Peripheral nerve injuries, particularly in the upper limb, may have devastating consequences. The outcome of injury is determined by the amount of cellular damage, and by variables which include the site of the lesion, the degree of disruption of the connective-tissue sheaths that surround the nerve, the extent of associated injuries, particularly vascular injuries (Fig. 1), and the age and health of the patient.
Meticulous surgical repair cannot guarantee full functional recovery because the surgeon does not control the 'biological battlefield' which rages inside a damaged nerve.1 Therapeutic manipulation of the response to injury at the molecular level has the potential to keep more neurones alive, encourage their axons to cross longer interstump gaps, to maximise the accuracy of target re-innervation and to manage neuropathic pain. For now, these objectives remain aspirational - they are predicated on a more detailed understanding of the way in which the peripheral nervous system responds to injury than is presently available. This brief update on the peripheral arm of the response to injury in the peripheral nervous system highlights areas where translational research may prove to be beneficial, for information on axotomy-related central phenomena, the reader is referred to earlier reviews.2-4
The injury response in the peripheral nervous system - an overview
Peripheral neurones are some of the largest and most spatially complex cells in the body. Their size means that they are unable to function without the structural and metabolic support provided by approximately ten times as many glial cells. It also means that a focal axonal injury which occurs centimetres from a neuronal cell body induces a response that involves the entire cell and its associated glia. Centrally, some axotomised neurones die, primarily as a consequence of a loss of targetderived neurotrophic support.5 Numbers quoted in the literature vary according to the experimental model used, but can be substantial, e.g. approximately 30% to 40% of the small diameter sensory neurons which contribute to a dorsal root ganglion apoptose after nerve transection. Proximal injuries produce more marked neuronal loss than distal injuries,6 and groups of neurones are differentially susceptible to injury, for example cutaneous afferents appear to be more vulnerable than muscle afferents. Persisting neurones switch to a 'survivor' phenotype and the expression of hundreds of genes8,9 is changed to compensate for the loss or diminution of target-derived neurotrophic factors,10 and in order to regrow their axons across the site of the injury and back into the periphery. Proximal changes, such as synaptic reorganisation in the cortex11-13 and spinal cord, occur upstream of axotomised first-order motor and sensory neurones, and may influence the functional outcome months or even years later.14-16
Distal to the injury, a series of molecular and cellular events, some simultaneous, others consecutive, and collectively called Wallerian degeneration, is triggered throughout the distal nerve stump and within a small reactive zone at the tip of the proximal stump (Fig. 2).17-19
Within hours of physical interruption, the ends of the severed axons are sealed. The mechanism is probably similar to that used to seal invertebrate giant axons.20,21 Anterograde axoplasmic transport continues in the proximal stump, and retrograde transport persists for several days in the distal stump. As a consequence the ends of the sealed axons swell as they fill with organelles which are unable to progress beyond the site of the lesion. Potent vasoactive peptides such as CGRP (calcitonin gene-related peptide) accumulate in the axonal end-bulbs in the proximal stump, and probably contribute to local hyperaemia around the site of the injury.22 Loss of the axoplasmic cytoskeleton begins one to two days after injury in small laboratory rodents, and within seven days in humans: the different latencies are approximately directly proportional to the size of the animal.23 Increased intracellular Ca^sup 2+^ is both necessary and sufficient to induce axonal degeneration, and to activate axonal calcium-dependent proteolytic enzymes, such as phospholipases and calpains, which mediate cytoskeletal breakdown.24-29 The rate of axonal degeneration has been slowed experimentally by exposing axons to lower extracellular concentrations of Ca^sup 2+^ and by cooling within 12 hours of injury.29,30
Until recently it was assumed that axons withered away because they were no longer supported by their cell bodies. That view, although intuitive, is no longer tenable. It was challenged first by work on a spontaneous mouse mutant Wallerian degeneration, slow, WW,31-34 which displays retarded axonal degeneration for up to three weeks after transection or crush. More recent studies on normal nerves have revealed that disconnected axons destroy themselves, probably through a local caspase-independent process ' triggered by events which occur before any morphological or electrophysiological changes can be detected. It has been suggested that these very early events, which may include activation of m-calpain23 and/or the ubiquitin-proteasome system,37 'light a fuse'29 which ultimately leads to cytoskeletal disintegration. Therapeutic manipulation of processes which occur within minutes of an injury to a nerve is an unrealistic clinical goal except perhaps in the case of intra-operative injuries in which a nerve has been bruised but not cut, when focal application of selective antagonists, perhaps aided by cooling, might stabilise the axonal cytoskeleton sufficiently to prevent subsequent axonal degeneration. Until axolemmae break down, some conduction may be maintained in disconnected nerves for at least a week after injury, although there is no response to direct stimulation of the injured nerve distal to the lesion during this time.38,39
The inflammatory response in Wallerian degeneration
T-cells, neutrophils and macrophages infiltrate the site of an injury within two days;40-42 the neutrophil response is very limited in both time and extent. Within hours, endoneurial levels of the early inflammatory cytokines, tumour necrosis factor alpha (TNF-α) and interleukin (IL)-1α, secreted mostly by Schwann cells, start to increase in the distal nerve stump. Within days, this network has been amplified by cytokines, chemokines and other bioactive molecules released by recruited macrophages, mast cells and activated endothelial cells.43-51 Some of these molecules influence the behaviour of the Schwann cells (e.g. macrophage derived IL-I regulates nerve growth factor (NGF) synthesis by Schwann cells)' and others may play a role in the generation and/or maintenance of neuropathic pain. Any or all may therefore be appropriate targets for therapeutic manipulation. TNF-α and nitric oxide have attracted particular attention as potential mediators of the type of pain which is reported soon after injury,22,53-60 whereas cyclo-oxygenase-2 expressed by macrophages which remain within the endoneurium after the initial phase of clearance of debris, may mediate chronic post-traumatic neuropathic pain.61 TNF-α has several functions in Wallerian degeneration, e.g. activation of the neuroprotective transcription factor nuclear factor-kappa B.10
Macrophages. There are two populations of macrophages in an injured peripheral nerve, resident and recruited. Resident endoneurial macrophages, which constitute approximately 4% of the endoneurial cellular population in a normal nerve, respond extremely rapidly to injury.62 They are joined by haematogenously-derived osteopontinnegative,63 CCR2-positive (chemokinel (c-c motif) receptor 2)42,64 macrophages which flood into the endoneurium three to four days after injury by crossing a temporarily leaky blood-nerve barrier. Recruited macrophages are attracted by locally produced chemokines, including monocyte chemotactic protein-1 expressed by denervated Schwann cells,41,42,64 and are presumably activated by a neutrophil-independent pathway.
Macrophages penetrate the tubes of the Schwann cell, degrade the myelin sheaths contained therein and phagocytose the debris.65-68 Removal of debris is not just endoneurial 'good housekeeping', but an essential stage in Wallerian degeneration. Degradation of myelin and the subsequent clearance of myelin debris, whether by macrophages or by Schwann cells69 liberates a Schwann-cell mitogen from the debris,70-78 and removes myelin-associated molecules, such as myelin-associated glycoprotein (MAG),79 which would otherwise inhibit axonal growth. Treatment with anti-MAG antibodies enhances regeneration,80 whereas axonal elongation is slowed when recruitment of macrophages is impaired experimentally.41,46,81-83 Macrophages also secrete ApoE (apolipoprotein E), which may scavenge lipids from axonal and myelin debris, and redeliver them to Schwann cells for re-use during regeneration.
Lipid-laden macrophages leave the Schwann tubes by passing through the basal laminae. Many remain free within the endoneurium for several weeks, but most eventually disappear, as a result either of local apoptosis or by migrating to draining lymph nodes and the spleen.84
Mast cells. There is a sustained increase in the number of mast cells within both the epineurium and endoneurium distal to a traumatic injury. Mast cell-derived vasoactive agents, together with matrix metalloproteinases secreted by endothelial cells, and TNF-α and Π-β secreted by macrophages, mediate the increased permeability of the bloodnerve barrier in early Wallerian degeneration, and so facilitate recruitment of macrophages.85 Mast cells may also participate in the generation of pain and itching. In truth, relatively little is known about their possible contribution to Wallerian degeneration and subsequent regeneration in the peripheral nervous system.
In an intact nerve, chains of Schwann cells either myelinate axons of large calibre (> 2 µm) on a one-to-one basis, or wrap groups of small (
The functional relationship between axons and their ensheathing Schwann cells is normally tightly regulated by reciprocal signalling.86 The way in which Schwann cells respond to the loss of that relationship, whether as a result of segmentai demyelination, when axonal integrity is maintained but myelin is removed,87 or of axonal degeneration after crush or transection, is a critical component of the response to injury in the peripheral nervous system.
Acutely-denervated Schwann cells. Within 48 hours of injury, denervated myelinating Schwann cells downregulate expression of genes encoding myelin-associated proteins, e.g. myelin proteins iMBP (myelin basic protein), PO (myelin protein zero) and PMP22 (peripheral myelin protein 22),88-91 and proteins such as connexin 32,92-94 E-cadherin, which is important for maintaining the complex structural organisation of nodes, paranodes and incisures, 95,96 and caveolinl,97 which may regulate the transport of cholesterol. The extent to which Schwann cells participate in the breakdown of their own myelin sheaths is uncertain. They are not professional phagocytes, but are capable of substantial degradation of myelin if the numbers of macrophages are depleted.69,81,98
Three to four days after injury, Schwann cells throughout the distal stump and at the tip of the proximal stump start to divide, probably responding to mitogens exposed during the processing of myelin and axonal debris by macrophages. Some of the regulatory steps in the mitotic pathway are known. They include upregulation of the expression of erythropoietin, which may potentiate division of Schwann cells through an autocrine pathway involving phosphorylation of JAK2,99 and of ERK (extracellular signal-regulated kinase)100,101 and downregulation of a matrix metalloproteinase (MMP-3)102 which normally acts on fibronectin to generate a fragment that inhibits division of Schwann cells.103 If the proliferative burst is blocked experimentally, axonolysis continues, but other major events, such as the recruitment of macrophages, myelinolysis and axonal outgrowth from the proximal stump, are delayed until the onset of division of Schwann cells.83 The de-differentiated daughter cells upregulate expression of numerous regeneration-associated genes, whose protein products (some of which are listed in Table I), either facilitate axonal elongation or maintain the Schwann cells in an axon-responsive state (but see below).
Denervated Schwann cells which are contacted by regenerating axons uncouple.92,93 They frequently go through another division, probably responding to a contact-dependent, neuregulin-containing axonal mitogen,104 and then leave the cell cycle and differentiate.105-109 Driven by axonal signals, some of the differentiating cells will upregulate expression of myelin-related mRNAs91,110 and start to secrete myelin sheaths, while others remain unmyelinated.
Chronically-denervated Schwann cells. With time, many of the Schwann cells which have not been re-innervated apoptose and disappear.111,112 Apoptosis is driven by either a Bcl-2-blockable pathway, initiated by loss of trophic support, or by a Bcl-2-independent pathway, initiated by endogenously produced NGF.113,114 Cells which have been denervated for more than six months are morphologically and functionally different from their acutely denervated counterparts.115,116 They remain S-100- and laminin-positive, but downregulate expression of c-erbB117 and p75NTR 118 receptors. This change is significant because pathways for c-erbB-neuregulin and p75^sup NTR^ -neurotrophin normally play important roles in Schwann-cell axon signalling. Loss of these receptors may therefore be the reason why denervated Schwann cells become progessively less able to support regenerating axons.119 From a therapeutic perspective, it is encouraging to know that this transformation is reversible, at least in rats, and that chronically-denervated Schwann cells revert to an axon-responsive phenotype when explanted in vitro.120,121 They could presumably be persuaded, with appropriate post-operative intervention, to retain this phenotype in vivo e.g., at the distal end of a long graft and/or distal stump.
The weight of experimental evidence strongly suggests that there is a relatively narrow window of opportunity when transected neurones are in survival mode and denervated Schwann cells are axon-responsive. This reinforces the view that nerve repair should not be delayed when there is unequivocal evidence of the separation of nerve stumps.122-124
Cellular outgrowth from the proximal nerve stump. At the interface between the normal and 'reactive' regions of a proximal stump, sprouts start to bud from the damaged axons at their sealed tips and at hemi-nodes of Ranvier. The sprouts grow towards the lesion site inside the basal lamina tubes which enveloped their parent axons, in association with the de-differentiated progeny of the original Schwann cells and a transient population of invading macrophages. Although sprouting usually starts within hours of injury, it may be several days before a cellular outgrowth emerges from the proximal stump, and at least four weeks before all regrowing axons have negotiated the interface between directly-coated proximal and distal stumps, a process which has been termed 'regeneration stagger'.125,126
Axon sprouts and Schwann cells in the proximal stump are 'compartmentalised' by fibroblasts and perineurial cells derived from the inner layers of the disrupted perineurium. The process coincides with an increased endoneurial expression of s-laminin, which is the isoform of laminin that characterises the basal laminae of perineurial cells but not of Schwann cells and of desert hedgehog (dhh), a member of the hedgehog family of signalling molecules involved in normal Schwann-cell-perineurial cell signalling.127
In the absence of a distal stump or nerve graft, the cellular outgrowth from a proximal nerve stump consists of small bundles of axons and Schwann cells. Each bundle is surrounded by perineurial cells and fibroblasts and is usually called a minifascicle. The cellular outgrowth from a distal nerve stump is not similarly organised, suggesting that the formation of minifascicles may be neuronally driven, and is perhaps a means of protecting the osmotic milieu of outgrowing axons in the absence of a competent perineurium. This would be consistent with findings of a minifascicular neuropathy in the dbh-null mutant mouse where the perineurium is dysfunctional,128 and in a nerve biopsy from a patient with a homozygous mis-sense mutation of the dhh gene.129 Compartmentalisation and the formation of minifascicles presumably affect patterns of axonal dispersion across an interstump gap.
A disinhibited microenvironment. The microenvironment of an intact peripheral nerve is hostile to regrowing axons130"134 and that of a chronically-denervated distal stump supplies very limited support. The conventional wisdom that the peripheral nervous system is 'regeneration-friendly', in marked contrast to the CNS, is therefore true only when speaking of an acutely-denervated distal stump or nerve graft. Proliferation of Schwann cells and axonal sprouting and elongation are all inhibited in normal nerve, but are permitted in repairing nerve.
Axons do not sprout in an intact nerve. The fact that they do so in Wallerian degeneration and also in experimental demyelination, in which axonal continuity is maintained but contact with Schwann cells is transiently lost, suggests that axonal sprouting may normally be inhibited by signals derived from endsheathing Schwann cells.135,136
Depending upon the type of repair, most axon sprouts either negotiate the site of a suture and enter a distal stump or nerve graft, or grow in minifascicles within a wound bed or conduit lumen. Those that enter an endoneurium penetrate the open ends of the Schwann tubes which they encounter and their growth cones palpate the laminin-rich inner surface of the basal laminae surrounding each tube. This response is routinely exploited in tissue-culture experiments, when explanted neurones are grown on laminincoated cover slips. It was also the reason for using acellular muscle grafts as an alternative to nerve grafts, on the grounds that laminin-rich muscle sarcolemmae would provide a supportive substrate for regenerating axons, which they did, but only in the presence of Schwann cells.137 Laminins are the most abundant non-collagenous structural glycoproteins in basement membranes, and have numerous functions in different tissues,138 including supporting axonal growth. The neurite-promoting activity of the laminin isoform found in Schwann cell basal laminae is inactivated in the intact nerve by CSPG (chondroitin sulphate proteoglycan),139,140 but during Wallerian degeneration, matrix metalloproteinases expressed by Schwann cells and macrophages degrade CSPG, revealing the neurite-promoting activity of laminin to the ingrowing axon sprouts. Experimental local application of chondroitinase ABC, which removes CSPG glycosaminoglycans, improved axonal regrowth across the interface of coapted sciatic nerve stumps,141 and also enhanced axonal regrowth into acellular nerve grafts,142 suggesting that a similar protocol may have a therapeutic application. Downregulation of another matrix metalloproteinase, MMP-3, facilitates proliferation of Schwann cells.
Pathway selection. One of the most important determinants of a satisfactory functional outcome is the accuracy of target re-innervation. If axons degenerate without rupture of the basal laminae which surround each Schwann tube, e.g. in an ischaemic or compressive lesion, then the axon sprouts are unlikely to be misrouted upon resolution of the underlying pathology. That is not the case after traumatic injuries in which a nerve is physically disrupted. Whether the resulting proximal and distal nerve stumps are sutured without tension,143-145 or are bridged by an intervening graft, the axon sprouts which emerge from the proximal stump are bound to encounter unfamiliar Schwann tubes. Most sprouts, once they have negotiated the site of the suture, will remain within the endoneurium of the distal stump or graft. Those nearest to the periphery of the proximal stump may either escape with their Schwann cells into the epineurium through breaches in the damaged perineurium, or they may grow ectopically between the layers of the perineurium. In both situations their behaviour may produce a painful neuroma.
The mechanism by which axonal growth cones select Schwann tubes has yet to be established. In a mixed nerve, the 'specificity' of re-innervation of motor and sensory tubes appears to be produced by the selective pruning of axon collaterals which initially elongate within inappropriate tubes,146,147 and may be influenced by the relative levels of target-derived trophic support148 and/or by molecular cues on Schwann cells, e.g. the carbohydrate epitope L2/HNK-1, expressed on Schwann cells, may specify motor tubes.149,150
Do motor and sensory nerves supply different molecular cues to axon sprouts? A recent demonstration that motor axons regenerate better across motor or mixed nerve grafts than across sensory nerve grafts,151 is consistent with an earlier suggestion that motor axons may respond to as yet unidentified motor-specific factors within a mixed nerve that are not present in a pure sensory pathway.152 The ability to manipulate axonal outgrowth to maximise the occupation of modality-specific tubes would be a significant clinical advance. Motor autografts are not a practical clinical option, but allografts or biosynthetic conduits seeded with suitably manipulated Schwann cells, if indeed they are the source of the cues, are attractive alternatives.
Axonal elongation may be confirmed by the proximodistal progression of a positive Tinel's sign. Since axons grow slowly (1 mm/day), distance may ultimately defeat successful reinnervation even when Schwann tubes have not been disrupted by injury, i.e. even when axons grow within appropriate Schwann tubes they may not reach their targets before the latter have succumbed to the effects of chronic denervation.
Little is known about the way in which different structural elements of a peripheral nerve normally respond to mechanical loading. In the context of the surgical repair of an injured nerve, changes in these structural components, e.g. in terms of their capacity to respond to stretch and deformation, are likely to influence outcome.133 Thus extraneural fibrosis and wound-bed adhesions may tether the suture site(s) and adjacent nerve or graft in the wound bed, not only impairing local sliding of the site in response to movement of the limb or digit,154 but also possibly generating painful dysaesthesiae. They may cause increases in intraneural tension capable of compromising the clinical outcome153,156 (but see157). Internal endoneurial fibrosis at the site of a suture will inevitably divert, and may also compress, regrowing axons, particularly if they are growing within a rigid conduit. Any scarring, whether extraneural or intraneural, which compromises the microvascular bed of a nerve may potentially provoke secondary axonal degeneration.
Alternatives to autografts
Nerve autografts remain the 'gold standard' against which all other protocols for bridging an interstump gap are judged. Since they contain acutely-denervated Schwann cells within a scaffold of longitudinally aligned Schwann tubes, it has always been assumed that they offer the best microenvironment to support regrowing axons. However, experience has shown that they are not ideal, particularly when defects are extensive, or when autologous sensory nerve grafts are used to repair deficits in motor nerves.151
Alternative protocols include allografting in combination with low-grade immunosuppression,158-160 terminolateral neurorraphy,161-166 and entubulation, when the nerve stumps are enclosed (entubulated) within some type of nonneural conduit, either synthetic or biological.167-171
Conduits. Much of the information about the cellular and molecular events which occur during Wallerian degeneration has been obtained from studies using empty or salinefilled silicone tubes to bridge short gaps (
Bridging a long (> 10 cm) interstump gap remains a major challenge, both experimentally and clinically (Fig. 3).122,172 An empty silicone tube is not fit for this purpose and no bio-engineered device has yet proved capable of supporting axonal regrowth across long gaps in laboratory models. There are undoubtedly many reasons, operating locally or at a distance, why axons fail to cross long interstump gaps within a conduit, e.g. poor vascularisation or internal fibrosis. One of the most intensively researched ideas has been that axons stop growing because the pool of available co-migrating Schwann cells has become exhausted. To compensate for this perceived loss, exogenous Schwann cells have therefore been added to the lumen or walls of a conduit, e.g. by sandwiching lengths of nerve between segments of acellular muscle,173 or by introducing a bolus of cultured cells into either a vein autograft174-176 or into conduits containing longitudinal polyglactin sutures.177 These strategies have achieved modest increases, of the order of an additional 2 to 3 cm, in the distances which axons will regrow in experimental animals. Given that axonal regrowth depends upon the precisely regulated interactions of numerous cell types, and that Schwann cells, although essential, do not operate in a 'cellular vacuum', this is perhaps not surprising.
It is possible to speculate about the design specification of an ideal conduit, particularly one that is to be used either for bridging long interstump gaps or when taking an interventionist approach with shorter gaps. The data distilled from numerous preclinical experiments over the last 20 years suggest that a device needs to have walls that are biocompatible and resorbable, sufficiently robust to resist collapse, and yet not so rigid that they compress the structures which they surround, and a lumen whose contents (e.g. Schwann cells, growth factor-releasing biodegradable beads, aligned collagen fibrils, micropatterned biodegradable films), facilitate orientated and sustained axonal elongation (Fig. 4). It goes without saying that it must also be easy to handle and to suture. It also goes without saying that such a device does not currently exist.
Stem cells. Obtaining sufficient numbers of autologous human Schwann cells is not a practical proposition in the clinic, on the grounds of technical difficulty and the time required to expand cultures. Stem-cell technology for the treatment of nerve injuries is in its infancy, but may ultimately provide an alternative source of Schwann cells.178 Very recently, bone-marrow stromal cells have been induced to differentiate into cells with the characteristics of Schwann cells that appear to support regeneration when transplanted into degenerating rat sciatic nerves.179,180
Therapeutic intervention, using some type of tissue-engineered device to manipulate endoneurial events at the molecular level, offers a potentially attractive alternative to the use of autografts.181 Collaboration between basic scientists and clinicians working in fields in which tissue engineering is now widely applied, such as orthopaedics and cardiovascular surgery, is likely to prove rewarding, and is to be encouraged.
1 am indebted to Professor R. Birch for reading and commenting on drafts of this review, and to Professor G. Lundborg for permission to use his diagram of Wallerian degeneration (Fig. 2).
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From King's College London, London, England
* S. Hall, PhD, DSc, Professor & Head
Department of Anatomy & Human Sciences
King's College London, School of Biomedical Sciences, Guy's Campus, London SE1 1UL, UK.
Correspondence should be sent to Professors. Hall; e-mail: email@example.com
©2005 British Editorial Society of Bone and Joint Surgery
doi:10.1302/0301-620X.87B10. 16700 $2.00
J Bone Joint Surg [Br] 2005;87-B:1309-19.
Copyright British Editorial Society of Bone & Joint Surgery Oct 2005
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