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Peripheral Nerve Repair and Regeneration

Peripheral Nerve Repair and Regeneration

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09/27/2012

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   P  u   b   l   i  s   h  e   d   b  y   M  a  n  e  y   P  u   b   l   i  s   h   i  n  g   (  c   )   W .   S .   M  a  n  e  y   &   S  o  n   L   i  m   i   t  e   d
Hyperbaric oxygenation in peripheral nerverepair and regeneration
E. Cuauhtemoc Sanchez
Hyperbaric Medicine Department, Hospital Angeles del Pedregal, Mexico City, DF, Mexico 
Peripheral nerves are essential connections between the central nervous system and muscles,autonomic structures and sensory organs. Their injury is one of the major causes for severe and longstanding impairment in limb function. Acute peripheral nerve lesion has an important inflammatory component and is considered as ischemia-reperfusion (IR) injury. Surgical repair has been the standard of care in peripheral nerve lesion. It has reached optimal technical development but the end results still remain unpredictable and complete functional recovery is rare. Nevertheless, nerve repair is not primarily a mechanical problem and microsurgery is not the only key to success. Lately, there have been efforts to develop alternatives to nerve graft.Work has been carried out in basal lamina scaffolds, biologic and non-biologic structures in combination with neurotrophic factors and/or Schwann cells, tissues, immunosuppressive agents, growth factors, cell transplantation, principles of artificial sensory function, gentechnology, gangliosides, implantation of microchips, hormones, electromagnetic fields and hyperbaric oxygenation (HBO). HBO appears to be a beneficial adjunctive treatment for surgical repair in the acute peripheral nerve lesion, when used at lower pressures and in a timely fashion 
,
6 hours).
[Neurol Res 2007;
29
: 184–198]
Keywords: Peripheral nerve injury; nerve repair; nerve regeneration; hyperbaric oxygenation;growth factors; ischemia-reperfusion injury 
INTRODUCTION
Reports of acute nerve injury can be traced to3500 years ago, in a biblical story
1
. In the seventhcentury, Paulus Aegineta was the first to report the useof suture and agglutination to repair nerves
2
. Thepioneer of peripheral nerve surgery was GabrieleFerrara who described the technique of suturing stumpsof a transected nerve
3
.Dysfunction of peripheral nerves results from damageto the neuron, to the Schwann cells or to the myelinsheath
4
. Many mechanisms of injury to peripheralnerves exist, including mechanical damage, crushinjury, lacerations, penetrating trauma, stretch injury,high-velocity trauma, frostbites and iatrogenic injury
5
.Peripheral nerve injuries are relatively common
6
. Theyare one of the major causes for severe and longstandingimpairment of limb function and remain as one of themost challenging and difficult reconstructive problems. Iwill classify the degree of injury, describe the surgicalrepair options and discuss adjunctive therapies, includ-ing hyperbaric oxygen.
CLASSIFICATION OF PERIPHERAL NERVE INJURY
The classification of nerve injury was described bySeddon
7
and later expanded by Sunderland andBradley
2
and Mackinnon and Dellon
8
. The first-degree,neuropraxia, involves a temporary conduction blockwithdemyelinationofthenerveatthesite ofinjury.Itisadysfunction and/or paralysis without loss of nerve sheathcontinuity and peripheral Wallerian degeneration.Electrodiagnostic study results are normal above andbelow the level of injury, and no denervation musclechangesare present. No Tinel’s sign is present. Completerecovery occurs once the nerve has remyelinated at thedamage area. Recovery may take up to 12 weeks
5,9
.A second-degree injury, axonotmesis, results from amore severe trauma or compression. The internalarchitecture is relatively preserved and can guideproximal axonal regeneration to reinnervate distal targetorgans
10
. This causes Wallerian degeneration distal tothelevelofinjuryandproximalaxonaldegenerationtoatleast the next node of Ranvier. In more severe traumaticinjuries, it could extend beyond the next node. Electro-diagnostic studies demonstrate denervation changes intheaffectedmuscles,andincasesofreinnervation,motorunit potentials (MUPs) are present
5
.In the third-degree injuries, axon continuity isdisrupted by loss of endoneurial sheaths but theperineurium is preserved
9
. It is a more severe injurythan the second-degree. Wallerian degeneration occursand electrodiagnostic studies demonstrate denervationchanges with fibrillations in the affected muscles.Because the endoneurial tubes are not intact, theregenerating axons may not reinnervate their originalmotor and sensory targets
5
.
Correspondence and reprint requests to: E. Cuauhtemoc Sanchez, MD,Hyperbaric Unit Director, Hyperbaric Medicine Department, HospitalAngeles del Pedregal, Mexico City, DF 10700, Mexico. [crosati@medovate.com] Accepted for publication 27 April 2006.
184
Neurological Research, 2007, Volume 29, March 
#
2007 W. S. Maney & Son Ltd10.1179/016164107X181824
 
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In the fourth-degree injury, the nerve fasciculi aredamaged but nerve sheath continuity is preserved
5,9
. Itresults in a large area of scar at the site of nerve injuryand precludes any axon from advancing distal to thelevel of nerve injury. Electrodiagnostic studies revealthat denervation changes the affected muscles and noMUPs are present. No improvement of function is notedand the patient requires surgery to restore neuralcontinuity, thus permitting axonal regeneration andmotor and sensory reinnervation
5
.In the fifth-degree injuries, there is a complete tran-section of the nerve. They correspond to Seddon’sclassification of a neurotmesis lesion. It requires surgeryto restore neural continuity. Electrodiagnostic studiesare the same as in the fourth-degree injury
5,9
.Mackinnon introduced a sixth-degree injury to describea complex peripheral nerve injury. It is a mixed nerveinjury that combines the other degrees of injury
9
.
PATHOPHYSIOLOGY
The physiologic response is different, depending on thetype of injury. If the axon is spared, as in the first-degreeinjury, conduction is interrupted due to demyelination,but is reinstated whenever the aggravating stimulus isremoved and the myelin layers are restored. If the axon,or more, is transected, causing a second- to fifth-degreeinjury, the response has two main phases, degenerationand regeneration, and takes substantially longer
11
.Pathologically, three phases were identifiable: phase 1(0–3 hours): minimal pathologic changes and minimaledema, phase 2 (7–14 days): prominent fiber degenera-tion and endoneurial edema, and phase 3 (28–42 days):abundant small regenerating fiber clusters and minimaledema
12
.The first phase of axon injury, degeneration, was firstdescribed by Waller in 1850 (Ref. 13). Following injury,changes occur in the cell body, axon and the Schwanncell. Both distally and proximally, the axon begins todisintegrate and undergoes apoptosis. Local Schwanncells and macrophages clean up the apoptotic debris,creating long, clean endoneurial tubes. Once the debrishas been removed, Schwann cells proliferate andorganize themselves into columns that lie within theendoneurial tubes, creating the bands of Bunger
8,11,14
.After injury, there is a great increase in the productionof mRNA and proteins
15
. These products are transporteddown the axon, providing the material and energyfor nerve elongation to the distal tip. The severedaxons begin to sprout and contain an expanded regionknown as the growth cone. This is the site of axonelongation and sends out many small processes thatseek specific markers, which influence the axon in itsmovements to preferentially select neural tissue andeven exhibit a preference for endoneurial tubes with thesame function
16
.The axon’s response is regulated by neurotrophicfactors that direct and attract the axon
17
. Neurotrophicfactors induce maturation and elongation of the axon
14
.They are released by macrophages, Schwann cells andother supporting cells.If the nerve is too far away, the axons are not stronglyattracted to the distal end and eventually stop advan-cing, causing aberrant innervation at the end organlevel
14,17
.Large gaps, greater than 15 mm, cannot be crossedreliably by axons. This is usually because proliferatingSchwann cells or fibroblasts grow between the severenerve ends and form a physical blockage
18
. If the axonsprouts stop proliferating and take residence in a dif-ferent tissue, they will form a neuroma
19
.Neuroinflammation in primary demyelination andWallerian degeneration is an ischemia-reperfusion(IR) injury and is mediated by cytokines and otherimmune mediators (
Figure 1
)
12,13,20–36
. IR injury con-tributes to both axonal degeneration and regeneration
13
.Reperfusion, by oxidative injury, worsened nerve func-tion and aggravated fiber degeneration, but in the longertime frame, permitted fiber regeneration to occur
12
.During peripheral nerve injury, hypoxia createsseveral cellular shock stages that could be reversibleor irreversible. The reversibility depends on the cellscapability to maintain adenosine-5’-triphosphate (ATP)production
37,38
. Once ATP production is stopped, thecell can no longer maintain the homeostatic functions.This produces cytotoxic edema and release of calciumby the mitochondria
39
.ATP has many important functions on peripheralnerve repair and regeneration. It is important tomaintain cellular functions and is also the energy sourcefor axoplasmic transport. It is indispensable for thetransport of nerve growth factors (NGF)
40
. There is apotential interplay between ATP and NGF in thesignaling pathways triggered on their target cells
41
.ATP has neuritrogenic and trophic effects, which arecomparable to those sustained by NGF and involveseveral overlapping pathways
42
. ATP exerts a protectiveeffect on the neurons, which is valuable for nerveregeneration after nerve injury
42
.
NERVE REPAIR
The surgical reconstruction of peripheral nerve damageis crucial. Although the surgical procedure may beoptimal and an excellent rehabilitation program isconducted, the end results still remain unpredictableand complete functional recovery is still rare
43
. A nervelesion is different from other tissue injury because itrequires more than only local processes. Transection of axons has implications for the whole length of theneuron and the repair process involves outgrowth of neurites over very long distances. In addition, a nerveinjury, in contrast to most other injuries of the body, hasimmediate functional consequences for the brain interms of rapid functional reorganization in braincortex
43
.From the biologic point of view, the physiologic resultfollowing nerve injury and repair is dependent onfactors such as the extent of nerve cell survival after theinjury, the rate and quality of axonal outgrowth, theorientation and specificity in growth of regenerationaxons, the survival and state of end organs, and cortical
HBO in peripheral nerve repair and regeneration: E. C. Sanchez 
Neurological Research, 2007, Volume 29, March 
185
 
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reorganizational processes in somatosensory and motorbrain cortex. From the clinical viewpoint, the outcomeis often incomplete, as expressed in symptoms such aspoor and abnormal sensory function, deficient motorfunction, cold intolerance, pain, impaired function,quality of life and problems at work, leisure and insocial life
43
.The surgical approximation of severed nerve ends hasreached the most desirable technical refinement.Nevertheless, nerve repair is not primarily a mechanicalproblem and microsurgery is not the only key tosuccess. At most, the surgeon can manage to co-aptindividual groups of fascicles, but the behavior of theseparate axons inside individual fascicles cannot beaddressed as they are regulated by biologic mechanismsat the molecular level
43
.Autologous nerve graft remains the standard of care;however, much effort is now focused on developingalternatives directed to the biologic mechanisms inside.Work has been carried out in basal lamina scaffolds,biologic and non-biologic structures in combinationwith neurotrophic factors and/or Schwann cells, tissues,immunosuppressive agents, reimplantation of avulsednerve roots (brachial plexus surgery) and end-to-sideanastomosis.Other biologic factors may also be important tools topromote survival and regeneration processes of thesevered ends, and improve the functional results. Thishas spearheaded new research into growth factors, celltransplantation, principles of artificial sensing, genetechnology, gangliosides, implantation of microchips,hormones, electromagnetic fields and hyperbaric oxy-genation (HBO) as potential adjuvant therapies.Nevertheless, these therapies have gained very limitedclinical application.
SURGICAL ASPECTS OF NERVE REPAIR
The purpose of the surgical reconstruction is to align theproximal and distal nerve segments. In the last 30 years,there has been great advancement in the technicalaspects of nerve reconstruction
44–56
. Direct muscularneurotization has been used for cases where the nervehas been avulsed from the muscle and the repair is
Figure 1:
The core of the inflammatory cascades is the reduction of energy and subsequent mitochondrial dysfunction. They are verycomplicated and have several interactions between them. The only feasible way to stop the cascades is the timely restitution of energy before they all ‘kick in’. This could be accomplished with the prompt application of hyperbaric oxygenation (HBO). It couldexplain the efficacy of HBO in the ischemia-reperfusion injury
HBO in peripheral nerve repair and regeneration: E. C. Sanchez 
186
Neurological Research, 2007, Volume 29, March 

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