2012).
    • 34. Jeans LA, Gilchrist T, Healy D. Peripheral nerve repair by means of a flexible biodegradable glass fibre wrap: a comparison with microsurgical epineurial repair. J. Plast. Reconstr. Aesthet. Surg. 60(12), 1302–1308 (2007).
    • 35. GLASBYM A, GILMOUR JA, GSCHMEISSNER SE, HEMS TEJ, MYLES LM.The repair of large peripheral nerves using skeletal muscle autografts: a comparison with cable grafts in the sheep femoral nerve. Br. J. Plast. Surg. 43(2), 169–173 (1990).
    • 36. IkumiA, Hara Y, Yoshioka T, Kanamori A, Yamazaki M. Effect of local administration of platelet-rich plasma (PRP) on peripheral nerve regeneration: an experimental study in the rabbit model. Microsurgery 38(3), 300–309 (2018).
    • 37. Ronchi G, GambarottaG, Morano M et al. Critical analysis of the value of the rabbit median nerve model for biomedical research on peripheral nerve grafts. J. Tissue Eng. Regen. Med. 14(5), 736–740 (2020).
    • 38. Liu F, XuJ, LiuA et al. Development of a polyacrylamide/chitosan composite hydrogel conduit containing synergistic cues of elasticity and topographies for promoting peripheral nerve regeneration. Biomater. Sci. 10(17), 4915–4932 (2022).
    • 39. QiaoW, Lu L, Wu G et al. DPSCs seeded in acellular nerve grafts processed by Myroilysin improve nerve regeneration. J. Biomater. Appl. 33(6), 819–833 (2019).
    • 40. MitsuzawaS, Ikeguchi R, Aoyama T et al. The Efficacy of a Scaffold-free Bio 3D Conduit Developed from Autologous Dermal Fibroblasts on Peripheral Nerve Regeneration in a Canine Ulnar Nerve Injury Model: A Preclinical Proof-of-Concept Study. Cell Transplant. 28(9–10), 1231–1241 (2019).
    • 41. BurrellJC, Bhatnagar D, Brown DP et al. Tyrosine-derived polycarbonate nerve guidance tubes elicit proregenerative extracellular matrix deposition when used to bridge segmental nerve defects in swine. J. Biomed. Mater Res A. 109(7), 1183–1195 (2021).
    • 42. Peng Y, Li KY, Chen YF et al. Beagle sciatic nerve regeneration across a 30mm defect bridged by chitosan/PGA artificial nerve grafts. Injury 49(8), 1477–1484 (2018).
    • 43. YaoY, Cui Y, Zhao Y et al. Efect of longitudinally oriented collagen conduit combined with nerve growth factor on nerve regeneration after dog sciatic nerve injury. J. Biomed. Mater. Res. B Appl. Biomater. 106(6), 2131–2139 (2018).
    • 44. KornfeldT, 0Nessler J, Helmer C et al. Spider silk nerve graft promotes axonal regeneration on long distance nerve defect in a sheep model. Biomaterials 271, doi: 10.1016/j.biomaterials.2021.120692 (2021).
    • 45. Roballo KCS, Burns DT, Ghnenis AB, Osimanjiang W, Bushman JS. Long-term neural regeneration following injury to the peroneal branch of the sciatic nerve in sheep. Eur. J. Neurosci. 52(10), 4385–4394 (2020).
    • 46. Alvites RD, Branquinho MV, Sousa AC et al. Establishment of a Sheep Model for Hind Limb Peripheral Nerve Injury: Common Peroneal Nerve. Int. J. Mol. Sci. 22(3), 1401 (2021).
    • 47. MukherjeeP, Roy S, Ghosh D, Nandi SK. Role of animal models in biomedical research: a review. Lab. Anim. Res. 38(1), 18 (2022).
    • 48. Morrison JL, Botting KJ, Darby JRT et al. Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic. J. Physiol. 596(23), 5535–5569 (2018).
    • 49. KwanMK, Wall EJ, Massie J, Garfin SR. Strain, stress and stretch of peripheral nerve. Rabbit experiments in vitro and in vivo. Acta Orthop. Scand. 63(3), 267–272 (1992).
    • 50. Barthold SW, Bolser DC, Garcia KD, Haywood JR, Leland SE, Miller L. Scientific and humane issues in the use of random source dogs and cats in research. National Academies Press (US), WA, USA (2009).
    • 51. FULLARTONAC, LENIHAN DV, MYLES LM, GLASBY MA. Assessment of the method and timing of repair of a brachial plexus traction injury in an animal model for obstetric brachial plexus palsy. J. Hand Surg. 27(1), 13–19 (2002).
    • 52. Fullarton AC, Lenihan DV, Myles LM, Glasby MA. Obstetric brachial plexus palsy: a large animal model for traction injury and its repair. Part 1: age of the recipient. J. Hand Surg. (Br) 25(1), 52–57 (2000).
    • 53. Kaslin J, Ganz J, Brand M. Proliferation, neurogenesis and regeneration in the non-mammalian vertebrate brain. Philos. Trans. R Soc. Lond. B Biol Sci. 363(1489), 101–122 (2008).
    • 54. Monte-RasoVV, Barbieri CH, Mazzer N, Yamasita AC, Barbieri G. Is the Sciatic Functional Index always reliable and reproducible? J. Neurosci. Methods 170(2), 255–261 (2008).
    • 55. SayanagiJ, Tanaka H, Ebara M et al. Combination of electrospun nanofiber sheet incorporating methylcobalamin and PGA-collagen tube for treatment of a sciatic nerve defect in a rat model. J. Bone Joint Surg. Am. 102(3), 245–253 (2020).
    • 56. MohammadiR, Mehrtash M, Mehrtash M, Sajjadi SS. Nonexpanded adipose stromal vascular fraction local therapy on peripheral nerve regeneration using allografts. J. Invest. Surg. 29(3), 149–156 (2016).
    • 57. WangG, Cao L, WangY et al. Human eyelid adipose tissue-derived Schwann cells promote regeneration of a transected sciatic nerve. Sci. Rep. 7, doi: 10.1038/srep43248 (2017).
    • 58. MikeshM, Ghergherehchi CL, Rahesh S et al. Polyethylene glycol treated allografts not tissue matched nor immunosuppressed rapidly repair sciatic nerve gaps, maintain neuromuscular functions, and restore voluntary behaviors in female rats. J. Neurosci. Res. 96(7), 1243–1264 (2018).
    • 59. MarquardtLM, Ee X, Iyer N et al. Finely tuned temporal and spatial delivery of gdnf promotes enhanced nerve regeneration in a long nerve defect model. Tissue Eng. Part A. 21(23–24), 2852–2864 (2015).
    • 60. Dayawansa S, Wang EW, LiuW et al. Allotransplanted DRG neurons or Schwann cells affect functional recovery in a rodent model of sciatic nerve injury. Neurol. Res. 36(11), 1020–1027 (2014).
    • 61. hangLQ, Zhang W, Li T et al. GLP-1R activation ameliorated novel-object recognition memory dysfunction via regulating hippocampal AMPK/NF-kappaB pathway in neuropathic pain mice. Neurobiol. Learn. Mem. 182, DOI: 10.1016/j.nlm.2021.107463 (2021).
    • 62. Rayner MLD, Brown HL, Wilcox M, Phillips JB, Quick TJ. Quantifying regeneration in patients following peripheral nerve injury. J. Plast. Reconstr. Aesthet. Surg. 73(2), 201–208 (2020).
    • 63. Isvoranu G, Manole E, Neagu M. Gait Analysis Using Animal Models of Peripheral Nerve and Spinal Cord Injuries. Biomedicines 9(8), 1050 (2021).
    • 64. Kornfeld T, Vogt PM, Radtke C. Nerve grafting for peripheral nerve injuries with extended defect sizes. Wien Med. Wochenschr. 169(9–10), 240–251 (2019).
    • 65. Lee DH, Lee JK. Animal models of axon regeneration after spinal cord injury. Neurosci. Bull. 29(4), 436–444 (2013).
    • 66. ContrerasE, Traserra S, Bolivar Set al.Repair of long peripheral nerve defects in sheep: a translational model for nerve regeneration. Int. J. Mol. Sci. 24(2), 1333 (2023).
    • 67. Narayan SK, Arumugam M, Chittoria R. Outcome of human peripheral nerve repair interventions using conduits: a systematic review. J. Neurol. Sci. 396, 18–24 (2019).