An understanding of the morphology, physiology, and electrophysiology of peripheral nerve regeneration is fundamental to clinical decision-making by the peripheral nerve surgeon. Questions regarding the type and timing of nerve repair can be addressed logically only if the underlying condition of the injured nerve can be ascertained.
After nerve injury, a detailed history of the mechanism of injury along with a directed physical examination and electrophysiologic studies are obtained by the surgeon. The clinical course is followed carefully in terms of improvement, stabilization, or deterioration. These data should then be transformed into mental images of the histology and physiology within the nerve fascicles at the injury site, and in the nerve segments proximal and distal to that site. Appropriate decisions can then be made regarding the clinical options of further observation, exploration, and neurolysis with or without nerve grafting, or reconstructive procedures such as tendon transfers.
The morphology, physiology, and electrophysiology of peripheral nerve regeneration cannot be analyzed in isolation. These regenerative processes are a continuum of the entire response to nerve injury, including concomitant degenerative processes.
Just as degenerative and regenerative processes are simultaneous and interdependent, so are the structural and physiological aspects of the responses to nerve injury. The discussion is broad enough to apply to most major mechanisms of nerve injury-traction or stretch, contusion, laceration, missile injury, injection, entrapment, and compression.

Classification of Nerve Injuries

Seddon described three basic types of nerve injury: neurapraxia, axonotmesis, and neurotmesis. All of these injuries initially produce complete loss of neurologic function. The clinical importance for the peripheral nerve surgeon of classification schemes lies in its prognostic significance.


In terms of nerve regeneration, neuropraxia injuries are not strictly relevant in that no true regeneration occurs. This injury involves interruption of signal conduction across the injured site, usually due to compression or ischemia, with full and relatively rapid recovery of function. The axon is preserved, there is no Wallerian degeneration, and pathological changes are mild and fully reversible. For unknown reasons, motor fibers are more susceptible to this type of injury than are sensory or sympathetic fibers. Susceptibility by modality, in descending order, is: motor, proprioception, light touch, temperature sensation, pain sensation, and sympathetic function. Recovery generally occurs in a reverse sequence, and is usually complete within days to a few months. Any residual deficit indicates a more severe degree of injury involving loss of axonal continuity.


This injury is defined pathologically by loss of axonal continuity and subsequent Wallerian degeneration. The endoneurial sheath is preserved, however, and each regenerating axon is confined to its original sheath. This ensures faithful reinnervation of the appropriate end organ, and full functional recovery inevitably results. In clinical terms, the initial deficit involves complete motor, sensory, and sympathetic function. Nerve conduction distal to the injury site disappears within 24-72 hours after the injury, and fibrillation potentials  are present within the denervated muscles. Recovery of motor function in this type of injury follows sequentially from proximal to distal muscles. The timing of recovery follows quite predictably the rate of axonal growth-approximately 1 mm per day or 1 inch per month, although the growth rate is more complex when carefully studied. The progression of regeneration can be followed along sensory fibers by tracing the progress of Tinel's sign. The delay in recovery of function exceeds that observed after neuropraxia, and is usually measured in months rather than days or weeks.

Third-Degree Injury

Third-degree  injuries proposed by Sunderland are intrafascicular injuries that involve disruption of axons as well as their endoneurial tubes (basal lamina of Schwann cells), with subsequent Wallerian degeneration. The perineurium is spared and, therefore, the fascicular architecture of the nerve is preserved. Retrograde degeneration is severe, and some neuronal cell bodies are lost, reducing the number of axons available for regeneration. Intrafascicular fibrosis (scar), which results from the associated hemorrhage, edema, and ischemia, presents an impediment to axonal regeneration. Recovery is, therefore, incomplete. Regenerating axons are confined within their original fasciculi, but are no longer confined within their original endoneurial tubes. Therefore, misdirected regrowth can occur : e.g. sensory axons may regenerate along original motor tubes. This constitutes wasteful regeneration. More proximal injuries are more likely to result in neuronal cell death and in a significant proportion of misdirected axons. Recovery after third-degree injury is considerably delayed. The Tinel's sign is not a reliable marker of functional recovery after third-degree injury because sensory axons may be descending along a "dead-end" motor endoneurial tube. The external appearance of such a nerve will not accurately reflect the severe degree of intrafascicular disruption and disorganization present -an important point for the peripheral nerve surgeon to remember.

Fourth-Degree Injury

This severe injury by Sunderland involves rupture of the perineurium and, thus, disrupted fasciculi. The nerve trunk is still in continuity, but is converted at the injury site into a solid scar containing Schwann cells and regenerating axons, which enlarge to form a neuroma. Retrograde neuronal effects are more severe than in third-degree injuries; therefore, even fewer axons survive to regenerate. Those axons that do regenerate are no longer confined within fascicles, and many stray into surrounding interfascicular tissue to end blindly. Few axons reach their appropriate targets. Functional recovery, if any, is usually quite limited. Fourth degree injuries require surgical excision of the involved segment and an appropriate type of nerve repair.


This most severe degree of nerve injury in­volves complete loss of nerve trunk continuity. The severed nerve ends may remain separated, or they may be joined by a scar tissue bridge composed of fibroblasts, Schwann cells, and regenerating axons. The extent of scar tissue varies, but often there is a proximal neuroma and distal bulb that form either a dumbbell-shaped structure or an amorphous mass of scar tissue. Regeneration across this formidable barrier is severely limited, at best, and is functionally negligible. Even with resection and nerve repair, significant barriers to full recovery remain. These include loss of axons due to retrograde effects of the injury, and misdirected axons. The chances of useful recovery are markedly enhanced by an appropriate surgical repair.

Morphologic and Physiologic Changes after Nerve Injury Repair

Degenerative Changes

Before regeneration of nerve fibers can occur, a series of degenerative processes must take place. Many of these are direct preludes to regeneration. The success of regeneration depends to a large extent upon the severity of the initial injury and the resultant degenerative changes. Pathologic changes are mild or absent in neuropraxia injuries in which conduction block alone occurs, and no true degeneration or regeneration occurs. In axonotmesis, there is little histologic change at the site of the injury or proximal to it. The major changes occur distal to the injured segment in what is well-known as Wallerian, or anterograde degeneration. The primary histologic change in this process involves physical fragmentation of both axons and myelin, which begins to appear within hours of the injury. Ultrastructurally, both neurotubules and neurofilaments become disarrayed, and axonal contour becomes irregular, due to varicose swellings. By 48-96 hours post-injury, axonal continuity is lost and conduction of impulses is no longer possible. Myelin disintegration lags slightly behind that of axons, but is well advanced by 36-48 hours. Axonal and myelin debris is removed by the phagocytic action of macrophages and Schwann cells, a process which can take from 1 week to several months. Schwann cells become active within 24 hours of the injury, exhibiting nuclear and cytoplasmic enlargement as well as an increased mitotic rate. Schwann cells appear to ingest axonal and myelin debris, and then pass this on to macrophages. The latter migrate into the traumatized region, primarily through a hematogenous route, passing through the walls of capillaries, which have become permeable in the injury zone. Endoneurial mast cells play a pivotal role in this process, proliferating markedly within the first 2 weeks. They release histamine and serotonin, which enhance capillary permeability and allow macrophage migration. During the initial stages the endoneurial tubes swell in response to the trauma, but after the first 2 weeks these tubes become smaller in diameter. By 5-8 weeks, the degenerative process is usually complete, and the nerve fiber is composed of Schwann cells within an endoneurial sheath. In third-degree injuries, a more severe local reaction to the trauma occurs. These intrafascicular injuries involve retraction of the severed nerve fiber ends due to the elastic endoneurium. , Local vascular trauma leads to hemorrhage and edema, which results in a vigorous inflammatory response. Fibroblasts proliferate, and a dense fibrous scar results in a fusiform swelling of the injured segment. Interfascicular scar tissue also develops so that the entire nerve trunk, which is left in continuity, is permanently enlarged. Often, it is adherent to perineural scar tissue as well. Distal to the injured segment, Wallerian degeneration follows a sequence very similar to that observed in axonotemesis injuries. One important difference is that intrafascicular injury impairs axonal regeneration and, therefore, the endoneurial tubes remain denervated for prolonged periods. Shrinkage of the endoneurial tubes (diameter 2-4 µm) reaches a maximum at approximately 4 months post-injury. The endoneurial sheath progressively thickens due to collagen deposition along the outer surface of the Schwann cell basement membrane. If the endoneurial tube does not receive a regenerating axon, progressive fibrosis ultimately obliterates the tube. The stacked Schwann cell processes comprising collapsed endoneurial tubes have been labelled "bands of Bϋngner."  Schwann cells appear to contribute to the deposition of collagen, and then revert to a more primitive form indistinguishable from fibroblasts. In addition to these degenerative changes that occur distal to the injured segment, retrograde changes occur proximal to the injury site in third-degree and in more severe injuries. In fourth- and neurotmesis injuries, local reaction to the severe trauma is pronounced. Endoneurial tubes, as well as fasciculi, are disrupted and Schwann cells and axons are no longer confined. The epineurium is also damaged and reactive epineural fibroblasts are present at the severed nerve ends within 24 hours. These are accompanied by proliferating Schwann cells and perineurial and endoneurial fibroblasts. Vigorous cellular proliferation peaks within the first week and continues for a prolonged period. As in third-degree injuries, capillary permeability increases, probably as a result of mast cell degranulation, and edema and macrophage infiltration follow. Each nerve end becomes a swollen mass of disorganized Schwann cells, capillaries, fibroblasts, macrophages, and collagen fibers. Regenerating axons reach the swollen bulb of the proximal stump and encounter formidable barriers to further growth. Many axons form whorls within the scar tissue, or are turned back along the proximal segment or out into surrounding tissue. Some of the regenerating axons may reach the distal stump, an accomplishment which is dependent upon multiple factors, including the severity of the original in­jury, the extent of scar formation, and the delay before axons reach the injury site. As in third-degree injuries, endoneurial tubes left unoccupied for prolonged periods undergo progressive shrinkage and fibrosis, ultimately be­coming completely obliterated by collagen fibers. Changes in neuronal cell bodies and in nerve fibers proximal to the site of injury depend upon the severity of the injury as well as the proximity of the injured segment to the cell body. Schwann cells are lost a few millimeters proximal to the injured segment, and axons and myelin are reduced in diameter. If the cell body actually degenerates, which occurs in severe trauma, the entire proximal segment undergoes Wallerian degeneration. The Wallerian degeneration lags somewhat behind this pro­cess in the distal segment. In the presence of a surviving neuronal cell body the axon is reduced in diameter, particularly if functional connections to appropriate end organs are not re-established. Nerve conduction velocity is accordingly reduced. As regeneration proceeds, the axonal diameters increase, but may never reach normal levels. A definite interdependence exists between the cell body and the axon in terms of recovery: the cell body does not recover fully without the re-establishment of functional peripheral connections, and the final axonal caliber depends to a great extent upon the recovery of the cell body. The nerve cell body itself reacts in a relatively predictable fashion after axonal injury. Within 6 hours of the injury, the nucleus mi­grates to the periphery of the cell and Nissl granules break up and disperse. This process is called chromatolysis. Simultaneously, there is a brisk proliferative response of perineuronal glial cells, most likely signalled by the process of chromatolysis. Glial cell processes extend to the affected neuron and interrupt synaptic connections, possibly to isolate the neuron for its recovery phase. Some neurons go on to degen­erate and are subsequently phagocytosed by microglia. More often, recovery begins within 2-3 weeks of the injury and continues for up to several months. The earliest signs of recovery are the return of the nucleus to the cell center and the reappearance of compact Nissl granules. Subcellular metabolic functions are altered during the chromatolytic and recovery phases, including an increase in ribonucleic acid (RNA) synthesis, a decrease in neurotransmitter synthesis, and an increase in production of proteins and lipids needed for axonal regeneration. Both fast and slow components of axoplasmic transport supply materials from the cell body to the sites of axonal regeneration.

Regenerative Changes

In neurapraxia and axonotmesis restoration of function is the rule. This is either early through reversal of conduction block, or late through axonal regeneration. Functional recovery is complete in these milder degrees of injury. Both morphologic and physiologic changes are fully reversible. In the more severe nerve injuries in which endoneurial tubes are disrupted, regenerating axons are no longer confined to their original sheaths. These axons may meander into surrounding tissue or into inappropriate endoneurial tubes, thus failing to reinnervate their proper end organs. Neurologic recovery is compromised, generally to a degree proportional to the severity of the injury. Functional recovery after nerve injury involves a complex series of steps, each of which may delay or impair the regenerative process. For any degree of nerve injury, it is useful initially to categorize these regenerative steps anatomically on a gross level. The sequence of regeneration may be divided into zones: (1) the neuronal cell body, (2) the segment between the cell body and the injury site, (3) the injury site itself, (4) the distal segment between the injury site and the end organ, and (5) the end organ itself. A delay in regeneration or unsuccessful regeneration may be attributed to path­ologic changes which impede normal reparative processes at one or more of these zones.

Neuronal Cell Body

Recovery of the neuronal cell body is marked by a reversal of chromatolysis and its associated depression of protein synthesis. Nucleoproteins reorganize into the characteristic form of Nissl granules. A complex and incompletely understood interaction occurs between the cell body and the regenerating axon tip. Axoplasm, which serves to regenerate the axon tip, appears to arise in the axon segment proximal to the injury site. An intense increase in the rate of protein synthesis in the cell nucleus influences the rate of advance and the final caliber of the regenerating axon. The human peripheral neuron's capacity to initiate a regenerative response appears to persist for at least 12 months after injury; and a robust response can be elicited even after repeated injuries.

Segment Between Cell Body and Injury Site

The length of the segment between the regenerating axon tip and the injury site depends on the severity of the original injury and the consequent retrograde degeneration. The first signs of axon regrowth in this segment may be seen as early as 24 hours after injury, they may be delayed for weeks in more severe degrees of injury. The rate of axonal regrowth is determined by changes within the cell body, the activity of the specialized growth cone at the tip of each axon sprout, and the resistance of the injured tissue between cell body and end organ. There may be multiple axon sprouts within each endoneurial sheath, even in milder injuries, which do not involve destruction of the sheath itself. The fate of these multiple sprouts is not clear even in experimental paradigms. The timing of degenerative and regenerative processes is such that there must be a significant overlap between these in certain segments. For example, in milder injuries in which there is no significant delay in regeneration across the injury site, the advancing axon tip must encounter the debris of Wallerian degeneration in the distal segment. This debris does not appear to impose a barrier to regeneration. However, in very proximal injuries in which there is a considerable delay before the advancing axon tip reaches the distal segment, the empty endoneurial tubes distally have decreased in diameter. This factor may be responsible, in part, for a terminal slowing in axonal regrowth. Surgical intervention that interrupts entering nutrient arteries does not appear to impair axonal regeneration, provided that longitudinal arteries within the nerve itself are not disrupted.

Injury Site

In severe nerve injuries that disrupt the endoneurial tubes, nerve fascicles, or trunks, formidable obstacles face the regenerating axons that reach the injury site. There may be a gap between the disrupted nerve ends, allowing regenerating axon sprouts to wander into surrounding tissue. Scarring is inevitably present at the site of severe injury; the extent depends upon multiple factors, including the timing of arrival of the regenerating sprouts after injury. It has been well documented that regenerating axons may at times successfully traverse long gaps spontaneously, despite the presence of substantial scar tissue. However, there is no question that an appropriate surgical repair can eliminate the gap and reduce the amount of intervening scar tissue. This procedure provides no guarantee of proper fascicle orientation, of course, and regenerating axons may grow into functionally inappropriate endoneurial tubes or even may fail to re-enter an endoneurial tube. Either circumstance results in wasted axons. Previously nonmyelinated axons may regenerate into endoneurial sheaths which formerly contained myelinated axons (and vice versa). This regeneration will not be wasteful. The resistance that an axon meets at the injury site results in the formation of multiple smaller axon sprouts. These daughter axons do not all find their way into the distal segment. No specific neurotropism is known to enhance the growth of a regenerating axon into its original endoneurial tube, but some form of neurotropic influence has been demonstrated in experimental paradigms. Scarring within the bridging tissue impedes regeneration and misdirects axon sprouts into functionally unrelated endoneurial tubes. Residual scar tissue also interferes with the maturational processes of axons that do negotiate the injury site.

Segment Between Injury and End Organ

Axons that successfully enter endoneurial tubes in the segment distal to the injury site stand a good chance of reaching the end organ, given reasonable growth conditions. The distal regeneration rate is slower if the endoneurial tubes have been disrupted. The specialized growth cone at the tip of each axon sprout contains multiple filopodia, which adhere to the basal lamina of the Schwann cell. Several small axon sprouts may enter the same endoneurial tube. Hence, a regenerated nerve fiber may contain more axons than the original nerve. If a functionally unrelated end organ is reached, further development of the axon and remyelination do not occur. Similarly, axonal development and maturation are aborted if the end organ, due to prolonged denervation, has undergone degenerative changes that do not allow the establishment of functional connections. If the entry of regenerating axons into the distal segment is delayed more than approximately 4 months, the axons are entering endoneurial tubes of small diameter, generally 3 µm or less. This shrinkage does not appear to impede regeneration or to impair functional recovery, most likely due to the elastic properties of the endoneurium. The return of function does not require absolutely faithful recovery of nerve fiber architecture. The effects of prolonged denervation, which do appear to impair functional recovery, are at the level of the injury site: i.e. preventing the regenerating axons from entering appropriate endoneurial tubes-or at the end organ.

End Organs

End organs undergo characteristic histologic changes with nerve degeneration and subsequent reinnervation. Muscle fibers atrophy quite rapidly (70% average reduction of cross-sectional area by 2 months) and cell nuclei assume a central rather than the normal peripheral position. The synaptic folds of motor end plates are preserved for at least a year after denervation. Tremendous proliferation of fibroblasts also characterizes the histologic picture of denervation. New collagen is deposited in both the endomysium and perimysium. In general, muscle fibers are not replaced by connective tissue, but rather atrophied fibers are separated by thickened connective tissue, so that the overall internal pattern of muscle architecture is preserved. Occasional dropout of muscle fibers does occur. This is a relatively late phenomenon, generally observed between 6-12 months after denervation. Regenerating axonal sprouts follow the original Schwann cells to the denervated motor end plates to reform neuromuscular junctions. Collateral sprouting also occurs, resulting in groups of reinnervated muscle fibers, all of the same fast or slow types. This is a characteristic finding in reinnervated muscle, contrasting sharply with the random pattern observed in normal muscle. Unfortunately, incomplete motor recovery is a common occurrence after moderate-to-severe nerve injuries. This is due to a number of factors, within the muscle itself and in the regenerating nerve. Intramuscular fibrosis may limit the efficiency of the contraction produced by a nerve impulse. Appropriate physical therapy can be an important intervention that maintains the denervated muscles in an optimal condition to receive the regenerating axon terminals. The role of electrical stimulation of denervated muscle or of regenerating nerve remains controversial. Motor recovery is obviously impaired if a significant number of axons do not successfully reform functional connections with the muscle. Even if the numbers are adequate, erroneous cross-reinnervation may produce a suboptimal functional result: an originally "fast" muscle may be reinnervated by axons previously innervating a "slow" muscle, and the result may be a mixed form with inefficient contraction. Concomitant sensory deficits, particularly in proprioception, further impede functional motor recovery. A variety of explanations have been proposed for the generally poor recovery of intrinsic hand muscles after a severe, proximal upper extremity nerve injury with or without nerve repair. One of the explanations most commonly proffered is a loss of motor end plates in the denervated muscles due to the long delay before reinnervation occurs. While this factor may well play a role, Sunderland seriously questioned its overall significance and cited instead a number of primarily neurogenic factors for the disappointing recovery of hand function. Denervated sensory receptors survive and may make useful functional recoveries after 1 year and possibly after many years. In neuropraxia and mild degree of axonotmesis injuries, return of sensation is complete in its original pattern, even after 6-12 months of denervation. This is due to faithful reinnervation of sensory receptors by their original axons. After more severe injuries and nerve repair, sensory recovery is never complete. This is undoubtedly due to a combination of factors, including failure of sensory axons to reach the skin, cross-innervation (an axon originally from one type of receptor making connections with a different type of receptor), and possibly degeneration of sensory receptors. Some controversy exists over the fate of denervated encapsulated sensory receptors, the Pacinian and Meissner corpuscles (rapidly adapting receptors mediating light touch and vibration), and the Merkel cells (slowly adapting receptors mediating constant touch and pressure). It is believed that these specialized receptors survive in an atrophied state for prolonged periods of time, awaiting the arrival of an appropriate nerve terminal. The survival period has not been clearly established, however, and there is some evidence to suggest that the protective sensation, which recovers years after denervation, is mediated by less elaborate sensory receptors. The rate of axon regeneration has been assumed to be constant, and in clinical situations is generally estimated to be 1 mm per day. However, reported rates of regeneration vary over a broad range, from 0.5-9.0 mm per day. This variability is due to several factors: (1) the rate of axon growth decreases with increasing distance from the cell body to the advancing axon tip; (2) measurements of axonal regeneration were made in different species after different methods of nerve injury; and (3) the techniques for measuring regeneration were different. Moreover, the rate of regeneration can vary, depending on the nature and severity of the nerve injury, the duration of denervation, and the condition of the peripheral tissues. Regeneration after surgical nerve repair is slower than uncomplicated regeneration, most likely reflecting the severity of the original injury. In addition to axonal regeneration, a process of maturation precedes functional recovery. Morphologic changes of maturation proceed along the regenerating axon at a slower rate than axon regrowth and continue for a protracted period-as long as 1 year. Remyelination takes place in a manner similar to that for developing nerve fibers, involving alignment of Schwann cells and encircling of the axon to form a muItilamellated sheath. This process begins within 2 weeks of the onset of axonal regeneration and results in myelinated axons quite similar to the originals except for shortened internodes. Axonal diameter increases progressively until normal dimensions are reached. This enlargement is dependent upon the establishment of functional connections between the axon tip and the appropriate end organ.

Electrophysiology of Nerve Regeneration

Electromyography (EMG) is a useful laboratory adjunct in the evaluation of patients with peripheral nerve injuries. The appropriate application of EMG, it should be emphasized, is performed as a supportive technique rather than as a replacement for clinical diagnosis. The technique is very useful in the evaluation of patients with clinically complete lesions who may have a few surviving motor fibers, as it can demonstrate nerve continuity. EMG also provides the earliest and most sensitive indicator of reinnervation of denervated muscles. Within 10-18 days of denervation, fibrillations occur in muscle fibers in the form of fine, rapid, irregular rippling contractions that cannot be detected clinically through the skin. On EMG these are represented by spontaneous fibrillation potentials, which are low amplitude (100-300 µV) mono- or biphasic spikes. The spikes are largely negative in polarity following an initial positive deflection, and of short duration (1-2 msec). Fibrillation potentials indicate a nerve injury severe enough to produce Wallerian degeneration-Sunderland second through fifth degrees. Spontaneous positive sharp waves may also be observed. These are characterized by steeply rising positive (downward) deflections of large amplitude (50-4000 µV), followed by a slow descent lasting up to 200 msec. Increased insertional activity is observed in all forms of denervation. In partial denervation, the number of motor units with voluntary contraction is reduced. This results in an incomplete interference pattern. Reinnervation is characterized on EMG by a reduction and, ultimately, a disappearance of fibrillation potentials as well as the appearance of reinnervation potentials. The latter are low-amplitude, very long duration polyphasic potentials, which must be differentiated from the polyphasic potentials of normal duration occasionally observed in normal muscle. (Normal muscle typically has < 10% polyphasic motor unit potentials.) These reinnervation potentials are reliable guides to the onset of muscle fiber reinnervation, but are not necessarily predictive of functional voluntary contraction. For useful return of function, there must be reinnervation by regenerating axons in sufficient numbers. The EMG cannot quantitate this. Kline's technique of intraoperative nerve action potential (NAP) recording provides the most reliable guide to clinically useful recovery after nerve injury. He found that more than 90% of patients in whom NAP can be recorded across a lesion-in-continuity make an acceptable functional recovery without resection of the lesion and nerve repair.
Nerve conduction velocity (NCV) studies also provide information relevant to nerve injury and regeneration. When performed 7-10 days after nerve injury, NCV studies may distinguish between conduction block (neurapraxia) and axonal loss. The preservation of the distally invoked compound muscle action potential (which may be seen even in complete paralysis), indicates proximal conduction block rather than Wallerian degeneration. The latter results in loss of amplitude proportionate to the number of axons lost. The time course of axon regeneration and maturation may be followed, as well as assessment of the outcome of regeneration. However, NCV studies do not provide any prognostic information regarding the return of useful motor function. Following uncomplicated regeneration without surgical nerve repair, conduction velocity slowly returns toward normal over 6-15 months. After surgical repair, the conduction velocity never returns to normal and improves even more slowly.

Future Directions

Basic neurobiology research has advanced our understanding of the fundamental mechanisms of nerve growth and regeneration. In practical terms, this has not yet translated into a great deal of useful information for the peripheral nerve surgeon. Clinical and laboratory studies of practical utility have dealt with techniques and timing of nerve repair, as well as the appropriate selection of patients for surgery. Future studies will likely involve the development of methods for enhancing axonal regeneration, including transport systems, growth factors, specific neurotropic factors, and possibly the use of nerve allografts or synthetic bioabsorbable conduits. Axonal transport systems play an important role in the normal maintenance of nerve processes and in regenerative efforts-conveying structural proteins, enzymes, and organelles to and from the advancing axon tip. Adjustments in fast and slow transport systems are to be expected during regeneration, and have been measured in various experimental paradigms. The literature to date contains conflicting reports regarding the nature of these changes. A greater understanding of the regulatory mechanisms controlling these transport systems may allow manipulation of axonal transport to effect more efficient regeneration. New techniques are being developed to study transport mechanisms. Neurite growth-promoting factors have recently been revived as subjects of intense investigation. Levi-Montalcini and colleagues initiated this field with pioneering studies of nerve growth factor (NGF) in the 1950s. This polypeptide induces sprouting of sympathetic and sensory neurons in tissue culture; it plays an important role in vivo in the regulation of growth and the development and maintenance of these neurons in sympathetic and dorsal root ganglia. The nature of its role in axonal regeneration after nerve injury and repair is poorly understood. It is presumably produced by Schwann cells (among others), and is transported in a retrograde manner to neuronal cell bodies. In situ hybridization studies of NGF receptor mRNA suggest a role for NGF in motor neuron regeneration. Other neurite growth-promoting factors have captured the spotlight in nerve regeneration research. Acidic fibroblast growth factor (aFGF) is the first highly purified protein since NGF that has been shown to enhance nerve regeneration in vivo. A collagen-aFGF mixture inside a polyethylene guide tube increases axonal growth across a gap in a transected rat sciatic nerve. Whether this is a direct effect on neurons, on angiogenesis, or on non-neuronal cells has not been determined. Components of the extracellular matrix and basement membranes have been examined for their potential neurotropic effects. The glycoprotein laminin, the major noncollagenous protein of basement membranes, has received considerable attention because of its ability to enhance neurite outgrowth both in vitro5 and in vivo. A novel homologue of laminin, s-laminin, has been identified in association with the basal lamina of the synaptic cleft. This glycoprotein may be responsible, in part, for the striking topographic specificity of synapse formation demonstrated by regenerating motor axons on denervated muscle fibers. P30, a heparin-binding protein with cell adhesive properties, promotes neurite outgrowth in developing rat central nervous system and appears to play a role in interactions between neurons and Schwann cells in regenerating peripheral nerves. Gangliosides have also been proposed as neurite growth promoters in both in vitro and in vivo studies. Electromagnetic field and direct current stimulation of regenerating axons has received a great deal of investigative attention, analogous to the orthopaedic studies of these modalities in bone healing. While the latter studies demonstrated a beneficial effect on fracture healing related to increased collagen deposition, the nerve regeneration studies have not been conclusive. A variety of biological and synthetic nerve conduits have been proposed as replacements for nerve autografts in nerve repair; these include prepared skeletal muscle, collagen membrane, arterial and nerve allografts, polyglycolic acid, and Silastic. Proposed replacements for traditional suture repair techniques include fibrin glue and laser welding. Although none of these techniques has demonstrated convincing advantages in the clinical setting over the "gold standard" of the nerve autograft and careful microsurgical suture repair, there are promising theoretical arguments for pursuing them.

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