Elsevier

Journal of Neuroscience Methods

Volume 243, 30 March 2015, Pages 39-46
Journal of Neuroscience Methods

Basic Neuroscience
Review
The sciatic nerve injury model in pre-clinical research

https://doi.org/10.1016/j.jneumeth.2015.01.021Get rights and content

Highlights

  • The far most used experimental model for the study of peripheral nerve repair and regeneration is based on the injury of the sciatic nerve.

  • The potential application of the sciatic nerve injury model in pre-clinical research is critically reviewed.

  • The aim is to help researchers in properly employing this in vivo model and interpreting the results in a clinical translation perspective.

Abstract

In the pre-clinical view, the study of peripheral nerve repair and regeneration still needs to be carried out in animal models due to the structural complexity of this organ which can be only partly simulated in vitro. The far most used experimental model is based on the injury of the sciatic nerve, the largest nerve trunk in mammals. In this paper, the potential application of the sciatic nerve injury model in pre-clinical research is critically reviewed. This paper is aimed at helping researchers in properly employing this in vivo model for the study of nerve repair and regeneration as well as interpreting the results in a clinical translation perspective.

Introduction

Because of their spread distribution throughout the body, peripheral nerves are particularly subject to injuries mainly due to traumatic, e.g. work accidents, or iatrogenic, e.g. for tumor excision lesion (Evans, 2001, Siemionow and Brzezicki, 2009, Isaacs et al., 2013). Although usually not threatening the patient's life, nerve injuries represent a heavy social burden in terms of both long term disability and economic costs (Asplund et al., 2009, Rosberg et al., 2013). For this reason, growing efforts are dedicated to the development of effective treatment for peripheral nerve injuries which increase tissue regeneration and functional recovery and might be eventually translated to the patients for improving the clinical outcome (Tos et al., 2013, Griffin et al., 2013).

This body of pre-clinical research is mainly carried out in animal models since, so far, in vitro investigation of nerve regeneration is very limited due to the structural complexity of this organ which can hardly be reproduced in vitro (Geuna et al., 2009). The far most used experimental paradigm for the pre-clinical investigation of peripheral nerve regeneration is represented by the sciatic nerve injury (SNI) model (Siironen et al., 1996, Beer et al., 2001, Varejão et al., 2004a, Varejão et al., 2004b, Nichols et al., 2005, Savastano et al., 2014). Among the various reasons that might explain the preponderancy of SNI employment, two are the most important: (i) the large size of the sciatic nerve which facilitates surgery; (ii) the easy surgical access; (iii) the sought for data that can be comparable with previous studies, the very large majority of which have been carried out using the SNI model.

Due to the enormous number of experimental papers reporting data obtained with SNI model, a comprehensive review would be almost impossible and, probably, not so useful for researchers. By contrast, the aim of this paper is to overview a selection of relevant papers with the goal of providing the reader with some useful indications about the potentiality of employment of the SNI model as well as some methodological information that might help researchers in critically interpreting the results in a translational perspective.

Section snippets

Compression lesions

Experimental models based on the mechanical compression of the sciatic nerve have been widely used in experimental research in order to investigate the changes occurring to the nerve, proximal and distal to the lesion, as well as to the other central (e.g. neuronal cell bodies) and distal (e.g. muscles) anatomical structures. Sciatic nerve compression can be obtained by either ligation or crush of the epineurium. While ligation, that can be transiently applied and is used for the study of

Transection lesions

Although the experimental model based on the sciatic nerve crush injury has several advantages in terms of feasibility and reproducibility, its translational potential is limited for two main reasons. First, most surgically relevant nerve lesions in human patients are characterized by at least partial transection/laceration of the nerve. Second, crush lesions in patients have a different clinical history in comparison to experimental crush lesions in laboratory animals, namely spontaneous axon

Considerations about selection of the animal species

The SNI model has been used in number different animal species. The rat is by far the most used species (Angius et al., 2012) as shown by more than 13,000 entries obtainable in a PubMed query up to July 2014. When the same query is carried out for the mouse, the second most used animal species, the number of entries drops to about 3500, while the third most widely used species for SNI model is the rabbit with about 1500 entries. Whereas the rat clearly represent the species of choice for SCI

Surgery

Experimental surgery on the sciatic nerve is relatively easy due to its large size (the largest nerve in mammals). The sciatic nerve is a mixed nerve (Schmalbruch, 1986) which originates from the lumbo-sacral plexus and ends at the knee level with its terminal division that is usually represented by a trifurcation: the tibial nerve (the biggest one) the common peroneal nerve and the sural nerve (Rupp et al., 2007b). However, there is a high anatomical variability in the number and site of

Discussion

The investigation of nerve repair and regeneration has a long history and still today represents, un-doubtfully, the most addressed issue in the study of the peripheral nervous system.

The growing ethical concerns regarding the use of animals in biomedical research and the progressive spread among the scientific community of the “Three Rs” concept (replacement, reduction, and refinement of animal studies) (Russell and Burch, 1992) pushes for an increase in the replacement of in vivo models with

Acknowledgement

This work has been supported by the European Community's Seventh Framework Programme (FP7-HEALTH-2011) under grant agreement no. 278612 (BIOHYBRID).

References (131)

  • L. De Medinaceli et al.

    An index of the functional condition of rat sciatic nerve based on measurements made from walking tracks

    Exp Neurol

    (1982)
  • M.C. Dodla et al.

    Differences between the effect of anisotropic and isotropic laminin and nerve growth factor presenting scaffolds on nerve regeneration across long peripheral nerve gaps

    Biomaterials

    (2008)
  • M. Fornaro et al.

    Neuronal intermediate filament expression in rat dorsal root ganglia sensory neurons: an in vivo and in vitro study

    Neuroscience

    (2008)
  • S. Geuna et al.

    Histology of the peripheral nerve and changes occurring during nerve regeneration

    Int Rev Neurobiol

    (2009)
  • A. Gramsbergen et al.

    Sciatic nerve transection in the adult rat: abnormal EMG patterns during locomotion by aberrant innervation of hindleg muscles

    Exp Neurol

    (2000)
  • K. Haastert-Talini et al.

    Chitosan tubes of varying degrees of acetylation for bridging peripheral nerve defects

    Biomaterials

    (2013)
  • K. Hara et al.

    Neural progenitor NT2N cell lines from teratocarcinoma for transplantation therapy in stroke

    Prog Neurobiol

    (2008)
  • S.H. Hsu et al.

    Peripheral nerve regeneration using a microporous polylactic acid asymmetric conduit in a rabbit long-gap sciatic nerve transection model

    Biomaterials

    (2011)
  • J. Isaacs

    Major peripheral nerve injuries

    Hand Clin

    (2013)
  • S. Kaplan et al.

    Calibration of the stereological estimation of the number of myelinated axons in the rat sciatic nerve: a multicenter study

    J Neurosci Methods

    (2010)
  • W.S. Kingery et al.

    The resolution of neuropathic hyperalgesia following motor and sensory functional recovery in sciatic axonotmetic mononeuropathies

    Pain

    (1994)
  • D.P. Kuffler

    Ultrasound imaging of regenerating rat sciatic nerves in situ

    J Neurosci Methods

    (2010)
  • J.O. Larsen

    Related stereology of nerve cross sections

    J Neurosci Methods

    (1998)
  • B.S. Lutz et al.

    Selection of donor nerves – an important factor in end-to-side neurorrhaphy

    Br J Plast Surg

    (2000)
  • M.T. Moreno-Flores et al.

    A clonal cell line from immortalized olfactory ensheathing glia promotes functional recovery in the injured spinal cord

    Mol Ther

    (2006)
  • X. Navarro et al.

    Sweat gland reinnervation by sudomotor regeneration after different types of lesions and graft repairs

    Exp Neurol

    (1989)
  • X. Navarro et al.

    Methods and protocols in peripheral nerve regeneration experimental research: Part III. Electrophysiological evaluation

    Int Rev Neurobiol

    (2009)
  • C.M. Nichols et al.

    Choosing the correct functional assay: a comprehensive assessment of functional tests in the rat

    Behav Brain Res

    (2005)
  • T.H. Nijhuis et al.

    Natural conduits for bridging a 15-mm nerve defect: comparison of the vein supported by muscle and bone marrow stromal cells with a nerve autograft

    J Plast Reconstr Aesthet Surg

    (2013)
  • I. Papalia et al.

    On the use of the grasping test in the rat median nerve model: a re-appraisal of its efficacy for quantitative assessment of motor function recovery

    J Neurosci Methods

    (2003)
  • J.E. Pereira et al.

    A comparison analysis of hindlimb kinematics during overground and treadmill locomotion in rats

    Behav Brain Res

    (2006)
  • J.H. Pereira et al.

    Comparison of results of repair of digital nerves by denatured muscle grafts and end-to-end sutures

    J Hand Surg

    (1991)
  • S. Raimondo et al.

    Methods and protocols in peripheral nerve regeneration experimental research: Part II. Morphological techniques

    Int Rev Neurobiol

    (2009)
  • P. Rao et al.

    Muscle autografts in nerve gaps. Pattern of regeneration and myelination in various lengths of graft: an experimental study in guinea pigs

    J Orthop Sci

    (2001)
  • A.J. Reid et al.

    Long term peripheral nerve regeneration using a novel PCL nerve conduit

    Neurosci Lett

    (2013)
  • F.J. Rodríguez et al.

    Nerve guides seeded with autologous Schwann cells improve nerve regeneration

    Exp Neurol

    (2000)
  • G. Ronchi et al.

    Standardized crush injury of the mouse median nerve

    J Neurosci Methods

    (2010)
  • A. Rupp et al.

    Electrophysiologic assessment of sciatic nerve regeneration in the rat: surrounding limb muscles feature strongly in recordings from the gastrocnemius muscle

    J Neurosci Methods

    (2007)
  • H. Saito et al.

    Delayed nerve repair increases number of caspase 3 stained Schwann cells

    Neurosci Lett

    (2009)
  • K. Sak et al.

    Neuronal and glial cell lines as model systems for studying P2Y receptor pharmacology

    Neurochem Int

    (2005)
  • S.J. Archibald et al.

    A collagen-based nerve guide conduit for peripheral nerve repair: an electrophysiological study of nerve regeneration in rodents and nonhuman primates

    J Comp Neurol

    (1991)
  • M. Asplund et al.

    Incidence of traumatic peripheral nerve injuries and amputations in Sweden between 1998 and 2006

    Neuroepidemiology

    (2009)
  • A.F. Baptista et al.

    High- and low-frequency transcutaneous electrical nerve stimulation delay sciatic nerve regeneration after crush lesion in the mouse

    J Peripher Nerv Syst

    (2008)
  • D.M. Basso et al.

    A sensitive and reliable locomotor rating scale for open field testing in rats

    J Neurotrauma

    (1995)
  • G.M. Beer et al.

    Standardizing nerve crushes with a non-serrated clamp

    J Reconstr Microsurg

    (2001)
  • B. Behr et al.

    Magnetic resonance imaging monitoring of peripheral nerve regeneration following neurotmesis at 4.7 Tesla

    Plast Reconstr Surg

    (2009)
  • A. Berger et al.

    Nerve grafting

    Clin Orthop Relat Res

    (1978)
  • R.E. Blanco et al.

    Ultrastructural studies of dorsal root axons regenerating through adult frog optic and sciatic nerves

    Microsc Res Tech

    (1999)
  • C.L. Blom et al.

    Nerve injury-induced c-Jun activation in Schwann cells is JNK independent

    Biomed Res Int

    (2014)
  • E. Bontioti et al.

    Regeneration and functional recovery in the upper extremity of rats after various types of nerve injuries

    J Peripher Nerv Syst

    (2003)
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